My PhD dissertation - Institut Fresnel

Various Facets of Organophosphorus Chemistry:
From a Probe for Assessing Carbanions Relative
Stabilities to Ligand Synthesis
Thèse de doctorat
Présentée à la
Faculté des sciences de base
Ecole Polytechnique Fédérale de Lausanne
Par
Michaël Maurin
Chimiste diplômé de l'Université Paris XI - Orsay
Soumise au Jury
Prof. Pierre Vogel, Président
Prof. Manfred Schlosser, Directeur de Thèse
Prof. Peter Kündig, Expert
Prof. Georg Pohnert, Expert
Prof. Philippe Renaud, Expert
LAUSANNE, 2005

"Penserions nous beaucoup et penserions
nous bien si nous ne pensions pas en commun
avec d'autres qui nous font part de leurs
pensées et auxquels nous communiquons les
nôtres ?"
E. Kant

III
Remerciements
Je tiens à remercier le Professeur Manfred Schlosser pour m'avoir accueilli au sein de
son groupe de recherche, et pour m'avoir guidé durant ces quelques années.
Je suis très reconnaissant envers les Professeurs Peter Kündig, Georg Pohnert,
Philippe Renaud et Pierre Vogel pour avoir accepté de lire et juger ce travail de thèse.
Durant ces quelques années passées à Lausanne, j'ai énormément apprécié la
gentillesse et la bonne humeur quotidienne de l'équipe du magasin de chimie, Gladys Pache,
Jacky Gremaud, et Giovanni Petrucci, mais aussi celle de Madame Ursula Kaenzig, dont les
conseils et le soutien m'ont touché. Merci beaucoup !
Martial Rey et Luc Patiny ont eux aussi beaucoup aidé le jeune chimiste que j'étais
pour toutes les expérimentations RMN que j'ai dû effectuer, et ce travail ne serait pas ce qu'il
est sans leur aide et leur patience. Je les en remercie.
Un énorme merci à mes amis et collègues de Lausanne qui m'ont épaulé et avec qui
j'ai partagé d'excellents moments tout au long de ces années. Je tiens à remercier tout
particulièrement la Signorina Carla Bobbio, Elena Marzi, Frederic Bailly, Olivier Lefebvre et
Marc Marull pour avoir été toujours présents, attentifs et sincères durant toutes les étapes de
mon doctorat.
La plupart des bons moments passés au laboratoire, en Suisse plus généralement, et
même ailleurs, durant ces années, l'ont été en compagnie de Levente Ondi. Je tiens
sincèrement à le remercier pour sa gentillesse, ses conseils avisés mais surtout pour son
amitié. Köszönöm.
Enfin et surtout, je remercie de tout mon cœur mes formidables parents, ainsi que ma
famille et tout particulièrement Jean-Claude sans qui je n’en serai pas là. Tom et Sergio font
presque partie de ma famille et je ne les remercierai jamais assez pour m'avoir toujours
soutenu, en particulier dans les moments de doutes, me disant en substance qu'on ne se "libère
pas des choses en les évitant mais en passant au travers"… C'est presque fait. Merci du
conseil !
Finallement, je tiens à rappeler à Jean-Claude, mon oncle, combien je lui suis
reconnaissant pour son soutien sans faille, son aide et ses conseils, en particulier lorsque ma
determination commencait à diminuer… je ne le dirai jamais assez, alors un petit merci écrit
pour un grand MERCI pensé !

IV
TABLE OF CONTENTS
Abstract VIII
Version Abrégée IX
General Part
1 Introduction 1
1.1 Atropisomerism and Axially Chiral Bisphosphine Ligands 1
1.2 Alkaline Decomposition of Quaternary Phosphonium Halides 3
1.3 Objectives of this Work 5
2 Preparation of Tertiary Phosphines by Means of Triethyl Phosphites 9
2.1 Uniformly Substituted Triarylphosphines 10
2.2 Preparation of Trifurylphosphines 12
2.3 Preparation of a Pyrrolylphosphine 14
3 Alkaline Decomposition of Phosphonium Salts: A Probe to Assess Relative
Stabilities of Alkyl Anions 19
3.1 Gas Phase Acidities of Alkanes 19
3.2 Alkyl Carbanions Stabilities in Solution 21
3.3 Assessment of the Relative Ease of Alkyl Expulsion from Phosphonium Salts 22
3.3.1 Mechanistic Discussion on the Alkaline Decomposition of Phosphonium Salts 23
3.3.2 Principle of the Method Devised 25
3.3.3 Qualitative and Quantitative Analysis of the Reaction Products 27
3.3.4 Starting Materials and Reference Substances 28
3.3.5 Alkaline Decomposition of Phosphonium Halides 32

3.3.6 Relevance of the Data Assessed and Influence of the Steric Strains on Alkane
V
Cleavage 36
4 A Novel Access to Atropisomeric Biphenylbisphosphines 39
4.1 Preparation of Enantiomerically Pure 6,6’-Dibromobiphenyl-2,2’-diol and Derivatives
Thereof 40
4.1.1 Racemic 6,6’-Dibromobiphenyl-2,2’-diol 41
4.1.2 Racemate Resolution of 6,6’-Dibromobiphenyl-2,2’-diol 42
4.1.3 Derivatization of 6,6’-Dibromobiphenyl-2,2’-diol 43
4.2 Preparation of Enantiomerically Pure 6,6’-Dibromobiphenyl-2,2’-dicarboxylic Acid and
Derivatives Thereof 45
4.2.1 Racemic 6,6’-Dibromobiphenyl-2,2’-dicarboxylic Acid 45
4.2.2 Racemate Resolution of 6,6’-Dibromobiphenyl-2,2’-dicarboxylic Acid 46
4.2.3 Derivatization of 6,6’-Dibromobiphenyl-2,2’-dicarboxylic Acid 47
4.3 Preparation of Biphenylbisphosphines 49
4.4 Dynamic 1 H-NMR Study of Some Biphenyl Substrates 53
4.4.1 The Use of Variable-Temperature NMR to Study Intramolecular Mobility 54
4.4.2 Coalescence Study of 2,2’-Dilithio-6,6’-bis(methoxymethoxy) biphenyl 57
4.4.3 Coalescence Study of 2,2’-Dilithio-6,6’-bis(methoxymethyl)biphenyl 60
5 Conclusions and Outlook 65

Experimental Part
VI
1 Generalities 69
2 The Preparation of Phosphines from Triethyl phosphite 71
2.1 Triarylphosphines 71
2.2 Furanylphosphines 74
2.3 Ethyl bis{N-[(1S)-1-phenylethyl]-1H-pyrrol-2-yl}phosphinite and Other Pyrrole
Derivatives 77
3 The Alkaline Decomposition of Quaternary Tetraalkylphosphonium Salts 81
3.1 Preparation of Trialkyl Phosphines and Corresponding Trivalent Phosphorus
Compounds 81
3.1.1 Dialkyl-N,N-diethylaminophosphines 82
3.1.2 Dialkylchlorophosphines 83
3.1.3 Trialkylphosphines 85
3.2 Trialkylphosphine Oxides 89
3.3 Tetraalkylphosphonium Halides 93
3.4 Alkaline Decomposition of Phosphonium Salts 95
4 The Preparation and Racemate Resolution of Biphenyls and
Biphenylbisphosphines 101
4.1 Preparation of 6,6’-Dibromobiphenyl-2,2’-diol and Derivatives Thereof 101
4.2 Preparation of 6,6’-Dibromobiphenyl-2,2’-dicarboxylic Acid and Derivative
Thereof 105
4.3 Preparation of Biphenylbisphosphines 109
4.4 Coalescence Studies of Dilithiobiphenyl Species 112
4.5 Seclected Crystallographic Data for Biphenylbisphosphines 114

VII
Literature References 115
Compounds Index 125
Curriculum Vitae 129

VIII
Abstract
Organophosphorus compounds found applications in varied fields of the organic chemistry:
they are particularly present in natural compounds such as the deoxyribonucleic acid (DNA) and in the
field of catalysis in which their utility is also proven. Thus, this thesis work first focused on the
preparation of various phosphorus ligands utilizable in transition metal catalysed reactions.
Being given the importance of this type of reaction in organic synthesis, it appears
essential to have many ligands at disposal in order to fine-tune and to optimize the reaction
conditions as much as possible. Thus, the first objective of this work was to propose a simple and
general method for the preparation of monodentate phosphorus ligands. Based on the use of
phosphites in substitution for the usual phosphorus trihalides, this method was initially tested during
the preparation of different simple triarylphosphines. Thereafter, this method was extended to the
synthesis of new ligands having more complex structures.The yields obtained for the latter as well
as the variety of the substrates authorized by this method confirmed its value and suggested its
application to the synthesis of new heteroaromatic phosphines.
The preparation of bidentate phosphorus ligands based on chiral biphenyl motifs was
then addressed. For that purpose, the 2,2',6,6' -tetrabromobiphenyl was chosen as a pivot
substrate for the development of a modular synthetic approach. Indeed, by means of
successive halogen/metal permutational exchanges and after treatment with the suitable
electrophile, it was possible to functionalize this substrate, isolate each atropisomer in
enantiomerically pure form, and finally convert each one of those into chiral
biphenylbisphosphines. In addition, it was also possible, during the synthesis of these ligands,
to evaluate the rotational stability of some enantiomerically pure dilithiobiphenyls.
Finally, after having acquired some expertise in the handling of phosphorus
compounds, some phosphonium halides were prepared in order to evaluate the relative
basicities of some alkyl carbanions. It is postulated that the ease of expulsion for the different
substituents of a quaternary phosphonium salt treated in alkaline conditions is controlled by
the relative stabilities of their related carbanions. Following this idea, the proportions of the
products obtained from this decomposition were quantified in order to evaluate the stabilities
of some aliphatic carbanions. Furthermore, those results were discussed in the light of the
mechanistic arguments reported, up to date, in the literature.

IX
Version Abrégée
Les composés organophosphorés trouvent des applications dans des domaines très variés de la
chimie organique: ils sont présents notamment dans les molécules du vivant comme l'acide
désoxyribonucléique (ADN) ainsi que dans le domaine de la catalyse, où leur utilité est aussi avérée.
Ainsi, ce travail de thèse s'est tout d'abord intéressé à la préparation de différents types de ligands
phosphorés utilisables dans des réactions catalysées par des complexes de métaux de transition.
Etant donnée l'importance de ce type de réaction en synthèse organique, il parait primordial
d'avoir de nombreux ligands à disposition afin d'adapter et d'optimiser au mieux les conditions
réactionnelles. Aussi, le premier objectif de ce travail a été de proposer une méthode simple et générale
pour la préparation de ligands phosphorés monodentates. Basée sur l'utilisation de phosphites en
substitution aux classiques trihalogénures de phosphore, cette méthode a d'abord été testée lors de la
préparation de différentes triarylphosphines simples. Par la suite, cette méthode a été entendue à la
synthèse de nouveaux ligands possédants des structures plus complexes. Les rendements obtenus pour
ces derniers ainsi que la variété des substrats autorisés par cette méthode ont confirmé son intérêt et
suggèrent son application à la synthèse de nouvelles phosphines hétéroaromatiques.
La préparation de ligands phosphorés bidentates basés sur des motifs biphenyliques chiraux a
ensuite été abordée. Pour cela, le 2,2',6,6'-tetrabromobiphenyle a été choisi comme composé pivot pour
le développement d'une approche synthétique modulable à souhait. En effet, par le biais de permutations
halogène/métal successives et après traitement avec l'électrophile approprié, il a été possible de
fonctionnaliser ce substrat, d'isoler chaque atropoisomère sous forme énantiomériquement pure, et
finalement de convertir chacun de ceux-ci en biphenylbisphosphines chirales. Par ailleurs, il a aussi été
possible, au cours de la synthèse de ces ligands, d'évaluer la stabilité rotationelle d'atropoisomères purs
de certains dilithiobiphenyls.
Finalement, après avoir acquis un certain savoir faire dans la manipulation de composés
phosphorés, des halogénures de phosphoniums ont été préparés afin d'évaluer les basicités relatives de
certains carbanions alkyls. Il est postulé que l'ordre d'expulsion des différents substituants d'un sel de
phosphonium quaternaire traité en conditions alcalines est gouverné par la stabilité relative de leur
carbanions. Selon cette hypothèse, les proportions des produits de cette décomposition ont été quantifiées
et ont conduit à l'évaluation de la stabilité de certains carbanions aliphatiques. De plus, ces résultats ont
étés discutés à la lumière de reflections méchanistiques proposées ces dernières décénnies.

General Part

1 Introduction
1
The present thesis work aims at linking organophosphorus chemistry and modern
organometallic techniques. Thus, phosphorus compounds will not only serve as targets of
synthesis obtained through organometallic methods, but also as probes for gaining better
insight into organometallic reactivity. One main objective is the preparation of new phosphine
ligands for transition-metal-catalyzed reactions. In the course of this work, thermodynamical
investigations will also be performed in order to assess the rotational stability of some
atropisomeric biphenyl substrates. On the other hand, tetraalkylphosphonium salt will serve as
a substrate for alkaline decomposition, allowing us to compare relative basicities of various
alkyl anions.
1.1 Atropisomerism and Axially Chiral Bisphosphine
Ligands
The biphenyl core belongs to the classical examples of so-called atropisomerism, a
particular case of axial chirality. This type of enantiomerism was first demonstrated in 1922
by G.H. Christie and J. Kenner
"atropisomerism" was later coined by R. Kuhn
[ ] 1 when they resolved 6,6'-dinitro-2,2'-diphenic acid. The term
[ ] 2 referring to the restricted rotation about the
pivot sp 2 -sp 2 single bond (from Greek, a meaning not, and tropos meaning turn).
O2N HOOC
COOH
NO2 HOOC NO2 O2N COOH
(M) atropisomer mirror plane (P) atropisomer
Biaryls have a "chiral axis" and can be isolated in two nonplanar enantiomeric forms,
provided that their helicity is maintained by hampered rotation about the aryl-aryl bond.

2
However, this statement clearly pointed out the lack of general definition or criteria to allow
one to talk about "atropisomerism". How slow should the interconversion between
atropisomers be? At what temperature should this interconversion be considered? Do
atropisomers have to be isolated to be called so, or does it suffice to identify them by
spectroscopic techniques? Numerous reports and books have discussed the prerequisites for
isolation and rotational stability of such isomers
[ - ] 3 5 which, of course, depends on the
temperature of study. M. Ōki [3] proposed, as a condition for the existence of so-called
"atropisomers", that their half life time t1/2 at 25 °C should be at least 1000 s (17 min), which
would correspond to a rotational barrier of approximately 22 kcal·mol -1 . However, for the
tetra-ortho substituted biphenyls, the steric congestion in the coplanar transition state causes
the barrier to free rotation to be usually far superior to that value, thus allowing separation of
enantiomers.
During the past two decades, atropisomeric biaryls have received attention due to the
increasing number of naturally occurring substances discovered in that class
[ - ] 6 8 (e.g.
vancomycin, ancistrocladin, michellamine, etc.). More importantly, the synthetic chemist has
recognized axially chiral biaryls as versatile auxiliaries for asymmetric synthesis
[ - ] 9 12 .
Hence, an impressively large number of chiral ligands are reported in the literature to ensure
amazingly high enantioselectivities in many catalytic reactions. Among them, Noyori's
[ , ]
BINAP [(1,1'-binaphthyl-2,2'-diyl)bis(diphenylphosphine)] 13 14 , and Schmid's BIPHEMP
[6,6'-dimethylbiphenyl-2,2'-diyl)bis(diphenylphosphine)]
dimethoxybiphenyl-2,2'-diyl)bis(diphenylphosphine)]
axially chiral bisphosphines ligands.
BINAP
PPh2 PPh2 BIPHEMP
PPh2 PPh2 [ 15 ]
and MeO-BIPHEP [6,6'-
[ ] 16 are the most prominent examples of
O
O
PPh2 PPh2 MeO-BIPHEP
Nevertheless, hundreds of other slightly modified ligands, based on those cores, have
proved to be at least as efficient as those reference compounds, depending on the reaction
involved. This clearly shows that catalysts are often substrate specific and small changes can
strongly affect their performances. Thus, ligands need to be "tailor made" for each individual
purpose and should be easily accessible in enantiomerically pure form. As a result, although a
large number of attractive procedures are already described in the literature
[13 - ] 19 , leading

3
research groups in the field are still trying to develop a very general method for preparing a
panel of readily available enantiopure "tunable" ligands. Furthermore, since this condition
obviously increases the chances for a ligand to be used for synthetic applications, research in
enantioselective catalysis should focus on a modular approach for their synthesis.
Although catalysis occupies a privileged place in the field of phosphorus chemistry,
phosphorus compounds have also been used for other purposes (e.g. fertilizing agents, water
softeners or pesticides). Another important application of phosphorus compounds is the use of
phosphine oxides as flame retardants additives in polymers
[ ] 20 . Hence, several investigations
have been conducted to propose more efficient preparations for that family of compounds.
Alkaline decomposition of phosphonium salts, one of the most promising methods to produce
mixed phosphine oxides was thus extensively studied during the last decades.
1.2 Alkaline Decomposition of Quaternary Phosphonium
Halides
The alkaline decomposition of a quaternary phosphonium salt to give a phosphine
oxide and a hydrocarbon is one of the best known nucleophilic displacement reaction at
phosphorus
J. Meisenheimer et al.
[ - ] 21 24 . A. Cahours and A.W. Hofmann
[ ] 25 followed by A. Michaelis
[ ] 26 , and
[ , ] 27 28 , first observed it upon distillation of aqueous solutions of
phosphonium hydroxides or simply by heating phosphonium halides in aqueous sodium
hydroxide solution. This reaction appeared to be an efficient method to produce various
trialkyl- or alkyldiphenyl phosphine oxides in high yield, and was thus deeply investigated
during the past years. L. Hey and C.K. Ingold postulated a possible mechanism
assumed it to proceed through a hydroxyphosphorane
[ ] 29 , and
[ ] 30 . According to these authors, the
entire reaction sequence is composed of four steps: fast and reversible addition of hydroxide
ion to the quaternary phosphonium salt; fast and reversible formation of the conjugate base of
the pentacovalent intermediate; rate-limiting and irreversible formation of the phosphine
oxide and expulsion of a carbanion; instantaneous protonation of the carbanion by water.
R 4P X
OH
fast
OH H2O R4POH R4PO R + R
fast
slow 3PO RH
fast

4
However, the mechanism proposed and the results reported thus far could also be
explained by a concerted mechanism in which the second equivalent of hydroxide ion and the
cleavage and protonation of the alkyl residue would happen simultaneously. This alternative
mechanistic possibility will be displayed in more details in the general part and discussed in view to
the results obtained. In view to the sequence suggested by L. Hey and C.K. Ingold, two hydroxide ions
and one phosphonium cation should be involved during or prior the rate limiting step of the reaction.
[ , ]
To verify this statement L. Horner and H. Hoffmann 31 32 [ , ]
and W.E. McEwen et al. 33 34 respectively
studied the kinetic of decomposition for several p-substituted-phenyltriphenylphosphonium halides
and p-substituted-benzyltribenzyl phosphonium halides. The results obtained by both research groups
confirmed that the reaction follows a third order kinetic, with a first order dependence on the
concentration of phosphonium and a second order dependence on the concentration of hydroxide ions.
Furthermore, L. Horner and H. Hoffmann [31] provided theoretical arguments to rationalize this
mechanism. Phosphorus, as an element of the second period of the Mendeleev Table, is able to exceed
the octet rule and form pentacovalent species. The ionic phosphonium hydroxide should thus exist in
equilibrium with its corresponding hydroxyphosphorane intermediate. The latter, being a weak acid,
also coexists with its conjugated oxidophosphorane base. Finally the formation of a stabilizing pπ-dπ
phosphorus-oxygen bond constitutes a driving force for the elimination of an alkyl anion. Although
this SN(P) mechanism is commonly accepted and accounts for experimental results reported so far,
[ ]
C.A. Vander Werf et al. 35 proposed two conceivable variations of that mechanism: the second attack
of hydroxide and the departure of the anion could be synchronous or the first step could involve the
formation of an unstable intermediate with two hydroxide ions bound to phosphorus. In addition to the
mechanism they proposed, L. Hey and C.K. Ingold [29] observed that if the phosphonium salt was
bearing different type of substituents, the relative ease of P-C bond cleavage in the pentacovalent
intermediate was following the anionic stability of the expelled group.
Later, many research groups oriented their efforts towards stereochemistry investigations
and studied enantiomerically pure cyclic
[ - ] 36 38 [35, ,
and linear 39 40] phosphonium halides, where
phosphorus constituted the sole stereogenic center. The phosphine oxides obtained by treatment of
these salts under alkaline conditions revealed that the reaction occurred stereospecifically with
complete inversion of configuration at phosphorus. Various suggestions [35, 37, 38] have been proposed
to explain this stereochemistry. The most plausible [35] rationalization of this experimental result was
the formation of a trigonal-bipyramidal transition state were the leaving group and the hydroxide both
occupy apical positions.
R 1
P
R3 R4 R2 K HO
I
HO
R 4
R 1
P
+ KI
R 3
R 2
K HO
H 2O
O
R 4
R 1
P
+ H 2O
R 3
R 2
H 2O
R 1
P
R3R4 + R2H O

5
However, this mechanism suffers from inconsistencies since some cyclic substrates
were found to show partial racemization or complete retention of stereochemistry at
phosphorus
[ , ] 41 42 . These results could be explained by ring strain. Phosphetanium (four-
membered ring) and phospholanium (five-membered ring) salts preferentially adopt, in the
trigonal bipyramidal intermediates, an equatorial-apical relation (90 °) due to angle constraint.
Since apical positions are assumed to be favored for the departing group and the hydroxide
[ 43 ]
[ 44 ]
, a Berry pseudorotation must mediate the move of the more stabilized anion to the
apical position. The latter pseudorotation thus accounted for the partial retention of
configuration at phosphorus center. In summary, even if applicable to non cyclic cases, this
general explanation of the observed stereochemistry for the alkaline decomposition of
phosphonium salts does not illustrate the whole scheme of this process.
1.3 Objectives of this Work
Organometallic techniques, particularly the halogen/metal permutation
proved to be the method of choice in many areas of organic synthesis
[ , ] 45 46 , have
[ ] 47 . This is especially
remarkable when it comes to organophosphorus chemistry and the preparation of tertiary
phosphine ligands. Thus, phosphorus will constitute a leitmotiv in the present thesis work, and
several aspects of its chemistry and applications will be taken into account.
Up to now, the principal method for the preparation of tertiary phosphines was the
treatment of phosphorus trichloride with the appropriate organometallic reagent
(organomagnesium or organolithium)
[ ] 48 . The present research work will first focus on the
preparation of tertiary phosphines via a modification of the above mentioned synthetic route.
The use of trialkyl phosphites
[ - ] 49 51 instead of phosphorus trichloride, already reported in few
instances, was believed to provide several advantages and allow large scale preparation of
different tertiary phosphines from simple and known to more elaborate ones.
R'=
P(OR) 3
N
O
R'M (M = Mg, Li)
O
O
OH
O
O
PR' 3
N
Ph

6
The second part of this work sets out to assess the relative stabilities of several
primary, secondary and tertiary alkyl anions by means of a well known reaction. Hence, by
preparing mixed tetraalkyl phosphonium halides, each one bearing two different type of alkyl
group, and submitting them to alkaline decomposition, one whish to determine kinetic
parameters related to their relative stabilities as probable carbanions. Furthermore, since
expulsion of alkyl groups is assumed to be governed by their relative stability and is proposed
to be stemming from the decomposition of a common transition state in the rate determining
step, the kinetic data provided by this study should legitimately be compared with computed
or gas-phase thermodynamics.
R 1 R 2
P + R
O
1
R2 OH
∆G1 R 1
P
R 2
R 1 R 2
X
OH
R 1 R 2
P
R O 1
Several research groups previously evaluated the ease of anion expulsion by
analyzing the decomposition products of some tetraaryl or aryl-alkyl mixed phosphonium
salts. Nevertheless, due to the practical difficulty to prepare and handle the majority of trialkyl
phosphorus compounds, very few tetraalkyl phosphonium salts were studied by this
decomposition reaction
∆G 2
+ R 2
[30, ] 52 . Furthermore, the ratios of phosphine oxides and anions
expulsed were generally measured either by direct isolation of the oxides or by gas
chromatography analysis of the products in case of tetraaryl or aryl-alkyl mixed phosphonium
salts only. In the former case, the lack of accuracy only afforded a broad idea of the relative
anions stability [29, 30, 52] . In the latter, useful and accurate data were obtained about aryl anions
basicity [36] . In this context, the present study attends to provide accurate data concerning the
alkaline decomposition of tetraalkylphosphonium salts and the deduced kinetic basicities of
primary, secondary and tertiary alkyl anions.
Finally, the object of this present task is to propose a novel access to atropisomeric
biphenylbisphosphine ligands for asymmetric catalysis. The first goal of this new synthetic
approach is to provide a general method that allows easy tuning of the ligands produced.
Having become readily accessible, 2,2',6,6'-tetrabromobiphenyl
[ ] 53 appeared to be a judicious
key intermediate. As a matter of fact, by taking advantage of the modern organometallic
techniques developed and inspired by the recent work of F. Leroux
[ ] 54 , it was possible to
subject this substrate to successive permutational halogen/metal exchanges [45, 46] in order to
allow diverse functionalizations.

7
At first, a double bromine/lithium permutation will be performed to produce the 2,2'-
dilithiobiphenyl derivative which could be turned into the corresponding biphenol or diacid.
Both axially chiral derivatives thus produced could then be resolved to afford pure
enantiomers. The latter compounds, after few derivatization or protection steps could simply
be converted to optically pure bisphosphines by reaction with an organolithium reagent and
subsequent treatment with chlorodiphenylphosphine.
R'' 2P
R'' 2P
R'
R'
R R'
'' 2P
R'' 2P R'
1) Metallation
Br Br
2) I2 Br Br
I
1) Derivatization
2) Br/Li permutation
3) ClPR'' 2
Br
Br
1) Br/Li permutation
2) CuBr 2
3) PhNO 2
R
R
Racemate resolution
Br R
Br R
Br Br
Br Br
Br R
Br R
R = OH, COOH
1) Br/Li permutation
2) functionalization
In addition, the efficiency of the designed synthetic route relies on a crucial condition
that had to be seriously taken into account. Hence, once produced, both pure atropisomers
should be subjected to several chemical modifications without noticeable loss of their optical
activity. For this reason, reaction conditions should be carefully chosen, especially for the last
bromine/lithium permutation sequence which could possibly induce racemization. Indeed,
though some calculations or experimental data were reported in the literature for binaphthyl
cores
[ 55 - 57 ]
, only little information is available about rotational barrier of
o,o'-dilithiobiphenyls
[ , ] 58 59 . In this context, some of the lithiated biphenyls prepared will be
used for dynamic NMR experiments in order to assess their rotational barrier. The value thus
obtained, by comparison with those of the corresponding reduced parent compounds should
provide helpful clues about the rotational stability of such species.

2 Preparation of Tertiary Phosphines by Means of
Triethyl Phosphites
9
The field of transition-metal catalyzed cross-coupling reactions has grown
significantly in the past decade, and important progress has been made in extending the scope
and efficiency of these reactions
[ ] 60 . The choice of the base, the solvent and the coordinating
ligands is at least as important as the choice of the transition metal used itself. Since no
general procedure is known for such reactions, and conditions have to be fine-tuned for each
substrate, an impressive number of reports about cross-coupling reactions has been published.
Numerous phosphines are already known to efficiently stabilize the palladium(0) species
involved in the course of cross coupling reactions. However, varying the bulkiness or electron
donating ability of the phosphorus ligands can remarkably change the reactivity of catalysts
[ ]
towards oxidative addition and transmetalation 61 . In this context, the ready availability of
various phosphine ligands is of obvious importance and endeavors should be made to propose
new ones.
The main objective of this work was to provide new heteroaromatic phosphines
[ 62 - 65 ]
bearing either furyl or pyrrolyl substituents. Only scarce syntheses of furylphosphines
and no pyrrolylphosphines were reported up to now. Because of the usually moderate to low
yields obtained while preparing these ligands [62 - 65] with classical methods using either
phosphorus trichloride or phosphorus tribromide [48] , a convenient and efficient preparation
had to be used. Since the main methods described in the literature to produce phosphines [48,
66, 67 ]
[51]
usually give variable yields , depending on the substituents used, it was important to
use a protocol which could be applicable to a large panel of substrates ranging from alkanes to
aromatic motifs or even heteroaromatic ones. Furthermore, to be valuable the chosen method
should be easily scalable and proceed with quantitative yields. As a matter of fact, if the
creation of one P−C bond does not proceed quantitatively but also generates by-products, the
proportion of these minor compounds produced would obviously increase in the case of a
"one pot" trisubstitution reaction at the phosphorus center and lead to tedious purifications.

10
Although the most frequently employed method for the preparation of tertiary
phosphines i.e. the reaction of phosphorus trihalide with Grignard reagents
[ , ] 68 69 or
organolithium species [48, 66, 67] is efficient in most cases, this method does not always give
satisfactory yields [51] o
-1 [ 70 ]
. Since the lower reactivity of the P−O bonds ( D298
≈ 596 kcal·mol )
o
compared to the P−Cl bonds ( D 289 kcal·mol
298 ≈
demonstrated by different research groups
-1 ) [ ]
71 towards organometallic reagents was
[ - ] 72 76 , the use of phosphites instead of phosphorus
trichloride was believed to give cleaner reactions and thus, should allow performing reactions
on larger scale without any special care. Since the use of phosphorus trichloride was thought
to produce, in situ, molecular chlorine and could cause partial oxidation of the phosphine
formed, its substitution by a phosphite constituted an additional advantage. As a matter of
fact, depending on its structure, the phosphine formed can be prone to rapid oxidation and
form, to some extent, the corresponding tertiary phosphine oxide which usually causes tedious
purification procedures. Although the use of phosphite for the preparation of tertiary
phosphines had already been mentioned in few reports from the beginning of the 20 th century
until now
[49 - 51, , ] 77 78 , no rational arguments were given to explain the failure of other
classical preparation procedures nor the better yields obtained with phosphites. Furthermore,
in most cases the yields were relatively low. Therefore, several already described
triarylphosphines were prepared by means of triethyl phosphite to evaluate and compare the
efficiency of this method compared to more classical ones. Once the "phosphite pathway"
procedure had been well established, new furyl and pyrrolylphosphines have been prepared.
2.1 Uniformly Substituted Triarylphosphines
Triarylphosphines were formed in excellent yields when triethyl phosphite was
condensed with three equivalents of aryllithiums (Table 1). The latter were generated from the
corresponding bromoarene by halogen/metal permutation using butyllithium. In the case of
tris(3,5-dimethylphenyl)phosphine (7), 1-iodo-3,5-dimethylbenzene
material.
R
X
1) LiC 4H 9, THF, - 75 °C
2) P(OEt) 3, - 75 °C to 25 °C
P
[ ] 79 served as the starting
R
3

11
Table 1. Preparation of variously substituted triarylphosphines 1-4
and 6-7 with triethyl phosphite and aryllithiums generated by
halogen/metal permutation of haloarenes Ar−X with butyllithium.
H 3CO
Aryl phosphine
Nr.
OCH 3
1
2
N(CH 3) 2 3
4
6
7
X Yield Lit. yield
Br
Br
Br
Br
Br
I
The triaryl phosphines 1 - 3, 6 and 7 were obtained in excellent yield (Table 1) and
by direct crystallization of the crude reaction product. However, tris(1-naphthyl)phosphine
(4) [83] had to be crystallized several times to afford an analytically pure product. As a matter
of fact, under the usual reaction conditions, 1 H NMR analysis of the crude reaction mixture
revealed the presence of ethylbis(1-naphthyl)phosphinite (5) stemming from incomplete
substitution at the phosphorus center. Increased reaction times in refluxing tetrahydrofuran
99%
99%
83%
86%
83%
81%
[ ] 80 89% [a]
[ ] 81 90% [b]
[ ] 82 19% [c]
[ ] 83 14% [d]
[ ] 84 -
[ ] 85 62% [e]
[a] Prepared with PCl3 and p-CH3OC6H4MgBr in THF; [b] Prepared with PCl3
and m-CH3OC6H4Li in THF; [c] Prepared with PCl3 and p(CH3)2C6H4MgBr in
THF; [d] Prepared with PCl3 and 1-naphthylMgBr in THF; [e] Prepared with PCl3
and 3,5-(CH3)C6H4Li in THF.
finally gave the pure phosphine (4) in 86% yield along with only 5% of phosphinite (5).
Br
1) LiC 4H9, THF, - 75 °C
2) P(OC 2H5) 3, reflux
P
3
+
P
O
4, 86% 5, 5%
2

12
The preparation of the latter phosphine revealed an additional feature of the use of
triethyl phosphites. In the case of bulky substituents, the possibility to fine-tune the reaction
conditions in order to substitute selectively each ethoxy group one by one depending on the
temperature provides an additional advantage of the use of phosphites, since it is hardly
feasible with phosphorus trichloride. Comparative study could have been made to parallel the
results obtained by means of various phosphites, however, since triethyl phosphite gave the
best yields for the first phosphines prepared, the whole series was done in that manner. On the
other hand, in order to establish the efficiency and reliability of the use of phosphites as
phosphorus sources, the yield of products obtained by this method were compared to those
reported in the literature using either organomagnesiums or organolithiums reagents with
phosphorus trichloride (see Table 1). As the use of phosphites proved to give comparable or
better results than those reported in the literature, this reagent could be used to prepare newly
designed furyl and pyrrolyl phosphines.
2.2 Preparation of Trifurylphosphines
Recently, a great attention in furyl phosphines, especially (2-furyl)phosphines
has been evident in the literature because of their increasing use in homogeneous catalysis
[ 87 - 90 ]
. Bristol-Myers researchers could show in 1988 that the use of furylphosphines
instead of the usual triphenylphosphine could significantly increase the rate and yields of
the Stille cross-coupling reaction for some deactivated chlorinated substrates [87 - 89] . V.
Farina et al. [87] postulated that the use of less coordinating, poorer donating phosphine
ligands should render the Pd(II)-Allyl intermediate more electrophilic and hence more
reactive in the rate determining transmetalation step. In view to this series of results, P.
Savignac, F. Mathey et al. [65] prepared a water soluble diphenylfurylphosphine derivative
for biphasic catalysis but failed in preparing a tris(2-furyl)phosphine from phosphorus
trichloride when the furan was substituted in position-5 by a chlorine or a bromine.
The parent tris(2-furyl)phosphine was prepared by various research groups with low
[ ]
yields (30% to 40%) using either phosphorus trichloride 91 [ ]
or phosphorus tribromide 92 . A.J.
Zapata and A.C. Rondon explained the low yields obtained by occurrence of undesirable
side reactions due to the high reactivity of the 2-furyllithium involved. They could raise
the yield of tris(2-furyl)phosphine to 74% by transmetalating the reactive lithiated species
with cerium(III) chloride and treating it with phosphorus trichloride. The preparation of
valuable trifurylphosphines ligands by the "phosphite route" was performed with
[ ] 86 ,

13
variously substituted furans in good to excellent yields and led to think that the low yields
previously observed were rather due to the phosphorylating reagent itself or a conjunction
the latter and the lithiated furan.
2-Methylfuran was first used as starting substrate and metalated with butyllithium
in tetrahydrofuran at - 75 °C. The transient lithiated species could be efficiently trapped
with the usual triethyl phosphite to afford the tris(5-methyl-2-furyl)phosphine (8) in 92%
yield.
O
1) LiC 4H9, THF, - 75 °C
2) P(OC 2H 5) 3
P
O
8, 92%
Another phosphine was prepared, starting from a heteroaromatic substrate, to
illustrate the versatility of this method. Benzofuran was chosen as substrate since it was of
comparable bulkiness as 2-naphthalene substituent and also because of the ease of
metalation of this motif. Thus, benzofuran was treated with butyllithium in
tetrahydrofuran at - 75 °C to undergo smooth metalation at 2-position, and subsequently
trapped with triethyl phosphite to give tris(2-benzofuryl)phosphine (9) [63] .
O
1) LiC 4H 9, THF
- 75 °C, 2 h
2) P(OC 2H 5) 3
P
O
9, 92%
Finally, the synthesis of a second furylphosphine was endeavored. The possibility
to link the phosphorus ligand on a polymer for an efficient recycling of the catalyst was
found attractive
[ ] 93 . A convenient way to link the final phosphine was to introduce an
alcohol functional group at position-5 in order to avoid any steric hindrance on the
vicinity of the phosphorus center. The preparation of tris(5-hydroxymethyl-2-
furyl)phosphine (13) was thus decided and first tried by direct metalation of furfurol (5-
hydroxymethylfuran) with two equivalents of organolithium reagents, or metalation of
silyl-protected furfurol. Unfortunately, trapping the transient species formed with
iodomethane resulted, in both cases, in complete decomposition of the furan adduct. Since
the presence of the hydroxymethyl chain was believed to cause the instability of the
metalated furfurol, an indirect route to phosphine (13) was followed. Furfural was
3
3

protected to its dioxolane derivative (10) by a method described by L. Brandsma et al.
14
and subsequently metalated at position-5 with butyllithium in tetrahydrofuran at - 75 °C.
The lithiated species thus formed was then treated with 1/3 equivalent of triethyl phosphite
to afford the expected tris[5-(1,3-dioxolan-2-yl)-2-furyl]phosphine (11) in 68%.
O
10
O
O
1) LiC 4H9,
THF, - 75 °C
2) P(OC 2H5) 3
P
O
O
11, 68%
Deprotection conditions had then to be carefully chosen since the furan core was
relatively susceptible to strongly acid media. Pyridinium chloride was found to be the most
efficient acid catalyst to cleave the acetal protection and allowed the isolation of tris(5-
formyl-2-furyl)phosphine (12) in excellent yield (88%). Finally, the reduction of the formyl
groups to give the tris(5-hydroxymethyl-2-furyl)phosphine (13) was achieved in 86% yield
with sodium borohydride in tetrahydrofuran at ambient temperature.
P
O
11
O
O
3
N
H Cl
Acetone / H 2O, reflux
2.3 Preparation of a Pyrrolylphosphine
P
O
H
O
3
O
NaBH 4, THF, 25 °C
12, 88% 13, 86%
A more ambitious target was the preparation of a new phosphine bearing several
enantiomerically pure chiral substituents. Since it was easily accessible in both pure enantiomeric
forms
[ ] 95 , N-(1-phenylethyl)pyrrole (14) was chosen as starting candidate for preparing a tertiary
phosphine from the triethyl phosphite. The ease of α-metalation of N-substituted pyrrole rings with
organolithium reagent
[ - ] 96 98 was also a decisive parameter, since it could allow its phosphorylation
with the appropriate phosphite. Hydrogen/lithium permutation was first performed in
tetrahydrofuran with a stoichiometric amount of butyllithium at -75 °C, and subsequently trapped
with iodomethane. 1 H NMR and gas chromatographic analysis of the crude reaction mixture
3
P
O
OH
3
[ ] 94

15
unfortunately revealed the presence of the expected 2-methyl-N-(1-phenylethyl)pyrrole (15), but
also of N-(2-phenylpropan-2-yl)pyrrole (16), stemming from metalation at the benzylic position, in
a 3 : 7 ratio and with a 85% overall yield. Since this method did not present any exploitable results,
the two products obtained were not separated from the reaction mixture.
N
1) LiC 4H 9, THF, - 75 °C
2) CH 3I
N + N
(S)-14 (S)-15, 25% (S)-16, 59%
Optimization of the reactions conditions were then tried by varying the organolithium
reagents (e.g. lithium diisopropylamide, lithium tetramethylpiperidide), the solvents (diethyl ether,
hexanes) or by addition of N,N,N',N'-tetramethylethan-1,2-diamine as co-solvent. Unfortunately, all
attempts resulted in either higher proportion of pyrrole (16) or in very low yield of metalated
product. Since it was assumed that bromine/lithium permutational exchange on the pyrrole ring
would be by far much faster than deprotonation at the benzylic position, the preparation of 2-bromo-
N-(1-phenylethyl)pyrrole (17) from the parent pyrrole (14) was endeavored. A literature overview
on the pyrrole chemistry revealing the lack of efficient methods to selectively mono-halogenate N-
substituted pyrroles in the α-position
[ , ] 99 100 , it was intended to optimize existing methods to afford
only pyrrole (17). Furthermore, the need for a clean mono-halogenation reaction was motivated by
the high instability of halogenated pyrroles which would make the purification of such type of
compounds relatively tedious. The classical bromination reaction using elementary bromine in
carbon tetrachloride only afforded a mixture of mono and polybrominated products as revealed by
gas chromatography analysis. The method described by M.P. Cava, Y.A. Jackson et al.
[ ] 101 to
mono-brominate the parent pyrrole, using 1,3-dibromo-5,5-dimethylhydantoin and catalytic
amounts of azoisobutyronitrile (AIBN) in tetrahydrofuran, when applied to pyrrole (14), afforded a
6 : 91 : 3 ratio of starting material, mono-brominated pyrrole (17) and 2,5-dibromo-N-(1-
phenylethyl)pyrrole (18) respectively, and was slightly improved when no AIBN was used (3.5 : 94
: 2.5). This result, however inspired the use of N-bromosuccinimide (NBS) in tetrahydrofuran at
- 75°C, and gave very good results when NBS was added solid and portionwise. The desired
monobrominated pyrrole (17) was thus obtained together with dibrominated pyrrole (18) in a 98 : 2
ratio as revealed by gas chromatography and 1 H NMR analysis, and could be purified by fractional
crystallization to give pure pyrrole (17) in 71% yield. Dibrominated products was two unstable and
rapidly decomposed on silica gel and thus, was not isolated.

N
(S)-14
1) NBS, THF, - 75 °C
2) - 75 °C to 25 °C
16
Br
N N Br
+ Br
(S)-17, 71% 98 : 2 (S)-18
Pure bromopyrrole (17) was then submitted to bromine/lithium permutation
with butyllithium at - 75 °C and treated with 1/3 equivalent of triethyl phosphite.
1 H NMR and thin layer chromatography analysis of the crude resulting reaction mixture
showed the presence of a mixture of mono-, di-, and trisubstituted phosphines, the major
product being the ethyl bis{N-[(1S)-phenylethyl]pyrrol-2-yl} phosphinite (19) which
could hardly be separated from the other phosphine and phosphinite. In view to this
result, a second attempt was tried and aimed at preparing the phosphinite (19)
selectively. Thus, the transient lithiated pyrrole generated with butyllithium in toluene at
0 °C was added to 1/2 equivalent of triethyl phosphite at - 75°C in order to prepare the
dipyrrolyl phosphinite (19) exclusively. This last reaction still gave a mixture of the
different substitution pattern products, but in much smaller proportions and allowed a
column chromatography isolation of phosphinite (19) in 47% yield. Although
characterization of the desired product was effected by 1 H, 13 C and 31P NMR, all
attempts of further purifications to provide analytically pure material for elemental
analysis failed. Further attempts to convert phosphinite (19) into a crystalline derivative
by means of phenyllithium resulted in no reaction, probably due to steric hindrance
around the phosphorus atom.
Br
N
(S)-17
1) LiC 4H 9, Toluene, 0 °C
2) P(OC 2H 5) 3 (0.5 équiv.)
O P
N
(S,S)-19, 47%
As in the case of binaphthyl phosphinite (5), the phosphinite (19) obtained was
believed to be an interesting phosphorylating reagent for preparing chiral ligands and
would be an alternative to chiral phosphine where the phosphorus atom is bearing the
chiral information [72, 73] . As a more efficient and convenient access to phosphinite (19)
was sought, the more robust and easily purified 2-chloro-N-(1-phenylethyl)pyrrole (20)
was prepared in an almost quantitative way by reproducing the previously described
selective mono-halogenation conditions with N-chlorosuccinimide (NCS). Chlorination
of the pyrrole (14) in tetrahydrofuran at - 75 °C was much slower than its bromination
2

17
and gave only the mono-chlorinated pyrrole at the 2-position in 74% after distillation.
Gas chromatography analysis of the crude reaction mixture revealed the presence of the
expected chloropyrrole (20) together with a by-product in a 4 : 1 ratio. This latter
product could be isolated as crystalline material in 11% and was identified as the N-{1-
[(1S)-phenylethyl]pyrrol-2-yl} succinimide (21) stemming from the addition of
succinimide on the chloropyrrole (20).
N
(S)-14
1) NCS, THF, - 75 °C
2) - 75 °C to 25 °C
Cl
N + N N
(S)-20, 74% (S)-21, 11%
The standard Grignard reaction conditions applied to chloropyrrole (20) in
tetrahydrofuran with commercial magnesium turning did not produce any trace of
organometallic species. Conditions were then varied by changing solvents or reaction
temperatures, and the formation of the Grignard reagent was followed by gas chromatography
after trapping of an aliquot with carbon dioxide and subsequent esterification with
diazomethane. Since only small amounts of Grignard species could be formed this way,
several activated magnesium were tried
[ ] 102 before R.D. Rieke's conditions
O
O
[ ] 103 revealed
effective and afforded the expected enantiomerically pure N-[(1R)-phenylethyl]pyrrole-2-
carboxylic acid (22) in 74% after crystallization although this yield was determined to be of
97% by gas chromatography when the reaction was ran with an internal calibrated standard.
Cl
N
(S)-20
1) K, MgCl 2, KI, reflux
ClMg
N
2) CO 2, THF
3) HCl 10%
HOOC
N
(S)-22, 74%
These conditions to produce the active magnesium chloride species were then
applied for the preparation of the phosphinite (19). Unfortunately, the same generated
Grignard reagent, when treated with 1/2 equivalent of triethyl phosphite gave only lower
yields of less pure product due to the difficulty to remove the magnesium salts. Few more
trials with other phosphites resulted either in lower reaction rate in the case of triphenyl
phosphite or in the formation of the corresponding methyldipyrrolylphosphine oxide
presumably by Michaelis-Arbuzov rearrangement as already encountered by H. Gilman and J.
Robinson
[ ] 104 .

3 Alkaline Decomposition of Phosphonium Salts: A
Probe to Assess Relative Stabilities of Alkyl Anions
19
Carbanion chemistry plays a central role in modern synthetic organic chemistry.
This relationship has grown up at an extremely rapid pace since the 1960's, due to the
commercial availability of a variety of alkyllithium species, and the development of
efficient organometallic procedures
[ ] 105 . In fact, carbanions are not only involved as
nucleophiles in various chemical processes, but also as bases since deprotonation is often
required to initiate a reaction. This latter property made accessible many structural types
of transient reactive species which are highly valuable as synthetic units since they
generally undergo efficient carbon-carbon bond formation with various electrophiles. To
fine-tune the reaction conditions and select the most suitable reagent for a given
transformation, it is not enough to know that carbanions are globally reactive entities.
What we need is kind of a yardstick that allows us to evaluate the relative chemical
potential of any individual carbanionic reagent.
Despite the interest there would obviously be in the knowledge of their relative
stabilities, little is known about the simple hydrocarbon carbanions. For that purpose, few
investigations have been conducted to collect informations about the "acidity" of simple
alkanes, either in gas phase [106 - 108] or in solution [109 - 112] .
3.1 Gas Phase Acidities of Alkanes
The study of the gas phase chemistry of ionic species is of considerable
importance since it allows an assessment of the intrinsic molecular properties in the
absence of complex interactions with solvent molecules. Thus, in many instances, gas
phase data allow one to discern whether correlations deduced from solution phase data can
legitimately be interpreted in terms of properties of isolated molecules or should be
attributed to solvation phenomena. Although the gas phase acidities of a large number of

20
organic molecules have been determined [113 - 116] , those of many of the simplest, namely
the linear and cyclic alkanes, remain to be established. This specific lack of information
accounts for the very weak acidity of such compounds which hardly generate the
corresponding carbanion in the gas phase
[ ] 117 and thus do not afford any thermodynamic
°
data evaluation. The exact acidity of methane ∆H CH ) [i.e. proton affinity, PA(CH4)]
acid ( 4
was calculated by means of a Born-Haber thermodynamic cycle (Figure 1) and using the
relationship PA(CH4) = D°(H3C-H) + IP(H · ) - EA(CH3 · ), involving the homolytic
bond-dissociation energy of methane D°(H3C-H) [118] , the ionization potential of hydrogen
IP(H · ) [119] , and the electronic affinity of the methyl radical EA(CH3 · ) [120] .
D ° (H 3C-H)
PA (CH 4)
H3CH CH3 + H
CH 3
+ H
CH3 +
IP (H )
Figure 1. Born-Haber cycle for the
determination of PA(CH4).
- EA (CH 3 )
Unfortunately, some of these thermodynamical values are unavailable for other
alkanes, which made the determination of their acidity impossible by this way. As a
consequence, C.H. DePuy, R. Damrauer et al. [108] devised a kinetic method for studying
extremely weak acids such as alkanes. By treatment of alkyltrimethylsilanes with
hydroxide ions in a flowing afterglow-selected ion flow tube (FA-SIFT), they could
produce a mixture of alkyldimethylsiloxide ions by loss of methane and trimethylsiloxide
ions by loss of alkane. Going by the linear correlation between the ratios of siloxide ions
formed and the pKa's of the expelled alkanes reported by C. Eaborn et al. [121] , C.H.
DePuy, R. Damrauer et al. [108] determined the relative basicities of methyl and various
alkyl anions. Furthermore, a calibration of this method by making use of the known
acidity of methane and benzene, allowed the deduction of the exact gas phase acidity of a
series of alkanes. In parallel to endeavors in establishing a "gas phase acidity scale" of
various hydrocarbons, several research groups investigated the behavior of various
carbanions in solution.
H

3.2 Alkyl Carbanions Stabilities in Solution
hydrocarbons
21
A few pioneering studies first carried out acidity measurements of
[109, , ] 122 123 such as indene, or phenylfluorene where the carbanions enjoyed
conjugative stabilization. The equilibrium studied were the exchange reactions of the type:
where M was sodium or potassium. Because of the non-polar media and of probable
covalent character in the RM bonds, it was not possible to derive Ka's which could be
compared quantitatively to those of stronger acids in aqueous media. Furthermore, none of
the techniques thus far described have been generally applicable to the less acidic
hydrogens found in simple hydrocarbons.
In order to evaluate the relative stabilities of carbanions derived from weakly acid
hydrocarbons, D.E. Applequist and D.F. O'Brien
[110] later studied equilibria by
permutational halogen/metal interconversion between cyclic (cyclobutyl, cyclopentyl) or
linear alkanes (ethyl, propyl, isobutyl, neopentyl). To determine equilibrium constants the
metalated substrates were added to halogenated ones and samples regularly withdrawn
were treated with water to replace lithium by hydrogen. Intending to avoid possible
complications due to the Wurtz coupling, and the dehydrohalogenation side reactions,
R.E. Dessy et al.
RH + R'M RM + R'H
[111] rather studied metal-metal exchange reactions between
organomagnesium and organomercuric species, relying on the fact that the most stable
carbanions would prefer to be paired to the most electropositive element. Although
meritorious, these earlier endeavors suffered a major problem. As the authors
admitted [110] , an ambiguity remained whether the results obtained were indeed reflecting
relative stabilities of carbanions in a quantitative way or whether they were partially
influenced by aggregation of the metallic species [47] . In conclusion, none of the
equilibrium techniques devised to sort carbanionic stabilities
[110, 111, , ] 124 125 could afford
accurate data concerning simple alkyl groups, devoid of any other factors' influence.

3.3 Assessment of the Relative Ease of Alkyl Expulsion
from Phosphonium Salts
22
The new method developed during this thesis work for quantitatively determining the
relative stabilities of various carbanions, and particularly the alkyl ones, was based on the use of
the alkaline decomposition of phosphonium halides. On the basis of their precursor work on this
field, G.W. Fenton and C.K. Ingold [30] postulated that the ease of expulsion of one of the
phosphonium substituents was governed by the stability of its related anion. These authors, and
more recently H.R. Hays and R.G. Laughlin [52] treated a series of mixed phosphonium salts
bearing phenyl, allyl, benzyl or various alkyl groups such as methyl, ethyl, propyl, dodecyl or
tridodecyl under alkaline conditions and evaluated the ratios of the different products formed. The
decomposition of dodecyltrimethyl or tridodecylmethyl phosphonium hydroxide [52] gave in both
cases, only one phosphine oxide and its associated alkane, corresponding to the expulsion of the
most stable methyl carbanion. On the other hand, when decomposing phosphonium salts bearing
different but more similar groups such as ethyltripropyl or triethylpropyl phosphonium salts, G.W.
Fenton and C.K. Ingold [30] obtained a mixture of tripropyl and ethyldipropyl phosphine oxide or
of diethylpropyl and triethyl phosphine oxide, respectively, and the corresponding alkanes.
Unfortunately, since the quantification of the reaction products was relying on gas evolution
measurements and isolation of the oxides by distillation, the data collected were only qualitative
or, to some extent, gave a vague idea of the relative ease of expulsion for the different alkyl
substituents. From these results, the different author involved in these studies proposed an
approximate scale of stability for various carbanions:
benzyl, allyl > phenyl > methyl > ethyl, higher primary alkyls
The aim of this new method was to provide accurate and quantitative data for a series of
primary but also previously unstudied secondary and tertiary alkyl substituents to probe relative
stabilities of alkyl carbanions and discuss the different parameters influencing their leaving
ability. As a matter of fact, even if few primary alkyl anions have been already described [29, 30, 52] ,
be it only qualitatively, no reports concerning secondary or tertiary alkyl anions stabilities in
solution have so far been published. The lack of informations for the alkaline decomposition of
tetraalkyl phosphonium salts probably partially accounts for the chemical properties of
alkylphosphine compounds which are fairly difficult to handle and easily prone to oxidation.
Furthermore, the collected results of this study were analyzed by the light of various mechanistic
discussions concerning the alkaline decomposition of phosphoniums halides.

3.3.1 Mechanistic Discussion on the Alkaline Decomposition of
Phosphonium Salts
23
Although various authors [29 - 35] assumed this decomposition to proceed trough
several independent equilibrated or irreversible steps, the kinetics and other results reported
thus far could perfectly match with other alternative mechanisms. A concerted mechanism
involving a pentavalent hydroxyphosphorane and a hydroxide ion could also be consistent
with the products obtained. This mechanistic pathway would then directly produce an alkane
without formation of a free carbanion as proposed by C.K Ingold et al. [29, 30] .
R 1
P
R3 R 4
R2 K HO
I
HO
R 4
R 1
P
+ KI
R 3
R 2
K HO
R1 R2 O H
H
K
O P
According to the Bell-Evans-Polanyi theory
R 4
R 3
R 2
P
R3R4 + R1H O
[ - ] 126 128 and provided that the different
reactants involved are being slightly polarized, the concerted alternative for this reaction
would require lower activation energy than its non-concerted analog. As a matter of fact, if
the cleavage of the P−R 1 bond (increase of the r P…R 1 distance) occurs simultaneously to the
formation of the R 1 −H bond (decrease of the r R 1 …H distance) the system can lower its
activation energy by a "concertation energy" factor. The amount of this stabilisation energy
essentially depends, as explained by R.P. Bell [128] , and M.G. Evans and M. Polanyi [126, 127] ,
on the ability of both bonds involved to be polarized. The concerted mechanism proposed, if
consistent, would possibly imply that the relative ease of substituent expulsion could be also
governed by other factors than the carbanion stability such as steric strains. Indeed, if no free
carbanions but only alkanes are produced, a question had to be adressed: does a negative
partial charge show up on the alkyl substituent in the course of the decomposition and to what
extent does it influence the departure of the alkyl group?
An evidence for the presence of a partial negative charge on the leaving alkyl group
was provided by surveying the effects of substituents on the alkaline decomposition of several
substituted triarylbenzylphosphoniums salts. H. Hoffmann [32] first reported the dependence of
the alkaline cleavage rate of variously p-substituted-benzyltriphenylphosphonium salts.
Electron withdrawing substituents caused acceleration of the rate of decomposition whereas
electron donating ones had the opposite effect. Application of the Hammett equation
[ ] 129 gave
a good correlation and afforded a rate factor ρ of +4.62 [36] . This result clearly showed the
importance of electron withdrawing substituents in stabilizing an anionic character developed

24
on the leaving alkyl group during the rate determining step of alkaline decomposition. Other
investigations on substituent effects were ran with o- and p-substituted-benzyltriphenyl phosphonium
salts in different conditions
[36, - ] 130 132 and showed ρ ranging from +2.2 to +5.6. Values of ρ ranging
from +4 to +5 are in good agreement with other known base-promoted reactions in which benzylic
carbanions in hydroxylic solvents are proposed as intermediates
[ , ] 133 134 . It was thus believed, at that
stage, that the relative ease of alkyl expulsion was governed by the stabilities of the corresponding
carbanions. However, B. Siegel [131] interestingly reported a Hammett analysis for variously
substituted Y-benzyltriphenyl phosphonium bromides in which σ – for substituents on the benzyl
group (Y) were graphed against log kY (kY being the third order rate constant of alkaline
decomposition of the salt). The plot, unfortunately, did not support a linear correlation which would be
expected if a carbanionic character was developed on the leaving group, and delocalized to the entire
aromatic ring, in the course on the expulsion of an alkyl carbanion. In contrast, a plot of those log kY
against σ gave a very good linear correlation (r = 0.99) with a slope ρ of +3.7. In view to those results,
it can be assumed that a polarization or partial negative charge is present on the leaving benzylic group
in the rate determining step but no proper negative charge is delocalized to the whole aromatic ring.
This assumption thus agrees with the hypothesis of a concerted expulsion-reprotonation of the alkyl
group.
Another argument favoring a concerted version of the alkaline decomposition of
phosphonium salts was suggested by a work reported by C. Eaborn et al.
[ ] 135 . Indeed, they assumed
that for a similar decomposition of silicon and tin compounds, the expelled anions were not
completely free but rather protonated as formed. When performing the reaction in MeOH−MeOD
(1:1) they observed kinetic isotope effects of kH/kD of 1.4 to 4.6 depending on the substrates. J.R.
Corfield and S. Trippett
[ ] 136 later performed alkaline decompositions of tetraphenylphosphonium
iodide and cumyltriphenylphosphonium iodide in H2O/D2O (1:1) and observed kinetic isotope effects
kH/kD of 1.22 and 1.21 respectively. These differences in reaction rates, even if lower than those
observed by C. Eaborn et al. [135] , can be explained by a mechanism of phosphonium salt
decomposition in which, in the rate-determining step, little breaking of the P−R bond has occurred
while there is a corresponding little transfer of a proton to the incipient carbanion. Furthermore, since
isotopic effects are dependent from the reaction solvents involved, the range of kH/kD values obtained
by J.R. Corfield and S. Trippett [136] can not be directly correlated to those obtained by C. Eaborn [135] .
δ
(1−δ)
H
C
P
O
O

25
The assumption reported by these authors were based on the fact that a "free"
carbanion is so reactive that it would presumably not significantly discriminate between a
proton and a deuterium in the rate determining step. In contrast, a partially polarized and
concerted transition state such as the one proposed above could show a more contrasted
reactivity toward reprotonation with deuterated solvent or not. This hypothesis was later
consolidated by a work of F.Y. Khalil and G. Aksnes
[ ] 137 in which they observed kinetic
isotope effects of larger magnitude, ranging from 1.55 to 2.36 depending on the temperature
of decomposition for tetraphenylphosphonium chloride in dioxane/H2O or dioxane/D2O
mixtures. These latter experimental observations, though not completely unequivocal, do fully
support the Hammett analyses according to what the alkaline decomposition would rather
proceed through a concerted mechanism.
Since electron-withdrawing substituents obviously accelerate the rate of the alkaline
decomposition of phosphonium salts, but no completely delocalized negative charge is
apparently formed in the course of the rate determining step, it was still legitimate to believe
that the ease of alkyl expulsion from the salt was somehow influenced by their ability to
accommodate a negative charge. In contrast, if a concerted mechanism appeared to be favored
in the light of the arguments discussed, steric factors could influence, to some extent, the
departure of one alkyl substituent rather than the other. As a matter of fact, it is known that
intramolecular strains play an important role on the rate of nucleophilic substitutions and
particularly SN2 type reactions
[ ] 138 . In this context, the results collected in this study will be
discussed and compared to those reported in the literature, to evaluate the importance of front-
strains (F-strains) as well as back-strains (B-strains), which could direct the course of the
decomposition reaction.
3.3.2 Principle of the Method Devised
For the purpose of this study, a series of phosphonium halides bearing two different
types of alkyl substituents were prepared and submitted to alkaline decomposition in a
butanol/water mixture. On the basis of the alkaline decomposition mechanism commonly
assumed [29 - 34] , a plausible energetic profile is proposed in figure 2 to illustrate the principle
of the study endeavored herein. It was, in this case, assumed that the ratio of the phosphine
oxides obtained should be directly proportional to the difference in free enthalpy between
≠
both products (mentioned as G in Figure 2). As a matter of fact, the crucial elimination
∆∆ 12
1
step where one alkyl group (for example, R ) is expelled rather than the other one present on

26
the reacting phosphonium salt (R 2 ), occurs in an irreversible process from the common
pentavalent phosphorus intermediate (Figure 2). From the ratio measured experimentally, it
was assumed that one can deduce the relative kinetic constant:
n
k 1/
2 =
n
where n1 and n2 are the amount of phosphine oxides 1 and 2 respectively formed.
Finally, the use of the Eyring equation allows the determination of the activation free enthalpy
difference which was thought to be representative of the relative ease of the alkyl substituents
to accommodate a carbanionic character according to the Bell-Evans-Polanyi Theory [126 - 128] :
G
R 1
P
R 2
R 1 R 2
+ KOH
X
1
R 1
R 1
R 2
P
R2 OH
2
∆∆ 12
≠
R 1
R 1
G = −RT
ln k = α ∆∆G
R 2
P
R2 O
∆G 1
3'
3
∆G 2
1
2
1/
2
∆∆G 12
o
12
R 1 R 2
P
R O 1
0
∆∆G12 R
P
O
2 R 2
R1 + R 2 H
+ R 1 H
Reaction Coordinates
Figure 2. Energetic profile of the alkaline decomposition of phosphonium
salts in case of a non concerted mechanism.

27
However, in the eventuality of an effective concerted mechanism as discussed
previously, the front and back strains occurring in the transition state could distort the results
obtained. Indeed, internal strains if not negligible, could either accentuate or counterbalance
the "negative partial charge stabilization" parameter which was aimed in this work. The
results presented in chapter 3.3.5 will possibly help to address this crucial issue and provide
new mechanistic insight on the alkaline decomposition of phoshonium salts.
3.3.3 Qualitative and Quantitative Analysis of the Reaction Products
For each experiment, stoichiometric amounts of phosphonium salt and internal standard
(tributylphosphine oxide or triisopropylphosphine oxide) were submitted to the alkaline reaction
conditions in a thermostated bath at 110 °C. A possible side reaction in alkaline conditions was
the β-elimination of hydrogen from the phosphonium salt, leading to the formation of an alkene
and a corresponding tertiary phosphine. Although such process had never been reported for
phosphonium salts and does not seem favored [30] under these conditions, it was deemed of capital
importance to check the complete absence of these undesired by-products which could distort the
results collected. Thus, during the whole reaction time, the gas evolutions were passed through a
[ ]
solution of bromine 139 in chloroform to detect the presence of alkenes. After the excess of
elementary bromine had been neutralized, the organic layer was systematically analyzed by gas
chromatography to detect any traces of possible dibrominated alkanes. Fortunately, this safety
measure followed the expectations and never revealed any detectable traces of such by-products.
Due to the volatility of the alkane products formed during the alkaline decomposition
of phosphonium salts, the relative amounts of those species could not be quantified by gas
chromatography. Furthermore, the quantitative analysis of the phosphorus derivatives formed
was first attempted, but gave non-reproducible results, probably due to an uncomplete
combustion of the phosphine oxide in the flame ionization detector (FID) which is known to
be the most accurate gas chromatography quantification technique. Thus, the ratios of both
possible phosphine oxides formed in the course of the decomposition reactions were
systematically quantified by 31 P NMR analysis. The assignment of each peak in the NMR
spectra of the crude mixture was effected by comparison with the spectra of each single
authentic phosphine oxides prepared independently. In this context, the NMR spectroscopy
appeared to be a useful and convenient method for this type of study since the 31 P NMR
spectra did not suffer any parasite signal making the interpretation or measurement inaccurate
[ ]
and the spectral window was wide enough to avoid any superimposition of peaks 140 .

28
Furthermore, the intensities of all signals were directly proportional to the amount of each
product present in the mixture, which allowed direct determination of the k1/2 values with
respect to the internal standard used. In order to get accurate results and devoid of any artifact,
the 31 P NMR spectra were recorded in a nondecoupling mode since it is known that the
Nuclear Overhauser Effect (NOE) causes changes in the peak intensities during the 1 H
decoupling process
[ ] 141 . On the other hand, for the peak intensities to be effectively
relevant to the exact amount of each product quantified, the 31 P nucleus relaxation time
(T1) had to be determined and set by classical NMR techniques so that all considered
nuclei went back to equilibrium. Under these conditions, the 31 P NMR analysis could
afford accurate and quantitative results.
To determine the standard deviation on each measurement, a series of phosphine
oxide pairs were prepared in different extreme ratios (ranging from 1 : 1 until 99 : 1) by
accurately weighting the substances. 31 P NMR analyses of each of these mixtures in the
above mentioned conditions revealed an average standard deviation of 0.5% (see
Experimental Part). Quantitative 31 P NMR analysis technique has been extensively used
during the last two decades for enantiomeric excess (ee) determinations of chiral alcohols,
diols and amines using phosphorus chiral derivatization agents (CDA)
[ - ] 142 146 . B.L.
Feringa et al. [143, 145] and A. Alexakis et al. [142, 144, 146] reported average incertitudes on
the measure in good agreement with those determined in this study when using this
technique of quantification. Finally, for the sake of testing the reproducibility of the
results, the data reported for each phosphonium halide were measured as an average of
three separate runs carried out in the same experimental conditions.
3.3.4 Starting Materials and Reference Substances
For the determination of relative alkyl anions stabilities, all the starting mixed
tetraalkylphosphonium halides had to be prepared by quaternarization of the
corresponding tertiary alkylphosphines with the appropriate alkyl halide. On the other
hand, all the phosphine oxides which could possibly form during alkaline decomposition
reactions also had to be prepared to serve as authentic reference compounds for 31 P NMR
assignment. These oxides were in most cases, synthesized by simple oxidation of the
tertiary phosphine already prepared.

29
To prepare tertiary phosphines bearing two different types of alkyl substituents,
the choice of dichloro-N,N-diethylaminophosphine
[ ] 147 as starting material was found to
be the most judicious. As a matter of fact, the use of organometallic reagents to selectively
substitute one or two chlorine atoms from phosphorus trichloride resulted, in most cases,
in a mixture of mono-, di- and trisubstituted phosphines. On the contrary, at low
temperature it was possible to treat dichloro-N,N-diethylaminophosphine with two
equivalents of an alkyllithium or alkylmagnesium reagent without any P-N bond cleavage,
affording a series of dialkyl-N,N-diethylaminophosphines 24a - 24d with moderate to
excellent yield (Table 2).
PCl 3
HNEt 2, DEE
- 75 °C to 25 °C
Cl
P
N Cl
23, 85%
RLi or RMgX
- 75 °C
R
P
N R
24a - 24d
Table 2. Dialkyl-N,N-diethylaminophosphines R2PN(C2H5)2.
Product R = RLi or RMgX Yield
24a -C(CH3)3 LiC(CH3)3 89%
[ ] 148
24b -C4H9 LiC4H9 88% [147]
24c -C2H5 H5C2MgBr 81% [147]
24d -CH3 LiCH3 49%
Each dialkyl-N,N-diethylaminophosphine of the series 24a - 24d was then
converted to the corresponding chlorophosphines 25a - 25d using a novel efficient
method. Treatment of phosphines 24a - 24d with a 4.8 M hydrogen chloride solution in
diethyl ether rather than with gaseous hydrogen chloride [147] gave
dialkylchlorophosphines 25a - 25d with better yields (Table 3) and a more convenient
work up procedure. Other attempts to prepare 25a - 25d from aminophosphine 23 in a one
pot synthesis gave comparable overall yields, without isolation of the intermediate
dialkylaminophosphines 24a - 24d.
[ ] 149

R
P
N R
24a - 24d
30
HCl / DEE 4.8 M
- 75 °C to 25 °C
Cl
R
P
R
25a - 25d
Table 3. Dialkylchlorophosphines R2PCl.
Product R = Yield
25a -C(CH3)3 79%
[ ] 150
25b -C4H9 86% [147]
25c -C2H5 64%
25d -CH3 47%
Mixed tertiary phosphines bearing two different alkyl groups were then
prepared either from chlorophosphines 25a - 25d or from chlorodicyclohexylphosphine
(25e) or Chlorodiisopropylphosphine (25f). The latter two chlorophosphines 25e and 25f
were prepared according to a procedure described by W. Voskuil and J.F. Arens
Treatment of these chlorophosphines with the suitable organometallic reagent afforded a
series of mixed trialkyl phosphines 26a - 26k with moderate to good yields (Table 4).
Cl
R
P R
25a - 25f
R 'Li or R 'MgX
DEE or THF, - 75 °C
R '
[ ] 151
[ ] 152
R
P R
26a - 26k
[ ] 153 .

31
Table 4. Mixed tertiary alkylphosphines R2R'P.
Substrate R = R'Li or R'MgX Product R' = Yield
-C(CH3)3 (25a) LiC4H9 -C4H9 (26a) 83%
-C(CH3)3 (25a) (CH3)2CHMgCl -CH(CH3)2 (26b) 52%
-C(CH3)3 (25a) LiCH3 -CH3 (26c) 63%
-C4H9 (25b) (CH3)3CCH2MgBr -CH2C(CH3)3 (26d) 65%
-C4H9 (25b) LiC(CH3)3 -(CH3)3 (26e) 58%
-C4H9 (25b) LiCH3 -CH3 (26f) 84%
-C2H5 (25c) LiC4H9 -C4H9 (26g) 51%
-CH3 (25d) LiC(CH3)3 -C(CH3)3 (26h) 67%
-CH3 (25d) LiC4H9 -C4H9 (26i) 68% [38]
-C6H11 (25e) LiC4H9 -C4H9 (26j) 82%
-CH(CH3)2 (25f) LiCH3 -CH3 (26k) 69%
The trialkyl phosphine oxides 27a - 27h were then prepared by simple oxidation
of the corresponding tertiary phosphines 26a, 26b, 26d, 26e, 26g, and 26i - 26k with
hydrogen peroxide in diethyl ether at 0 °C
[ ] 154
[ ] 155
[ ] 156
[ ] 157
[ ] 158
[ ] 159 . These phosphine oxides were obtained
in very good yield (75 to 93%) after distillation or sublimation in the case of solid
compounds and served as authentic samples for NMR comparison with the crude
products derived from phosphonium salt decompositions (Table 5).
R'
R
P R
26a, b, d, e, g, i - k
30% H2O 2
DEE, 0 °C
R O
P
R' R
27a - 27h

32
Table 5. Trialkylphosphine oxides R2R'P(O).
Product R = R' = Yield
27a -C(CH3)3 -C4H9 87%
27b -C(CH3)3 -CH(CH3)2 88%
27c -C4H9 -CH2C(CH3)3 86%
27d -C4H9 -C(CH3)3 75%
27e -C2H5 -C4H9 78% [37]
27f -CH3 -C4H9 84% [38]
27g -C6H11 -C4H9 93%
27h -CH(CH3)2 -CH3 86%
Other phosphine oxides needed as reference substances were prepared by means of
known procedure from the literature. Thus, di-tert-butylmethylphosphine oxide (27i) was
prepared by Michaelis-Arbuzov rearrangement of methyldi-tert-butylphosphinite
[ ] 160
[ ] 161
[ ] 162 with
iodomethane, whereas dibutylmethylphosphine oxide (27j) and tert-butyldimethylposphine
oxide (27k) where obtained by reaction of butylmagnesium bromide or methylmagnesium
bromide with methylphosphonic dichloride and tert-butylphosphonic dichloride
respectively
[ ] 163 . Finally, the quaternary phosphonium halides were obtained from mixed
trialkyl phosphines 26a, 26c, 26d, and 26f by reaction with the appropriate alkyl halide in
diethyl ether. The hygroscopic products were collected simple filtration under anhydrous
conditions to give the starting phosphonium salts 28a - 28d (see § 3.3.4) which were further
decomposed under alkaline conditions.
3.3.5 Alkaline Decomposition of Phosphonium Halides
Several solvents, concentrations and water / solvent ratios were initially tried before
optimum conditions have been found for the alkaline decomposition reaction. First of all, a
dimethylsulfoxide/water mixture was chosen for the alkaline decomposition of
dibutyldimethylphosphonium iodide (28a), di-tert-butyldimethylphosphonium iodide (28b)
[ 164 ]
and dibutyldi-tert-butylphosphonium iodide (28c) at 60 °C. The use of this polar aprotic
solvent was mainly governed by its ability to enhance the nucleophilic activity of hydroxide
ions to accelerate the reaction rate which is known to be relatively slow in the case of
tetraalkylphosphonium salts
[ , ] 165 166 . However, since the results collected in these conditions

33
were comparable to those obtained with a more classical butanol/water (8 : 2) mixture at
110 °C, and removal of the alcohol during work up was more convenient, this alcoholic
reaction media was chosen instead.
This study was not meant to be exhaustive but tried to select pertinent starting
substrates which allowed the comparison of primary, secondary and tertiary alkyl anion
stabilities in a systematic manner. Thus different primary alkyl carbanions were first
compared with each other, by studying the alkaline decomposition of three
tetraalkylphosphonium iodides bearing only primary alkyl groups. Decomposition of
tributylneopentylphosphonium iodide (28d) in a butanol/water mixture with an excess of
potassium hydroxide at 110 °C led to a mixture of tributylphosphine oxide and
dibutylneopentylphosphine oxide in a 17 : 83 ratio.
H9C4OH / H2O (8 : 2)
P I P O +
P O
KOH, 110 °C
28d
17 : 83
+ +
This ratio, after statistical corrections, related to a relative rate constant
k1/2 = 1.63 (±0.10) and revealed the butyl group to be cleaved more rapidly than its neopentyl
congener with a difference in activation free enthalpy of ∆∆G ≠ = 0.37 (±0.06) kcal·mol -1 . On
the basis of an expulsion governed by the relative stabilities of the corresponding carbanions
expelled, this difference in energy was expected due to the presence of the strong electron
releasing tertiary carbon center on the neopentyl groups. However, despite the presence of a
tertiary electron releasing carbon on the neopentyl substituent, this value appeared to be
relatively modest. More interestingly, when the two other phosphonium salts bearing four
primary alkyl groups were decomposed, only one phosphine oxide was formed quantitatively
in each case. As a matter of fact, when treated in alkaline conditions for 48 h at 110 °C,
dibutyldimethylphosphonium iodide (28a) and butyltriethylphosphonium iodide (28e)
gave only dibutylmethylphosphine oxide (27j) [162] and butyldiethylphosphine oxide (27e) [37]
respectively. These results suggested that, within the limits of error in determination, the
methyl and the ethyl substituents are more easily expelled than the butyl one with a difference
of activation free enthalpy of ∆∆G ≠ > 4.60 kcal·mol -1 .
27c
[ ] 167

34
Primary alkyl substituents were then compared to secondary ones by means of
alkaline decomposition of two mixed phosphonium halides. Butyltricyclohexylphosphonium
bromide (28f) was first decomposed under the usual butanol/water alkaline medium for 72 h
at 110 °C to give a mixture of butyldicyclohexylphosphine oxide (27g) and
tricyclohexylphosphine oxide in a 76 : 24 ratio.
P
3
28f
H 9C 4OH / H 2O (8 : 2)
Br
KOH, 110 °C
P
2
O
27g
+
76 : 24
+ +
Statistical corrections finally gave a relative rate constant of k1/2 = 1.02 (±0.06)
which lead to a difference in activation free enthalpy of activation between cyclohexyl and
butyl expulsion of ∆∆G ≠ ~ 0.0 kcal·mol -1 . Triisopropylmethylphoshonium iodide (28g) was
then also submitted to the usual alkaline treatment but, in this case, triisopropylphosphine
oxide was the sole product. This result, once again attested to the relatively large difference in
activation free energy between methyl and other alkyl expulsion since it can be assumed that
∆∆G ≠ > 4.60 kcal·mol -1 .
To assess the relative ease of alkyl cleavage between primary and tertiary groups,
dibutyldi-tert-butylphosphonium iodide (28c) and di-tert-butyldimethylphosphonium iodide
(28b) [164] were used as starting substrates. Phosphonium iodide 28c after alkaline
decomposition gave a mixture of butyldi-tert-butylphosphine oxide (27a) and dibutyl-tert-
butylphosphine oxide (27d) in a 97 : 3 ratio as revealed by 31 P NMR analysis.
P I P O
H9C4OH / H2O (8 : 2)
28c
KOH, 110 °C
O
P
27a 27d
97 : 3
+ +
The relative rate constant k1/2 was in this of 30.8 (±3.90) and indicated a marked
difference in promptness to form tert-butane and butane [∆∆G ≠ = 2.30 (±0.10) kcal·mol -1 ]
even if alkaline decomposition gave rise to the formation of both possible phosphine oxides.
Finally the alkaline decomposition of di-tert-butyldimethylphosphonium iodide (28b) [164] only
+
H
P
3
O

35
led to the formation of di-tert-butylmethylphosphine oxide (27i) quantitatively. In view of these
results, it it appears that methyl anion is formed more readily than tert-butyl anion (∆∆G ≠ >
4.6 kcal·mol -1 ).
The last issue of this work was finally to compare the relative cleavage readiness
between a secondary and a tertiary alkyl substituent. This was effectively assessed by
decomposing tri-tert-butylisopropylphosphonium iodide (28h) under the same alkaline reaction
conditions. The 31 P NMR analysis of the crude product mixture showed a 93 : 7 ratio of tri-tert-
butylphosphine oxide and di-tert-butylisopropylphosphine oxide (27b) respectively. These
products proportions gave a relative rate constant k1/2 = 4.68 (±0.09) which translated into a
difference in activation free enthalpy between the formation of tert-butane and isopropane of
∆∆G ≠ = 1.18 (±0.08) kcal·mol -1 . In order to have a better overview on these results, the
differences in activation free enthalpies, the results collected thus far are summarized in Figure 3.
>4.60
1.18 (±0.08)
0.37(±0.06)
~0.0
C(CH 3) 3
CH(CH 3) 2
CH 2C(CH 3) 3
C 4H 9
C 2H 5
CH 3
2.30 (±0.10)
>4.60
Figure 3. Relative ease of alkane formation determined by alkaline
decomposition of phosphonium salts (∆∆G ≠ in kcal·mol -1 ).
>4.60

3.3.6 Relevance of the Data Assessed and Influence of the Steric
Strains on Alkane Cleavage
36
Determination of the relative ease of cleavage for several alkyl substituents was
initially meant to assess their corresponding carbanion stabilities and thus, their related
basicities in solution. Although no accurate reference data are available concerning the
basicities of the species studied herein, the order of cleavage promptness for all the alkyl
substituents perfectly agreed with the experimental reactivity of each corresponding alkyl
carbanions considered. Gas phase acidities of few alkanes have been determined by C.H.
DePuy, R. Damrauer et al. [108] and show a different order for the relative stability of
carbanions:
-C(CH3)3 > -CH3 > -CH(CH3)2, -C2H5 (1)
It is well known that gas phase acidities are dramatically different from those
observed in solution
[ ] 168 . The four effects currently believed to account for these tremendous
variations are the polarization of the carbanions species, the possible resonance and inductive
effects and the hybridization of the carbon bearing the negative charge. In the case of simple
alkanes, the stabilization of the negative charge at the carbanionic center is mainly due to the
[ ]
polarization of the alkyl residue 169 . It is then of evidence that large alkyl anions like tertbutyl
are more efficiently stabilized than smaller ones like methyl group, and thus methane is
less acidic than 2-methylpropane in the gas phase. The stabilization of the same alkyl
carbanions in solution are rather due to solvation, or charge delocalization by mesomeric or
inductive effects. Therefore, the order of relative acidity of given substrates in solution are
usually inversed compared to the gas phase values since steric hindrance usually lowers the
carbanion solvation. For this study, the relative stabilities of alkyl carbanions determined in
solution have been compared to the corresponding gas phase data described in the literature.
According to C.H. DePuy, R. Damrauer et al. [108] , the experimental gas phase acidity order
(1) was unexpected. Furthermore, these authors admitted that the effects of successive αmethyl
substitutions on carbanion stability showed less consistency than that of β-methyl
substitutions, and could hardly be rationalized.
Although well studied in its general features, the exact mechanism still has to be
settled. In this context, the conclusions made from the results collected have to me moderated
due to the fact that steric strains could help favoring one expulsion rather than the other, in the
rate determining step. As a matter of fact, if the concerted mechanism turned out to be the
effective one, two cyclic transition states could be envisaged, as proposed in chapter 3.3.1,

37
depending on the alkyl substituent expelled. It is then obvious that both possible transition
states would not present comparable front and back strains, and thus the probability for each
alkyl group to be cleaved would be, to some extent, influenced by these steric factors. This
argument can be illustrated by the example of dibutyldi-tert-butylphosphonium iodide
alkaline decomposition:
For the sake of clarity, the above mentioned scheme do not show all steric strains
relationships, but only the significant ones showing the difference between both possible
transition states. In order to afford a much reasonable comparison between transition states,
the bulkiest substituent (e.g. tert-butyl group) was arbitrary placed in axial position to reduce
the steric congestion, since it is known that this type of P–C bond is slightly longer and
weaker than the equatorial ones. On the scheme presented above, the transition state leading
to elimination of tert-butane shows more important steric strains than the one one favoring
cleavage of butane. Following this hypothesis, one can legitimately believe that cleavage of
the sterically less hindered substituent, resulting from the less encumbered transition state,
will be favored in the rate determining step of alkaline decomposition of phosphonium salt.
As mentioned previously, the stabilisation of a carbanion in condensed phase is
mainly due to solvation of the negative charge. In this way, bulky carbanions are usually less
efficiently solvated than small ones, and thus are more basic. Steric strains depicted in this
chapter, even if negligible, can cause a distorsion between the effective stability of the alkyl
carbanions and the one measured in this study. However, since stabilities of the cabanions
considered are in presumably governed by their steric bulk, it appears difficult to evaluate the
real proportion of steric strains' influence in the expulsion of alkane from a phosphonium salt.

38
Only one study on alkaline decomposition of phosphonium halides compared the
product ratios, when the number of each phosphonium substituent was varied [30] . For
instance, for the degradation of triethylmethyl and ethyltrimethylphosphonium gave only rise,
in both cases, to methane and the corresponding phosphine oxide. If the steric strains were the
major factors determining the subsituent cleavage from the phosphonium salt, one would have
expected a change, even if low, in the product distribution, due to less marked differences
between the two possible transition states.

39
4 A Novel Access to Atropisomeric Biphenylbisphosphines
Two main strategies are currently followed to prepare pure atropisomeric
bisphosphine ligands. The first and most frequently used approach can be illustrated by the
preparation of MeO-BIPHEP [16] , where the phosphine and the methoxy substituants are
introduced at the very first steps of the synthesis, whereas the resolution is accomplished at
the end. Although very efficient and applicable to a large scale, this protocol suffers from a
lack of modularity since the structure of the targeted ligand is set since the second step of its
preparation. The whole sequence has then to be repeated for each subtle modification of the
ligand's structure. Furthermore, the racemate resolution of atropisomers occurs in the late
stages of the preparation, and implies losses of molecules with high added value. The second
strategy to produce enantiopure axially chiral bisphosphines was first introduced by
[ , ]
B.H. Lipshutz et al. 170 171 and relied on an asymmetric biaryl coupling process. Thus, by
linking two aryl units with a chiral tether such as 2,3-butanediol or 1,2-diphenyl-1,2ethanediol,
these authors could achieve copper-mediated intramolecular biaryl couplings with
asymmetric induction. This method afforded several biaryl substrates with reasonable to high
enantiomeric excesses (ee) depending on their substitution pattern. Once the optically pure
atropisomers are produced, it is possible to derivatize them and convert them into
bisphosphines by various classical methods [17] . However, since this synthetic route should
give ee close to 100% to be used for producing chiral ligands, only a limited number of
substrates were amenable to that technique.
The present work intended to propose and evaluate an alternative synthetic approach
to access pure atropisomeric biphenylbisphosphines via the key intermediate 2,2',6,6'tetrabromobiphenyl
(30). This achiral and readily available biphenyl motif was chosen as a
common pivot for the whole synthesis scheme, because of its versatility. The presence of four
heavy halogens in ortho- and ortho'- positions made it a particularly attractive candidate since
it was prone to successive and selective bromine/lithium permutations [45, 46] as previously
demonstrated by F. Leroux [54] .

4.1 Preparation of Enantiomerically Pure 6,6’-
Dibromobiphenyl-2,2’-diol and Derivatives Thereof
Since A. Rajca et al.
[ 172]
40
described the preparation of 2,2',6,6'-
tetrabromobiphenyl (30) in two step with a very low overall yield (31%), synthesis of
biphenyl 30 was first attempted in a one step procedure. The oxidative coupling of 2-
hydroxynaphtalene with iron(III) chloride to form 2,2'-dihydroxy-1,1'-binaphtyl (BINOL)
inspired this investigation and suggested the use of different metallic oxidants. For this
purpose, commercially available 1,3-dibromobenzene was first metalated at -75 °C with
lithium diisopropylamine (LIDA) in tetrahydrofuran to selectively afford 1,3-dibromo-2-
lithio-benzene
[ ] 174 . The transient species produced was then treated with various salts such as
iron(III) chloride or chromium(III) chloride at -75 °C, but the yield of biphenyl 30 was
unfortunately very low (8 to 14%) or even not existent. As the reaction effectively happened
but appeared to be sluggish at low temperature, the transient lithio- species was
transmetalated to its organozinc derivative by addition of anhydrous zinc(II) bromide at
-75 °C. The latter, more stable towards aryne formation, could hence be warm up to 0 °C and
treated with iron(III) chloride to afford 30 in 33% yield. However low, this yield remained
unoptimized and offers the promising advantage to produce the halogenated biphenyl in one
step.
LiC 4H 9, THF
Br Br - 75 °C Br Br
Li
[ ] 173
ZnBr 2, - 75 °C FeCl 3, O °C
Br Br
Br Br
Br Br
ZnBr
30, 33%
2,2',6,6'-Tetrabromobiphenyl (30) was, in parallel, efficiently prepared in two steps
from 1,3-dibromobenzene, following F. Leroux's modification [53] of the procedure described
by A. Rajca et al. [172] . The previously metalated 1,3-dibromobenzene was first treated with
iodine to afford 1,3-dibromo-2-iodobenzene (29) in nearly quantitative yield (96%).
LIDA, THF I 2, THF
Br Br
- 75 °C
Br Br
Br Br
Li
I
29, 96%

41
Since the homocoupling of the haloarene 29 to give biphenyl 30 by the classical
Ullmann reaction gave only poor yields, A. Rajca's procedure [172] was employed after slight
optimizations. Thus, iodobenzene derivative 29 was treated with butyllithium in diethyl ether,
followed by addition of copper(II) bromide to form presumably the diarylcuprate. Although
the dimerization of "lower order" cuprates (e.g. R2CuLi) has already been achieved by
oxidation with some copper(II) salts
[ , ] 175 176 , the copper species formed in our case apparently
followed a different mechanism had to be oxidized with nitrobenzene to afford 30 in 64%
yield.
Br
I
29
Br
LiC 4H9, DEE
- 75 °C Br Br
CuBr 2
- 75 °C
Br
Cu
Br
Br
PhNO 2
Li
Br
Br Br
Br Br
30, 64%
Since the two step preparation route to biphenyl 30 was applicable to a large scale
reaction and gave better overall yield, it was finally used to routinely prepare this starting
material. The tetrabromobiphenyl 30 thus formed had then to be turned into different chiral
and resolvable motifs. Therefore, 6,6’-dibromobiphenyl-2,2’-diol (31), and 6,6’-
dibromobiphenyl-2,2’-dicarboxylic acid (37) were prepared, and resolved through inclusion
complex or diastereomeric salts formation. The choice of phenol and carboxylic acid
functions was motivated by two main aspects. First of all, both functions are prone to form
inclusion complex with chiral hosts, or can be deprotonated with any kind of chiral base to
form diastereomeric salt, this property being essential for the racemate resolution to be
achieved. On the other hand, both phenol and carboxylic acid functions can be easily
derivatized, reduced, or even halogenated to allow various modifications on the chiral
biphenyl unit.
4.1.1 Racemic 6,6’-Dibromobiphenyl-2,2’-diol
Tetrabromobiphenyl 30 was first subjected to a double permutational
bromine/lithium exchange in tetrahydrofuran at -75 °C. Treatment of the transient 2,2'-
dibromo-6,6'-dilithiobiphenyl with fluorodimethoxyborane-diethyl ether
[ , ] 177 178 followed by
hydrogen peroxide in alkaline media afforded the expected biphenol 31 in 76% yield after
recrystallization. However, since this compound was formed quantitatively and without any

42
trace of organic byproducts, as suggested by a correct mass balance and 1 H-NMR of the crude
product, it was used without any purification for the preparation of derivatives in the racemic
series. On the other hand, as the only impurities in the crude product were believed to be
essentially boron salts, the analytically pure racemic material was utilized for the racemate
resolution step.
Br Br
LiC 4H9 (2.0 eq.)
Br Br THF, - 75 °C
Br Li
Br Li
1) FB(OCH 3) 2, DEE, - 75 °C
2) NaOH 2.O M, 0 °C
3) H 2O 2 35%, 0 °C
Br OH
Br OH
30 rac-31, 76%
4.1.2 Racemate Resolution of 6,6’-Dibromobiphenyl-2,2’-diol
Several methods were examined to resolve the axially chiral biphenol 31. The
first trial relying on a well established protocol was the conversion of the biphenol into a
cyclic phosphate derivative and subsequent treatment with cinchonine to separate the two
diastereomeric salts
[ ] 179 . Unfortunately, the low solubility of the biphenol-based cyclic
phosphate rendered this protocol practically not viable. A promising method described by
G. Delogu et al.
[ ] 180 was also applied to biphenol 31. Its conversion to the corresponding
diastereomeric dicarbonate, by means of (1R,2S,5R)-(-)-menthylchloroformate was
effectively performed in good yield. However, the racemic mixture 32 did not show a
sufficiently high difference in retention factor (Rf) to be properly resolved by column
chromatography, even with several different eluent solvent systems and either on silica or
basic alumina.
Br OH
Br OH
rac-31
(-)-menthylchloroformate (2.0 eq.)
N(C 2H 5) 3, CH 2Cl 2, 25 °C
O
Br O O
Br O O
R *
R *
O
32, 86%
R * =

43
Few other attempts to selectively crystallize either inclusion complex with
N-benzylcinchonidinium chloride
pseudoephedrine
[ , ] 181 182 , or diastereomeric salts with (1R,2R)-(-)-
[ ] 183 remained ineffective. The resolution of biphenol 31 was ultimately
achieved by its treatment with (1R,2R)-(-)-1,2-diaminocyclohexane (DACH) (33) in an
ethanol/hexanes mixture. Thus, both (+)-31·(-)-33 and (-)-31·(-)-33 inclusion complexes
separately by fractional crystallization
[ ] 184 . Simple hydrolysis of each diastereomeric
complex then gave the pure enantiomers in good yield (39 to 42%). Enantiomeric excess
(ee) were checked by conversion of each pure isomer of biphenol 31 into their
corresponding methyl phenol ether and then into MeO-BIPHEP [16] . Comparison of the
[ ] 20
rotatory power α measured with that reported by R. Schmid et al. in the same conditions,
gave ee ≥ 99% (see § 4.3.1).
D
This resolution method was not only practically easy going, but also had the
advantage to use an inexpensive resolving agent. Indeed, although pure (1R,2R)-(-)-DACH 33
was costly, it was possible to use the cheap racemic 33 and resolve it with the commercial L-
(+)-tartaric acid. Furthermore, the chiral amine could be quantitatively recovered as its L-(+)-
tartrate salt as described by Gilheany et al.
Br
Br
rac-31
OH
OH
H 2N
H 2N
(R,R)-(-)-33
Ethanol/Hexanes
(9:1), reflux
Precipitate
Mother liquors
[ ] 185 .
Br
Br
OH
OH
Br OH
Br OH
.
.
H 2N
H 2N
(P)-(-)-31 . (R,R)-(-)-33
H 2N
H 2N
(M)-(+)-31 . (R,R)-(-)-33
4.1.3 Derivatization of 6,6’-Dibromobiphenyl-2,2’-diol
10% aq.HCl
10% aq.HCl
Br
Br
OH
OH
(P)-(-)-31, 39%
Br OH
Br OH
(M)-(+)-31, 42%
The biphenol thus resolved was either O-protected or the two remaining bromines
were directly replaced by phosphino groups. Since the ortho- and ortho'- substituents on the
biphenyl core do not only affect its electronic properties but also the steric hindrance to
rotation, it was possible to control the dihedral angle of the biphenyl unit by varying the steric

44
bulk of the O-substituents. Thus, several phenol ether derivatives were prepared from each
pure enantiomeric form of biphenol 31. First of all, substrate 31 was converted to the
corresponding bis(methoxymethoxy) derivative 34 with 94% yield, using chloromethyl
methyl ether
[ ] 186 . The methoxymethoxy group had the advantage to tolerate the strongly basic
conditions applied during bromine/lithium permutations process with organolithium reagents.
It could also be later used as diastereotopic probe for dynamic 1 H-NMR experiments (see §
4.4.1).
Br
Br
OH
OH
(P)-(-)-31
1) NaH (2.0 eq.), THF, 25 °C
2) CH 3OCH
2Cl (2.0 eq.), 0 °C
Br O O
Br O O
(P)-(-)-34, 94%
Enantiomerically pure (M)- and (P)-biphenol 31 were also converted to methyl
phenol ether 35 and ethyl phenol ether 36. The former was prepared by subsequent treatment
the biphenol 31 with two equivalents of potassium hydroxide and excess of iodomethane in
dimethylsulfoxide at ambient temperature. This simple procedure afforded analytically pure
2,2’-dibromo-6,6’-dimethoxybiphenyl (35) in 90% yield without requiring any purification
since the product spontaneously crystallized from the reaction mixture.
Br
Br
OH
OH
DMSO, KOH
CH3I, 25 °C
Br
Br
O
O
(P)-(-)-31 (P)-(-)-35, 90%
Afterwards, this bisphenol ether was subjected to bromine/lithium permutation and
subsequent treatment with chlorodiphenylphosphine to lead to MeO-BIPHEP via an
alternative route to that proposed by R. Schmid et al. [16] . Furthermore, since the nature of the
phosphorus substituents is known to play a role, not only on the steric bulk, but also on the
electronic properties of the ligands by changing the phosphine basicity, dibromobiphenyl 7
could also be an advantageous precursor for the preparation of a series of "BIPHEP-type"
bisphosphines. For example, using various chlorodialkyl- or chlorodiarylphosphines as
electrophiles, the transient 6,6'-dilithio-2,2'-dimethoxybiphenyl could possibly be converted
into several of modified biphenylbisphosphines.

45
The second phenol ether 36 was finally prepared in a different way than its
homologue 35 since the former procedure only afforded moderate yields (56%). Thus,
biphenol 31 was first deprotonated in tetrahydrofuran using sodium hydride at 25 °C, and then
treated with an excess of ethyl bromide to form 2,2’-dibromo-6,6’-diethoxybiphenyl (36) in
92% yield.
Br
Br
OH
OH
1) NaH (2. 0 eq.), THF, 25 °C
2) C2H 5Br
(2.0 eq.)
Br
Br
O
O
(P)-(-)-31 (P)-(-)-36, 92%
4.2 Preparation of Enantiomerically Pure 6,6’-Dibromobiphenyl-
2,2’-dicarboxylic Acid and Derivatives Thereof
Following the strategy outlined previously, diacid 37 was prepared, starting from the
key intermediate tetrabromobiphenyl 30. The diacid was then resolved into both pure axial
enantiomers and reduced to the corresponding bishydromethyl derivative. Although numerous
ortho,ortho'-diphenic acids have been reported
still to be found on a trial-and-error basis.
[ ] 187 , the most suitable resolution method has
4.2.1 Racemic 6,6’-Dibromobiphenyl-2,2’-dicarboxylic Acid
Biphenol 30 was treated with two equivalents of butyllithium in tetrahydrofuran at
-75°C to produce 2,2'-dibromo-6,6'-dilithiobiphenyl. Subsequent trapping with carbon dioxide
and neutralization afforded 6,6’-dibromobiphenyl-2,2’-dicarboxylic acid (37) in 90% yield.
Br Br
Br Br
30
LiC 4H 9 (2.0 eq.)
THF, - 75 °C
Br Li
Br Li
1) CO 2, THF
2) HCl 10%
Br COOH
Br COOH
rac-37, 90%

4.2.2 Racemate Resolution of 6,6’-Dibromobiphenyl-2,2’-dicarboxylic
Acid
46
The most reliable procedure to resolve chiral carboxylic acids is the fractional
crystallization of a diastereomeric salt which can be easily obtained by treatment of
the racemic acid mixture with an enantiomer of a chiral amine such as alkaloids, amino
acids, terpene derivatives, etc.
methylbenzylamine
[5] . A first attempt was made with (S)-(-)-α-
[ ] 188 . Its low molecular weight constitutes an advantage for large
scale racemate resolution. Moreover, this chiral amine is commercially available in
both enantiomeric forms. Unfortunately, crystallization of the resulting diastereomeric
salt happened to be very slow and had to be repeated several times to give
enantiomerically pure products.
In view to the results reported by K. Mislow et al.
[ ] 189 and R. Adams et al.
[ 190 ]
, commercial alkaloids were used. The brucine dihydrate salt was prepared and its
crystallization attempted in various solvents. Unfortunately, both diastereomeric salts
co-crystallized. Quinine monohydrate finally proved to be a better choice.
Crystallization of its biphenol salt in ethanol followed by hydrolysis finally allowed
separation both atropisomers in good yield (42% and 39%).
Br COOH
Br COOH
rac-31
O
HO
H
H
N
(Quinine)
Ethanol
reflux
N
H
Precipitate
Mother liquors
Br
Br
COO Quinine, H
COOH
Br COO Quinine, H
Br COOH
10% aq. HCl Br
Br
COOH
COOH
(P)-(-)-37, 42%
10% aq. HCl
Br COOH
Br COOH
(M)-(+)-37, 39%

47
The enantiomeric purity was checked by reduction of each pure isomer (see § 4.2.3)
followed by conversion into their corresponding Mosher bisester using (R)-(-)-α-methoxy-α-
(trifluoromethyl)-phenylacetyl chloride
[ 191 ]
.
19 F-NMR analysis of each derivatized
atropisomer compared that of the racemic mixture showed an enantiomeric excess of 98 to
99% depending on the enantiomer.
Br
Br
(P)-(-)-37
COOH
COOH
Br COOH
Br COOH
(M)-(+)-37
Reduction
Br
Br
Br
Br
(P)-(-)-39
(M)-(+)-39
OH
OH
OH
OH
(R)-(-)-RCOCl (2.0 eq.)
CCl4, pyridine, 25 °C
Br
Br
Br
Br
(P)-40
(M)-40
4.2.3 Derivatization of 6,6’-Dibromobiphenyl-2,2’-dicarboxylic Acid
OR *
OR *
OR *
OR *
R * =
CF 3
OCH
Ph3
Enantiomerically pure diacid 37 was finally reduced to (6,6’-dibromobiphenyl-2,2’-
diyl)dimethanol (39). The latter was considered to be a versatile intermediate for further
derivatization such as conversion to ethers or acetals, cyclization into a benzoxepine-type
derivatives or even linkage to a solid support.
The diacid 37 was first treated with lithium aluminium hydride in diethyl ether at
ambient temperature. Unfortunately, although some reduction did effectively occur to produce
the diol 39, thin layer chromatography revealed also the presence of starting material and
unidentified by-products. As to be expected, dimethyl 6,6’-dibromobiphenyl-2,2’-
dicarboxylate (38) gave a far better result, providing diol 39 in 84% yield.
Br
Br
(P)-(-)-37
COOH
COOH
CH 3OH, cat. H 2SO 4
60 °C
Br
Br
COOCH 3
COOCH 3
(P)-(-)-38, 88%
LiAlH 4, THF, - 10 °C
Br
Br
OH
OH
(P)-(-)-39, 84%

48
Another advantage of the synthetic route chosen in this work was pointed out whilst
comparing these results with those published by R. Schmid et al. [15] . As a matter of fact,
R. Schmid et al. described the preparation of diol 39 in its racemic form only, starting from
2-bromoaniline and with an overall yield ranging 24%. In our case, the use of diacid 37
allowed the preparation of both enantiomerically pure atropisomers of 39 with a significant
gain in overall yield (38% and 36% depending on the isomer). Finally, diol 39 was converted
to the corresponding 2,2’-dibromo-6,6’-bis(methoxymethyl)biphenyl (41) in 93% yield, by
treatment with sodium hydride in tetrahydrofuran followed by addition of iodomethane at
25 °C.
Br
Br
(P)-(-)-39
OH
OH
NaH (2.0 eq.)
THF, 25 °C, CH 3I
Br
Br
O
O
(P)-(-)-41, 93%
The transformation of 39 into its dimethyl ether derivative 41 was steered by a
twofold motivation. First of all, after treatment of bisether 41 with a phosphorylating reagent,
the resulting bisphosphine could be used as a chiral ligand for enantioselective
hydrogenations or isomerizations of various substrates. The results obtained with ruthenium
or rhodium catalyzed reaction could be compared with those described for MeO-BIPHEP [16] ,
its phenolic equivalent. Several research groups independently studied the effect of phosphine
basicity on a catalytic process
[ - ] 192 194 . They could show that slight variation of this parameter
can induce tremendous increases in the reaction rates and turnover frequencies (tof), and even
branched to linear isomers ratio in some particular cases of asymmetric hydroformylations.
Thus, changing the phenol ether in compound 35 for its alcohol equivalent 41 was thought to
change the electronic properties of the biaryl unit and, consequently, the basicity of the
corresponding phosphine. Furthermore, since addition of one carbon atom in the ethereal
chain was expected to increase the steric bulk at both ortho- positions of the biphenyl unit, it
could slightly modify the dihedral angle of the corresponding bisphosphine thus, its bite angle
(β) in the metal complex. The intimate relationship between dihedral angle in a chiral
atropisomeric bisphosphine and the enantioselectivity of the metal catalyzed reaction involved
was shown by X. Zhang et al. [18] who prepared a series of conformationally rigid
bisphosphines with defined bite angles (TunaPhos).

49
A second purpose of this derivatization was to make the most of the diastereotopic
hydrogens present in the hydroxymethyl- chain. As a matter of fact, since both methylene
hydrogens of the -CH2OCH3 residue arediastereotopic, they could be utilized as probes for
dynamic 1 H-NMR experiments, in order to determine coalescence parameters. Therefore, it
seemed important to protect the free alcohol functions to allow a coalescence study of 2,2’-
dilithio-6,6’-bis(methoxymethyl)biphenyl without any intramolecular reduction of the lithio-
species formed or aggregation interference.
4.3 Preparation of Biphenylbisphosphines
The enantiomerically pure dibromobiphenyl derivatives were converted via the
dilithio intermediates to the corresponding bis(diphenylphosphines). Contrary to the first
double bromine/lithium permutation process, this last step required optimization of the
reaction conditions. As a matter of fact, a first attempt using the same conditions as
previously, led to a mixture of mono- and bisphosphine. Since the low solubility of the
monolithiated species was believed to account for the mixture obtained, various solvents were
tried. The double permutational bromine/lithium exchange was finally fully achieved with
two equivalents of butyllithium in an 8 : 2 mixture of toluene and diethyl ether at - 40 °C for
1 h. The use of four equivalents of tert-butyllithium instead of simple butyllithium, in
tetrahydrofuran afforded the same results within 10 min at -75 °C.
Another remaining problem which had to be envisaged while treating various 2,2'dilithiobiphenyl
derivatives with chlorodiphenylphosphine, was the possible formation of the
corresponding "phenyl-9-phosphafluorene" (phenyl-5H-benzol[b]-phosphindole) as reported
[ ]
by T.K. Miyamoto et al. 195 in the case of simple 2,2'-dilithiobiphenyl. The formation of the
unexpected 9-phenyl-9-phosphafluorene was reinvestigated by O. Desponds and
[ ]
M. Schlosser 196 , who postulated a concerted mechanism for the cyclization process and
subsequent formation of triphenylphosphine. However, this mechanism seems possible
provided that the Phenyl–P and Li–biphenyl bonds are either coaxial or close enough to
interact during free rotation around the biphenyl single bond, which would imply a relatively
small dihedral angle of the biphenyl unit. This undesired side reaction was in fact avoided by
slow addition of a diluted solution of chlorodiphenylphosphine to the lithiated species in order
to maintain the temperature below- 70 °C, thus "freezing" rotation about the biphenyl sp 2 -sp 2
pivot bond.

50
At first, bis(phenol ether) 7 was subjected to a double halogen/metal permutation
followed by addition chlorodiphenylphosphine to form the well characterized
MeO-BIPHEP 42 [16] in 64% yield. Since rotatory power obtained and those reported by
R. Schmid et al. for enantiopure MeO-BIPHEP (ee > 99%) happened to be the same, no
racemization must have occurred upon lithiation of the optically pure dibromobiphenyl 35.
Furthermore, this result permitted the deduction of the enantiomeric excess of the resolved
biphenol 31 (ee > 99%). On the other hand, the ease and rapidity to obtain ligand 42 in
enantiopure form with good overall yield showed the efficiency of the method developed.
Br
Br
O
O
(P)-(-)-35
LiC 4H 9 (2.0 eq.)
Tol./DEE (9:1)
- 75 °C to - 40 °C, 1 h
Li
Li
O
O
ClPPh 2 (2.0 eq.)
Tol., - 75 °C
Ph2P Ph2P O
O
(P)-(+)-MeO-BIPHEP 42, 64%
Another "BIPHEP-type" bisphosphine was prepared starting from diethoxyphenol
ether 36. This substrate was consecutively treated with four equivalents of tert-butyllithium in
tetrahydrofuran at -75 °C, and two equivalents of chlorodiphenylphosphine to afford (6,6’-
diethoxybiphenyl-2,2’-diyl)bis(diphenylphosphine) ("EtO-BIPHEP"; 43) in high yield (85%).
The enantiomeric excess of bisphosphine 43 thus produced was then determined by chiral
High Pressure Liquid Chromatography (HPLC). Thus each pure atropisomer was compared
with the racemic mixture under the same conditions, and ee was determined to be above 99%.
Br
Br
O
O
(P)-(-)-36
LiC(CH 3) 3 (2.0 eq.)
THF, - 75 °C, 30 min
Li
Li
O
O
ClPPh 2 (2.0 eq.)
Tol., - 75 °C
Ph2P Ph2P O
O
(P)-(+)-43, 85%
A single-crystal X-ray analysis has been carried out for (M)-(-)-43 (Figure 4)
The dihedral angle θ (C8-C7-C6-C1) was determined to be of 73.9 ° which is slightly larger
that the value found for its MeO-BIPHEP congener (70.3 °). X. Zhang [172] showed, for the
asymmetric hydrogenation of β-ketoesters, that a change of only 3 ° in the biphenyl torsion
angle could increase the enantioselectivities (ee) from 86% to 96% depending on the
[ ] 197 .

51
substrates considered. In consequence, since the biphenyl dihedral angle is correlated to its
natural bite angle (β) in the metal complexes [198 - 200] , the slight difference in dihedral angle
observed between MeO-BIPHEP and bisphosphine 43, can be exploited to fine-tune a given
reaction selectivity and increase ee of products obtained.
Figure 4. Stereoscopic drawing of (M)-(-)-43.
A last couple of enantiomerically pure bisphosphines was prepared in the biphenol
series, starting from (P)-(-)- or (M)-(-)-2,2’-dibromo-6,6’-bis(methoxymethoxy) biphenyl
(34). The usual organometallic treatment followed by addition of chlorodiphenylphosphine
provided the expected chiral [6,6’-bis(methoxymethoxy)biphenyl-2,2’-diyl]bis
(diphenylphosphine) ("MOMO-BIPHEP"; 44) in 69% yield, with ee > 99% according to
chiral HPLC analysis.
Br
Br
O
O
(P)-(-)-34
O
O
LiC(CH 3) 3 (2.0 eq.)
THF, - 75 °C, 30 min
Li
Li
O
O
O
O
ClPPh 2 (2.0 eq.)
Tol., - 75 °C
Ph2P Ph2P O
O
(P)-(+)-44, 69%
O
O

52
A single-crystal X-ray analysis of pure (M)-(-)-44 (Figure 5) [197] revealed a
particular configuration of the ligand. Contrary to the alkyl chains in bisphosphine 43, the two
terminal methyl groups in the acetal chain of 44 are facing each other. The resulting torsional
angle θ (C1A-C6A-C7A-C8A) was found to be of 84.4 °.
Figure 5. Stereoscopic drawing of (M)-(-)-44.
Finally, dimethyl ether 41, derived from optically pure diol 39, was also converted to
its corresponding bis(diphenylphosphine) derivative 45 under the same conditions. This
bisphosphine only differs from its phenolic equivalent 42 by the additional carbon in the
hydrocarbon chain.
Br
Br
(P)-(-)-41
O
O
LiC(CH 3) (2.0 eq.)
THF, - 75 °C, 30 min
Li
Li
O
O
ClPPh 2 (2.0 eq.)
Tol., - 75 °C
Ph 2P
Ph 2P
O
O
(P)-(+)-45, 74%

53
Single-crystal X-ray analysis of pure (-)-45 (Figure 6) [197] afforded the determination
of its absolute configuration which was found to correspond to (M) atropisomer. The dihedral
angle θ (C1A-C6A-C6-C1) was determined to be of 88.3 °, which is, this time, more
comparable to that of BIPHEMP (91 °) or BINAP (87 °) ligands.
Figure 6. Stereoscopic drawing of (M)-(-)-45.
4.4 Dynamic 1 H-NMR Study of Some Biphenyl Substrates
In the course of the previously detailed synthesis, the formation of various
enantiomerically pure 2,2'-dilithiobiphenyls without detectable loss of their optical activity
raised questions about their exact thermal stability towards rotation about the biphenyl single
bond. Since literature data concerning rotational barriers of dilithiobiaryls are somewhat
sporadic and essentially concern binaphthyl units
[55 - 57, 201, ] 202 , some of the dibromobiphenyls
prepared were converted to their dilithio congeners and subjected to dynamic nuclear
magnetic resonance experiments.

4.4.1 The Use of Variable-Temperature NMR to Study Intramolecular
Mobility
54
Intramolecular movements in rotational isomers can in principle be studied by
various spectroscopic methods e.g. Raman, infrared, microwave or NMR
spectroscopy
enriched materials
[ , ] 203 204 or by kinetic measurements of the racemization process for enantio-
[ ] 205 . However, each one of these techniques remains limited, to a certain
extent, either by the rate of the rotational process considered, or by the structural complexity
of the substrate investigated or even by the ease to access optically active substrates.
Vibration spectroscopy techniques can be used for the determination of rotamer populations
in case of very fast exchange processes with activation energy lower than 5 kcal·mol -1 [204] .
Furthermore, these techniques are solely applicable to relatively simple structures since
absorption bands for both rotamers should be clearly distinct in the spectrum to afford
accurate data. NMR spectroscopy has an advantage over vibration spectroscopies in the study
of rotational isomers owing to the fact that the intensities of signals are directly proportional
to the number of nuclei at the magnetic site. In addition, NMR technique, due to its "time
scale", afford the study of slower rotational process with activation energies of 5 to
-1 [ a, ]
25 kcal·mol 206 207 , which constitute the usual range of value for sterically little
encumbered biphenyls.
In the rotation about a bond in a molecule, there are certain energetically favoured
conformations. For instance, in biphenyl derivatives where free rotation about the pivot bond
is hindered by ortho- substituents, a coplanar arrangement of the aromatic rings corresponds
to an energy maximum. As a consequence, such kind of substrate are twisted in the ground
state to minimize their energy level
C
D
[ ] 208 .
A
B
k r
C
B
Ia Ib
A
D

55
To convert atropisomer Ia into Ib, it is necessary to supply the required free enthalpy
of activation ∆G ≠ (Ia-Ib). The magnitude of this free enthalpy determines the rate of the
thermally induced isomerization and is evidently depending on the temperature of study. The
rate constant kr of this process is related to ∆G ≠ (Ia-Ib) in accordance with the Eyring equation,
where T is the absolute temperature, R is the universal gas constant, kb is the Boltzmann's
constant, h is Planck's constant and κ is the transmission coefficient:
or
k
r
∆
= κ ⋅ k
b
⋅T
⋅ h
−1
⎛ − ∆
exp ⎜
⎝ RT
≠
G( Ia - Ib)
⎞
⎟
⎠
⎡
⎛ T ⎞⎤
⋅T
⎢10.
321+
log
⎜
⎟
⎟⎥
⎢⎣
⎝ kr
⎠⎥⎦
≠
−3
G (Ia - Ib) = 4.
57 ⋅10
(kcal·mol -1 )
Whenever rotation is too fast to allow isolation of isomers on laboratory time scale
(i.e. ∆G ≠ (Ia-Ib) < 22 kcal·mol -1 ), rapid racemization processes in chiral biphenyls can be
detected by NMR spectroscopy provided that the investigated substrate bears a diastereotopic
pair of NMR-active nuclei (e.g. A = B = -CH2R with A ≠ C and B ≠ D). Under this condition,
two types of magnetically non-equivalent hydrogens do exist, resulting from the hampered
rotation about the biphenyl single bond. The intramolecular rotation can thus be revealed by
the temperature dependence of the magnetic environment for the diastereotopic probes.
Hence, at low temperature, "slow" isomerization leads to two separate NMR signals for both
diastereotopic hydrogens whereas at higher temperature, "fast" rotation gives only one signal
with an average chemical shift.
W. L. Meyer and R.B. Meyer
[ ] 209 reported the first example of temperature-
dependent 1 H-NMR spectrum for "methylene-bearing" biphenyls. For instance, 2,2'-
bis(acetoxymethyl)biphenyl (46) exhibited an AB quartet signal for the methylene hydrogens
at ambient temperature, whereas the pattern collapse into a broad singlet at Tc = 94 °C
(Figure 7).

T > Tc
T = Tc
T < Tc
T

57
This finally allows one to use the Eyring equation to calculate the energy barrier for
free rotation at the coalescence temperature. Making the appropriate substitution in the Eyring
equation, one obtains:
∆G
≠
coal
=
4.
57⋅10
−3
⎡ ⎛
⎢ ⎜ Tc
⋅Tc
9.
972 + log
⎢ ⎜ 2
⎣ ⎝ ∆ν
+ 6 J
2
AB
⎞⎤
⎟⎥
⎟
⎠
⎥
⎦
(kcal·mol -1 )
4.4.2 Coalescence Study of 2,2’-Dilithio-6,6’-bis(methoxymethoxy)
biphenyl
The variable-temperature 1 H-NMR method was first employed to evaluate the
rotational barrier of the 6,6'-dilithiobiphenyl-2,2'-diol motif. Since the presence of a
suitable diastereotopic probe is required for such thermodynamical investigation, the two
hydroxyl functions in 31 were protected by reaction with chloromethyl methyl ether to
form 34 (see § 4.1.3). Indeed, the 1 H-NMR spectrum of methoxymethoxy-protected
biphenol 34 showed two distinct doublets (coupled AB system) for the methylene
hydrogens at ambient temperature, revealing their magnetic non-equivalence and
anisochrony. Dibromobiphenyl 34 was finally treated with four equivalents of tert-
butyllithium in perdeuterated tetrahydrofuran at -75 °C to generate the reactive 2,2’-
dilithio-6,6’-bis(methoxymethoxy)biphenyl (47).
HB HA Li
O
O
Li
47
O
O
Several 1 H-NMR spectra of 19 were then recorded at various temperatures,
starting from -50 °C and increasing it gradually until the AB-system "quartet" collapsed
into a broad singlet. To prove the reproducibility of the rotational process observed and
check wether no decomposition occurred, several spectra were then recorded while
lowering back the temperature from the coalescence to -50 °C. In this way, the
coalescence temperature was precisely determined to be Tc = -11 ± 1 °C and thus, the
HB HA

58
≠
-1
torsional barrier at that temperature was found to amount G = 11.7 ± 0.3 kcal·mol . A
full lineshape analysis was eventually achieved
∆ coal
[ ] 211 to evaluate the variation of the
rotation rate constant as a function of the temperature. An Eyring plot of ln(k/T) as a
function of 1000/T afforded a reasonable correlation (R² = 0.972) and gave a calculated
enthalpy ∆ =
≠
H 12.5 kcal·mol -1 and entropy ∆ = - 0.5 cal·mol
≠
-1 -1
S
·K . Evaluation of the
reaction order for the exchange process observed would probably help to get a better idea
about the aggregation state which possibly facilitates, or on the contrary, lowers the
rotation about the biphenyl bond. To achieve this aim, several coalescence experiments
were donein the same conditions as previously described but varying various parameters.
Thus the stoichiometry of the lithiating was first lowered to two equivalents, leaving two
equivalents of tert-butyl bromide in presence in the reaction mixture. Although the 1 H-
NMR spectra of the lithiated biphenyl generated were presented traces of impurities in the
high field zone, the coalescence temperature observed in the same experimental
conditions (concentration, solvent) was sensibly the same, indicating no major influence
of the tert-butyllithium concentration on the dilithiobiphenyl rotation. Attempts to
perform the same experiment with more than four equivalents of tert-butyllithium (excess
of lithiating reagent remaining in the reaction mixture) resulted in unexploitable spectra.
This fact is presumably due to the low stability of tert-butyllithium towards
tetrahydrofuran attack
[ ] 212 . Butyllithium was also used instead of tert-butyllithium to
generate the expected dilithiobiphenyl, in order to check the implication of the lithiation
reagent in a possible aggregate. Unfortunately, this reagent did not allow complete
lithium/bromine permutational exchange at the usual reaction temperature, giving a
mixture of brominated and lithiated biphenyl. This mixture of compounds did not allow
accurate determination of the coalescence temperature since the four doublets of
diastereotopic protons were partially overlapping. Finally, the experiment was tried once
more, increasing the concentration from 0.09 M initially chosen to 0.19 M. The coalescence
temperature was determined to be of Tc = -10 ± 1 °C which did not constitute a significant
difference in torsional barrier compared to what was calculated previously. Increasing
concentration resulted in the precipitation of the lithiated species formed, thus preventing
any NMR experiments. These modifications of the reaction parmeters, showing no
significant deviation compared to the initial experiments performed, suggested that the
rotational barrier calculated by means of this NMR study is independent from aggregation
factors. The free rotation of the biphenyl motif about the pivot single bond seemingly
occurs in a monomolecular process. However, since the energy required for the
"aggregation/disaggregation" process usually falls in the range of few kcal.mol -1 , it is
probable that NMR technique do not reveal such difference in energy. On the other hand,

the steric bulk and charge delocalization are accepted to disfavor aggregation
59
[ ] 213 and
could thus provide an explaination for the apparent unsensitivity of the dilithiobiphenyl
toward reaction parameters' variation. Furthermore, the entropy value calculated thanks to
the full lineshape analysis performed, is somewhat close to 0 and suggested that the
rotational process studied is happening as a monomolecular internal rotation. This
deduced fact tends to confirm the data collected experimentally by changing concentration
or stoichiometry of the lithiating reagent.
Accuracy of the results obtained by variable temperature "dynamic" NMR
experiments (DNMR) has been extensively discussed in many text books [206b, 214, 215] and
stems from two main factors. First of all, the equation used for the determination of
is derived from approximations, which obviously induce some deviations in the calculated
parameter. On the other hand, the determination of the coalescence temperature is the
major experimental source of error
≠
∆Gcoal [ 216 ]
. Indeed, M.L. Martin, J.J Delpuech and G.J.
Martin [215] evaluated that overestimating Tc by 2 °C at - 73 °C and for ∆ν = 20 Hz,
≠
-1
resulted in an increase of G of 0.1 kcal·mol . This error could be minimized
∆ coal
experimentally by calibrating the NMR temperature probe by means of a platinum
thermocouple, and by slowly increasing the temperature in the region around coalescence.
Although some thermodynamical data were available for o,o'-dilithiobiphenyl
derivatives [202, 59] , it was not yet possible to compare the value calculated with pertinent
examples since no literature precedents were reported for similar substrates. However,
O. Desponds and M. Schlosser [59] found the torsional barrier of 1,11-dilithio-5,5,7,7-
tetramethyl-5,7-dihydrodibenz[c,e]oxepin (48) to fall in the range of 12.0 - 12.5
kcal·mol -1 .
Li
O
48
Li
The fact that ortho- and ortho'- oxygen atoms should cause less steric repulsion
than isopropylidene groups at the same positions, and the presence of a rigid bridged
structure would bring to the conclusion that the oxepin derivative should have a much
higher energy barrier that biphenyl 47. Furthermore, despite the important steric
congestion, the bridge in the biphenyl structure forces the gem-dimethyl groups to face

60
each in the coplanar transition state. This steric constraint causes this configuration to be
energetically very high, thus contributing to a significant increase in activation energy
compared to unbridged dilithiobiphenyls. Contrary to all expectations, the torsional value
calculated for biphenyl 47 only varies from that of compound 48 by approximately 0.5
kcal·mol -1 . An explanation could be tentatively proposed with two arguments: first,
oxygen atoms, even if less bulky than isopropylidene groups, exert an electronic repulsion
thanks to their nonbonding electrons ("lone pairs"), thus increasing the coplanar transition
state energy. In addition, since the methoxymethoxy protective group is known to
efficiently coordinate lithium species
[ ] 217 , it could favor a twisted conformation and
induce some rigidity in the biphenyl motif by coordinating a lithium placed on the
adjacent aromatic ring.
Li
O
O
47
O
Li
O
4.4.3 Coalescence Study of 2,2’-Dilithio-6,6’-bis(methoxymethyl)biphenyl
Contrary to the previously investigated substrate, bis(hydromethyl) biphenyl 39 was
protected by conversion to its corresponding dimethyl ether 41 rather than with dimethoxymethoxy
group since the latter was partially prone to α-deprotonation and subsequent Wittig rearrangement
219 ]
upon treatment with organolithium reagents. 2,2’-Dilithio-6,6’-bis(methoxymethyl)biphenyl (49)
was generated by treatment of the corresponding dibromo derivative 41 with four equivalents of tert-
butyllithium in perdeuterated tetrahydrofuran at -75 °C.
The 1 H-NMR spectrum of dilithio- species 49 showed, once again, two distinct doublets
with a significant "roof effect", corresponding to the diastereotopic methylene hydrogens of the
hydromethyl- groups. The line shape variation of these signals was followed as a function of the
increasing temperature (Figure 8a) and displayed coalescence at Tc = 24 ± 1 °C, which eventually
≠
allowed to calculate an energy barrier to free rotation of G = 12.9 ± 0.2 kcal·mol
∆ coal
-1 .
[ 218,

61
To check the reproducibility of the isomerisation process and be sure that
decomposition of the dilithiated substrate occured, several other spectra were recorded while
decreasing back the temperature until –50 °C (Figure 8b)
T = 35 °C
T = 24 °C
T = 20 °C
T = 10 °C
T = 0 °C
T = - 10 °C
.
O
HA Li
HB Li
HB HA 21
O
T = 10 °C
T = 0 °C
T = - 10 °C
T = - 30 °C T = - 25 °C
T = - 50 °C T = - 50 °C
4.16 4.14 4.12 4.10 4.08 4.06 4.04 4.02
4.16 4.14 4.12 4.10 4.08 4.06 4.04 4.02
Figure 8. Temperature dependence of the 1 H-NMR (400 MHz) methylene
signals of 21 in perdeuterated tetrahydrofuran: (a) increase in temperature from
- 50 °C to 35 °C (left) and (b) reversible decrease to – 50 °C (right).
For the same purpose as previously reported, the concentration and the
stoichiometry of the lithiating reagent were varied and further 1 H-NMR spectra were
recorded. The coalescence temperature observed in all cases was once again unsensitive to
such modifications, suggesting a monomolecular process. These experimental
observations, as proposed in chapter 4.4.2, could possibly be explained by steric bulk and
charge delocalization arguments. Following the same trend as dilithiobiphenyl 47,
compound 49 showed, this time, an even larger activation barrier than dilithiobenzoxepin

62
48. This experimental result could once more be explained by possible lithium-oxygen
coordination, forcing the biphenyl unit to adopt a rigid twisted conformation, similarly as
would a carbon-bridge do.
A full lineshape analysis was also performed on dilithiobiphenyl 49 [211] (Figure 9) and Eyring
plot of the rate constant obtained (Graphic 1), revealed an activation enthalpy of ∆ =
≠
H 15.1
kcal·mol -1 and entropy of ∆ = 0.2 cal·mol
≠
-1 -1
S
·K (R² = 0.9655). It should be noticed that an
extremely accurate lineshape fitting was best achieved at high temperature since shim at very
low temperature (-50 °C) was tedious and rendered the spectrum base line "noisy" to some
extent. The low value of entropy found by calculation also helped to confirm that the
rotational isomerisation of the dilithiobiphenyl considered occurs as a monomolecular
phenomenon. The activation free enthalpy experimentally determined should thus be devoid
of aggregation factors.
ln(k/T)
25
20
15
10
5
0
-5
-10
-15
Li
O
49
Li
O
y = -7,6208x + 23,84
R 2 = 0,9655
0 1 2 3 4
5
1000/T
Graphic 1. Eyring plot ln(k/T) = f(1000/T) determined from the
full lineshape analysis of dilithiobiphenyl 49.

63
Figure 9. Full lineshape analysis of dilithiobiphenyl 49: experimental spectra at various
temperature (left) and corresponding rate constant for simulated spectra (left).

65
5 Conclusions and Outlook
Several fields of the phosphorus chemistry were studied, considering different
applications of organophosphorus compounds. First of all, new phosphine ligands have
been prepared by means of several different synthetic strategies. Achiral monodentate
tertiary phosphines were efficiently obtained, taking profit of organometallic techniques.
Several simple arylmetals generated by means of direct proton abstraction ("metalation")
or halogen/metal permutational exchange, have been treated with triethyl phosphites to
produce tertiary phosphines with excellent yields. Since this method proved to be
applicable to various structurally different substrates, more elaborated phosphines were
prepared by treatment of furyl or pyrrolyl derivatives. These phosphines could be used
for several types of cross coupling reactions and should widen the field of their
applications.
The field of asymmetric catalysis was also addressed by preparing chiral
bidentate phosphines. By successive halogen/lithium permutational exchanges on the
pivot starting substrate 2,2',6,6'-tetrabromobiphenyl, a panel of biphenylbisphosphines
was efficiently prepared in both enantiomerically pure forms. The method devised
allowed an important modularity of the ligands' structure, but also advantageously relied
on an early racemate resolution step. Furthermore, changing the biphenyl substitution
pattern permitted to vary the dihedral angle of the atropisomeric bisphosphines, which to
some extent can drastically increase the yields and selectivities of a catalytic reaction
process.
The generation of dilithiobiaryls to prepare a series of a biphenylbisphosphines
also gave the opportunity to determine their thermal and rotational stability. Biaryl
motifs are not only present in various chiral ligands but also in many natural products.
This observation made dilithiobiaryls very useful transient species since they can be
functionalized at will with different electrophiles. The crucial issue whether
enantiomerically pure dilithiobiphenyls could be generated and used without any loss of
their optical activity, was addressed. Dynamic NMR studies were conducted for two

66
suitably substituted dilithiobiphenyls and allowed rotational activation barrier to be
calculated. Correlation of the results obtained with known literature data suggested a
coordinative interaction between the lithium and oxygen atoms, causing a higher
activation energy than envisioned. As a matter of fact, in both cases the free enthalpy
values determined fell in the same range as those of bridged dilithiobiaryls, which
supported the idea of an internal rigidity induced by the lithium-oxygen coordination.
These assumptions should certainly be supported by a comparative study
between the dilithiobiphenyls used and their metal-free congeners (H instead of Li). In
the lithiated species, the two lithium atoms should logically tend to seek the proximity
of the oxygens and coordinate them, causing a certain rigidity of the molecule. In
contrast, it would be highly plausible that, in the metal-free congeners, no coordination,
thus no additional constraints exist in the biphenyl unit. In this eventuality, the
rotational activation barrier should be lower in the case of metal-free species,
corroborating the proposed hypothesis. Other usefull informations could possibly be
obtain by replacing the coordinating oxygens in the biphenyls used, by nitrogen or
carbon atom.
Finally, various phosphonium salts and phosphine oxides were prepared to
address another field of application of organophosphorus compounds. These substrates
served as probes for assessing relative stabilities of several alkyl carbanions. Based on
the use of the alkaline decomposition of phosphonium salts, the method developed was
meant to accurately determine differences in ease of cleavage between several alkyl
substituents and was believed to directly correlate to their corresponding carbanions
basicity. The data collected in this work provided unprecedented informations
concerning secondary and tertiary alkyl carbanions in solution. When available, gas
phase basicities of alkyl anions were compared to the results obtained by alkaline
decomposition of phosphoniums salts. The relative stabilities observed in solution were
coherent with the observed experimental reactivity but did parallel inverse order of the
reported gas phase results, as one could expect.
To provide a better overview on the factors influencing the alkaline
decompositionof phosphonium salts, it would be interesting to perform other
decompositions with phosphonium of the type RnR'pP + , X - where n and p would be
varied. These experiments would hopefully allow an estimation of the effective
importance of internal strains on the cleavage of the P–C bond from phosphonium salts.

67
If the ratio of the products formed does not appear to be depending on the substitution
pattern, it would be legitimate to believe that the steric strains do not significantly
influence the departure of a given substituent.
In the latter hypothesis, and to provide a more complete overview of the alkyl
carbanions basicities in solution, it would be useful to perform further experiments with
phosphonium salts bearing very similar alkyl substituents, in order to build a "step by
step" scale of basicity. On the other hand, since the alkaline decomposition of
phosphonium salt appeared to be an effective method to assess the relative basicities of
carbanionic species, it would be of interest to perform a systematic basicity assessment
with several phosphonium halides bearing various substituted aryl groups. These results
could then be correlated with those obtained for the same substrates, by means of other
methods. For instance, the relative basicities of methoxy-, trifluoromethyl-, or
haloarenes
[ ] 220 determined with both methods, could be compared to evaluate the
reliability of the values determined and the impact of solvents or aggregation effects.
X'
X OH
P
OH X'
+ O P
X
P O
∆G1 X
∆G2 X'
X, X' = OCH 3, CF 3, F, Cl
+ X

Experimental Part

1 Generalities
69
Commercial starting materials were purchased from Fluka AG (CH-9479 Buchs), Aldrich
(CH-9479 Buchs) or Acros Organics (B-2440 Geel). Their purity was checked before use adequately
(melting ranges, refractive index or gas chromatography). When known compounds where prepared
according to a literature procedure, pertinent references are given.
Butyllithium and tert-butyllithium were supplied by CheMetall, D-60478 Frankfurt. The titre
of these solutions was determined by double titration
[ ] 221 . Air and moisture sensitive compounds
were stored in Schlenk tubes or Schlenk burettes. They were kept and handled under an atmosphere of
99.995% pure nitrogen, using appropriate glassware (Glasgerätebau, Pfeifer, D-98711 Frauenwald).
Anhydrous diethyl ether and tetrahydrofuran were obtained by careful distillation from
[ ]
sodium wire after the characteristic blue color of in situ generated sodium diphenylketyl 222 was
found to persist. They were stored in Schlenk burettes under nitrogen atmosphere. Hexane was
distilled from lithium aluminum hydride after four hours stirring over the drying agent. Toluene was
dried azeotropically and stored over molecular sieves. Amines were distilled and stored over
potassium hydroxide pellets.
Reactions at low temperatures were performed using cold baths: water/ice at 0 °C,
water/ice/sodium chloride at -20 °C, ethanol/dry ice at -75 °C and diethyl ether/liquid nitrogen at
-100 °C. The temperature of ethanol/dry ice bath is consistently indicated as -75 °C and "room
temperature" as 25 °C.
Melting ranges (m.p.) are reproducible after resolidification unless otherwise stated
("decomp."), and were corrected using a calibration curve established with authentic standards
(Signotherm, furnished by Merck, CH-8029 Zürich). If no melting point is given, all attempts to
crystallize the liquid failed even at temperatures as low as -75 °C. Boiling ranges (b.p.) stated with no
precision of pressure were determined under ordinary atmospheric conditions (760 ± 25 Torr).
Nuclear magnetic resonance spectra of hydrogen ( 1 H-NMR), carbon ( 13 C-NMR),
phosphorus ( 31 P-NMR) and fluorine nuclei ( 19 F-NMR) were recorded from samples dissolved in

70
deuterochloroform (CDCl3) unless otherwise stated, at 400 MHz, 101 MHz, 162 MHz and 376 MHz
respectively, and with a Bruker DPX-400 spectrometer. The chemical shifts δ given are relative to the
signal of tetramethylsilane (δ 0.00 ppm) for 1 H-NMR and 13 C-NMR, and to trichlorofluoromethane
(δ 0.00 ppm) for 19 F-NMR. For the 31 P-NMR spectra, a 85% solution of phosphoric acid was used as
an external standard (δ 0.00 ppm). Variable-temperature 1 H-NMR studies were performed in
perdeuterated tetrahydrofuran, chemical shifts referring to the residual signal of the non deuterated
tetrahydrofuran (δ 3.58 ppm). The absolute values of the temperatures were determined by means of a
methanol probe
[ , ] 223 224 . Coupling constants (J) are given in Hz. Coupling patterns are described by
abbreviations: s (singlet), d (doublet), t (triplet), q (quartet), quint (quintet), m (multiplet), symm. m
(symmetrical multiplet). Composite patterns (dd, dt for example) are arranged according to decreasing
coupling constants.
Optical rotations were measured on a Perkin Elmer polarimeter 341, specific rotations being
indicated at the mentioned wave length (nm), concentration (g/100 mL), and solvent.
Mass spectra (Finnigan 4000 or Nermag R 10-10 spectrometer) were obtained by chemical
ionisation at 95.3 eV and at a source temperature of 100 °C in an ammonia atmosphere. The numbers
given in the parentheses indicate the intensities relative to the base peak (100%).
Elemental analyses were performed by the laboratories of I. Beetz, (D-96301 Kronach) or
Solvias (CH-4002 Basel). The expected percentages were calculated using the atomic weight numbers
listed in 2000 IUPAC recommendations.
X-ray diffraction analyses were performed with an Oxford Diffraction/Kuma diffractometer
having a kappa geometry and a CCD KM4CCD/Sapphire detector for 44 and 45 and with an IP
mar345 for 43. The software Crysalis RED
[ ]
structure was resolved and refined with SHELXTL version 5.1 226 .
[ ] 225 was used to determine the crystallographic data. The
If no literature quotation is associated with a compound, it means either that it had not been
previously described at all or without sufficient characterization. The literature search was performed
with the aid of Chemical Abstracts, Beilstein Crossfire and Scifinder and covers the period from 1900
up to February 2005.

2 The Preparation of Phosphines from Triethyl phosphite
2.1 Triarylphosphines
71
General procedure for the preparation of triarylphosphines: At -75 °C, butyllithium
(0.15 mol) in hexanes (0.10 L) was added to a solution of a bromo- or iodoarene (0.15 mol) in
tetrahydrofuran (0.30 L). Triethyl phosphite (8.7 mL, 8.3 g, 50 mmol) was added at -75 °C
and the suspension was stirred at 25 °C until Gilman color test I
[ ] 227 did not show the
presence of any organolithium reagent. The volatiles were evaporated and the crude product
was crystallized from ethanol to afford the desired compound.
Tris(4-methoxyphenyl)phosphine (1): Prepared from 1-bromo-4-methoxybenzene (28 g,
0.15 mol); colorless needles; m.p. 129 - 131 °C (ref. [80] m.p. 129 - 131 °C); yield: 17.5 g
(99%).
1 H NMR: δ = 7.2 (m, 6 H), 6.87 (dd, J = 9, 1 Hz, 6 H), 3.80 (s, 9 H) ppm.
13 C NMR: δ = 160.5, 135.2 (d, J = 21 Hz), 134.1 (d, J = 11 Hz), 114.1 (d,
J = 7 Hz), 55.2 ppm.
31 P NMR: δ = - 9.5 ppm.
MS: 352 (100%, M + ), 138 (48%).
Tris(2-methoxyphenyl)phosphine (2): Prepared from 1-bromo-2-methoxybenzene (28 g,
0.15 mol); colorless needles; m.p. 208 - 210 °C (ref. [81] m.p. 209 - 210 °C); yield: 17.4 g
(99%).

72
1 H NMR: δ = 7.32 (dddd, J = 9, 8, 2, 1, 3 H), 6.89 (ddd, J = 8, 5, 1 Hz, 3 H), 6.83
(t, J = 7 Hz, 3 H), 6.69 (ddd, J = 8, 5, 2 Hz, 3 H), 3.74 (s, 9 H) ppm.
13 C NMR: δ = 161.6 (d, J = 17 Hz), 134.2, 129.9, 124.7 (d, J = 13 Hz), 120.9 (d,
J = 2 Hz), 110.3, 56.1 ppm.
31 P NMR: δ = - 36.8 ppm.
MS: 353 (31%, M + + 1), 84 (100%).
Tris[4-(N,N-dimethylamino)phenyl]phosphine (3): Prepared from 4-bromo-N,N-
dimethylaniline (30 g, 0.15 mol); colorless needles; m.p. 267 - 269 °C (ref. [82] m.p. 265 -
275 °C); yield: 19.5 g (83%).
1 H NMR: δ = 7.28 (symm. m, 6 H), 6.57 (symm. m, 6 H), 2.92 (s, 18 H) ppm.
13 C NMR: δ = 149.7, 131.7 (d, J = 12 Hz), 114.1, 108.7, 40.7 ppm.
31 P NMR: δ = - 128.0 ppm.
MS: 392 (4%, M + ), 137 (100%), 120 (96%).
Tris(1-naphthyl)phosphine (4): Prepared from 1-bromonaphthalene (31 g, 0.15 mol). After
two successive recrystallizations from ethanol, the expected product was obtained as colorless
needles; m.p. 261 - 264 °C (ref. [83] m.p. 261 - 265 °C); yield: 17.8 g (86%).
1 H NMR: δ = 8.3 (m, 3 H), 7.8 (m, 6 H), 7.56 (dd, J = 6.7, 5.4 Hz, 3 H), 7.3 (m,
9 H) ppm.
13 C NMR: δ = 138.2 (d, J = 20 Hz), 133.7 (d, J = 20 Hz), 133.5 (d, J = 3 Hz),
129.9 (s), 128.9 (d, J = 6 Hz), 128.5 (d, J = 2 Hz), 126.0 (d, J = 2 Hz), 125.7 (d,
J = 1 Hz), 125.3 (d, J = 2 Hz), 125.1 (d, J = 3 Hz) ppm.
31 P NMR: δ = -32.4 ppm.

73
MS: 412 (5%, M + ), 301 (44%), 173 (100%), 141 (62%).
Ethylbis(1-naphthyl)phosphinite (5): This compound was obtained as a by-product in the
mother liquors, after recrystallization of the tris(1-naphthyl)phosphine (4). The solvent was
evaporated and the crude solid recrystallized from ethanol to afford colorless needles; m.p. 96
- 98 °C; yield: 1.03 g (5.2%).
1 H NMR: δ = 8.4 (m, 2 H), 7.9 (m, 4 H), 7.62 (ddd, J = 6.7, 5.4, 1.3 Hz, 2 H), 7.4
(m, 6 H), 4.05 (qd, J = 9.6, 7.0 Hz, 2 H), 1.35 (t, J = 7.0 Hz) ppm.
13 C NMR: δ = 137.6 (d, J = 21 Hz), 134.8 (d, J = 22 Hz), 133.7 (d, J = 4 Hz),
130.1, 129.9 (d, J = 7 Hz), 129.1 (d, J = 2 Hz), 126.6 (d, J = 2 Hz), 126.2 (d, J = 1
Hz), 125.9 (d, J = 3 Hz), 125.5 (d, J = 3 Hz), 66.8 (d, J = 21 Hz), 17.2 (d,
J = 8 Hz) ppm.
31 P NMR: δ = 104.7 ppm.
MS: 331 (64%, M + + 1), 301 (19%), 173 (49%), 128 (100%).
C22H19OP (330.12) calcd. C 79.98% H 5.80%
Found C 79.97% H 5.88%.
Tris(2-naphthyl)phosphine (6): Prepared from 2-bromonaphthalene (31 g, 0.15 mol);
colorless needles; m.p. 261 - 264 °C (ref. [84] no physical constants reported); yield: 17.2 g
(83%).
1 H NMR: δ = 7.89 (d, J = 8.6, 3 H), 7.82 (t, J = 9.0 Hz, 6 H), 7.73 (d, J = 7.9 Hz,
3 H), 7.5 (m, 9 H) ppm.
13 C NMR: δ = 134.7 (d, J = 11 Hz), 134.5 (d, J = 22 Hz), 133.7, 133.6 (d,
J = 8 Hz), 130.5 (d, J = 18 Hz), 128.5, 128.2 (d, J = 7 Hz), 128.2, 127.0,
126.5 ppm.
31 P NMR: δ = -17.1 ppm.
Tris(3,5-dimethylphenyl)phosphine (7): Prepared from 3,5-dimethyl-iodobenzene (35 g, 0.15
mol) [79] ; colorless needles; m.p. 158 - 160 °C (ref. [85] m.p. 160 - 162 °C); yield: 14.0 g (81%).

1 H NMR: δ = 6.96 (s, 3 H), 6.94 (d, J = 8.6 Hz, 3 H), 2.27 (s, 18 H) ppm.
74
13 C NMR: δ = 139.9, 135.0 (d, J = 12.1 Hz), 129.3, 94.3 (d, J = 16.3 Hz),
20.9 ppm.
31 P NMR: δ = -5.7 ppm.
2.2 Furanylphosphines
Tris(5-methyl-2-furyl)phosphine (8): At -75 °C, butyllithium (90 mmol) in hexanes (61 mL)
was added dropwise to a solution of 2-methylfuran (8.1 mL, 7.4 g, 90 mmol) in
tetrahydrofuran (90 mL) in order to keep the temperature below –70 °C. After further 30 min
at -75 °C, triethyl phosphite (5.2 mL, 5.0 g, 30 mmol) was added. After evaporation of the
volatiles, the solid residue was crystallized from toluene to afford white platelets; m.p. 85 -
86 °C; yield: 22.8 g (92%).
1 H NMR: δ = 6.66 (dd, J = 2.9, 1.6 Hz, 3 H), 5.98 (symm. m, 3 H), 2.33 (s, 9 H)
ppm.
13 C NMR: δ = 124.6 (d, J = 22 Hz), 121.9 (d, J = 22 Hz), 107.5 (d, J = 9 Hz),
106.8 (d, J = 6 Hz), 14.0 ppm.
31 P NMR: δ = 73.1 ppm.
MS : 291 (29%, M + +NH3), 275 (7%, M + +1), 193 (100%), 151 (55%).
C15H15O3P (274.25) calcd. C 65.69% H 5.51%
found C 65.63% H 5.50%.
Tris(2-benzofuryl)phosphine (9): Benzofuran (16 mL, 18 g, 0.15 mol) in tetrahydrofuran
(0.30 L) was treated with a solution of butyllithium (0.15 mol) in hexanes (0.10 L) at -75 °C.
The white suspension formed was vigorously stirred for 2 h until Gilman color test II
revealed the absence of remaining alkyllithium in the reaction mixture. Triethyl phosphite
(8.7 mL, 8.3 g, 50 mmol) was added to the white suspension and the reaction mixture was
[ ] 228

75
allowed to reach ambient temperature. The volatiles were removed under vacuum and the
resulting solid suspended in hot ethanol (50 mL). The solid was collected by filtration,
washed with cold ethanol (40 mL) and recrystallized from ethanol to afford the product as
colorless needles; m.p. 151 - 153 °C (ref. [63] m.p. 152 - 153 °C); yield: 17.5 g (92%).
1 H NMR: δ = 7.57 (d, J = 7.6, 3 H), 7.53 (dd, J = 8.3, 0.6 Hz, 3 H), 7.32 (ddd,
J = 8.3, 7.6, 1.3 Hz, 3 H), 7.26 (dd, J = 1.9, 0.9 Hz, 3 H), 7.22 (dd, J = 7.3, 0.6 Hz,
3 H) ppm.
13 C NMR: δ = 158.5 (d, J = 4 Hz), 151.1 (d, J = 5 Hz), 128.2 (d, J = 7 Hz), 126.0,
123.4, 121.9, 118.6 (d, J = 22 Hz), 112.0 ppm.
31 P NMR: δ = -68.5 ppm.
Tris[5-(1,3-dioxolan-2-yl)-2-furyl]phosphine (11): At – 75 °C, butyllithium (0.11 mol) in
hexanes (67 mL) was added dropwise in the course of 1 h, to a solution of
2-(2-furyl)-1,3-dioxolane [94] (19; 15 g, 0.11 mol) in tetrahydrofuran (0.20 L) in order to keep
the temperature below –70 °C. Triethyl phosphite (6.1 mL, 5.8 g, 35 mmol) was slowly added
to the dark green mixture during 30 min. The volatiles were removed under reduced pressure
and the residue dissolved in ethyl acetate (0.15 L). After addition of water (0.10 L), phases
were separated and the aqueous layer was extracted with ethyl acetate (70 mL). The combined
organic phases were dried with sodium sulfate and evaporated to afford brown crystals which
were treated with activated charcoal in hot ethanol and recrystallized from methanol to give
colorless prisms; m.p. 110 - 112 °C; yield: 10.4 g (68%).
1 H NMR (acetone-d6) : δ = 6.84 (dd, J = 3.2, 1.6 Hz, 3 H), 6.54 (dd, J = 3.2,
1.6 Hz, H ), 5.92 (s, 3 H), 4.03 (symm. m., 12 H) ppm.
13 C NMR (acetone-d6) : δ = 158.4 (d, J = 3 Hz), 149.6 (d, J = 1 Hz), 122.6 (d,
J = 22 Hz), 110.3 (d, J = 6 Hz), 98.1, 65.8 ppm.
31 P NMR (acetone-d6) : δ = - 73.8 ppm.
MS : 449 (4%, M + +1), 311 (21%), 173 (39%), 141 (100%), 73 (15%).

76
C21H21O9P (448.36) calcd. C 56.25% H 4.72%
found C 56.27% H 4.74%.
Tris(5-formyl-2-furyl)phosphine (12): Pyridinium chloride (0.70 g, 6.0 mmol) and
tris[5-(1,3-dioxolan-2-yl)-2-furyl] phosphine (20; 9.0 g, 20 mmol) were heated under reflux for 20 h in a
mixture of acetone (80 mL) and water ( 5.0 mL). The reaction mixture was then allowed to cool down to
25 °C and acetone was removed under reduced pressure. Ethyl acetate (80 mL) and a saturated aqueous
solution of sodium bicarbonate (40 mL) were added and the phases were separated. The organic layer
was dried with sodium sulfate and the solvent was evaporated to afford slightly colored crystals.
Recrystallization from ethyl acetate afforded colorless prisms; m.p. 127 - 129 °C; yield: 5.44 g (88%).
1 H NMR (acetone-d6) : δ = 9.73 (d, J = 1.0 Hz, 1 H), 7.51 (dd, J = 3.5, 1.3 Hz,
1 H), 7.22 (dd, J = 3.5, 1.0 Hz, 1 H ) ppm.
13 C NMR (acetone-d6) : δ = 178.9, 158.2 (d, J = 3 Hz), 153.4 (d, J = 7 Hz), 124.8
(d, J = 19 Hz), 122.1 (d, J = 5 Hz) ppm.
31 P NMR (acetone-d6) : δ = - 66.6 ppm.
C15H9O6P (316.20) calcd. C 56.98% H 2.87%
found C 57.05% H 2.91%.
Tris(5-hydroxymethyl-2-furyl)phosphine (13): At 0 °C, sodium borohydride (1.5 g, 39
mmol) was added in one portion to a solution of tris(5-formyl-2-furyl)phosphine (21; 4.2 g,
13 mmol) in tetrahydrofuran (40 mL). The suspension was then stirred at 25 °C for 6 h
before water (30 mL) was added. Phases were separated and the aqueous layer was extracted
twice with ethyl acetate (25 mL). The combined organic layers were dried with sodium sulfate
and evaporated under reduced pressure to afford a white solid. Recrystallization from ethanol
gave colorless prisms; m.p. 165 - 167 °C; yield: 3.60 g (86%).
1 H NMR (acetone-d6) : δ = 6.77 (dd, J = 3.2, 1.6 Hz, 3 H), 6.34 (symm. m, 3 H ),
4.55 (d, J = 6.1 Hz, 6 H), 4.32 (t, J = 6.1 Hz, 3 H) ppm.
13 C NMR (acetone-d6) : δ = 161.6 (d, J = 3 Hz), 147.8 (d, J = 2 Hz), 122.6 (d, J =
21 Hz), 109.1 (d, J = 6 Hz), 56.7 ppm.

31 P NMR (acetone-d6) : δ = - 73.1 ppm.
77
C15H15O6P (322.25) calcd. C 55.91% H 4.69%
found C 55.85% H 4.65%.
2.3 Ethyl bis{N-[(1S)-1-phenylethyl]-1H-pyrrol-2-yl}phosphinite
and Other Pyrrole Derivatives
(+)-(1S)-N-(1-Phenylethyl)pyrrole (S-14): A suspension of (S)-(-)-α-methylbenzylamine
(38 mL, 36 g, 0.30 mol) in glacial acetic acid (60 mL) was heated under reflux until a yellow
solution was obtained. 2,5-Dimethoxytetrahydrofuran (39 mL, 40 g, 0.30 mol) was then added
over a period of 30 min and the resulting brown solution was heated for a further 1 h. At
25 °C, the acetic acid was removed under reduced pressure and the black viscous residue was
distilled under reduced pressure to afford a colorless liquid; b.p. 82 - 85 °C/2.1 Torr (ref. [95]
20
b.p. 116 - 117 °C/7.0 Torr); = 1.559;
(68%).
n [ ] 20
D
α = +23.5 (c = 1.0, acetonitrile); yield: 34.9 g
D
(-)-(1S)-2-Bromo-N-(1-phenylethyl)pyrrole (S-17): N-Bromosuccinimide (44 g, 0.25 mol)
was added portionwise to a solution of (+)-(1S)-N-(1-phenylethyl)pyrrole [95] (14; 43 g,
0.25 mol) in tetrahydrofuran (1.2 L) at -75 °C. Once the reagent was completely dissolved,
the pale yellow solution was allowed to reach 25 °C and the solvent was removed. The
residue was dissolved in diethyl ether (40 mL) and washed with a saturated aqueous solution
(40 mL) of hydrogen carbonate. According to gas chromatography (30 m, DB-1, 200 °C), the
ethereal solution contained 3% of 2,6-dibrominated pyrrole (18). Once the solvent was
removed, the pale yellow oil was crystallized from hexanes at -25 °C to afford the product as
20
20
colorless needles which melted after filtration; m.p. -23 to -20 °C; n = 1.5757; d = 1.331;
[ ] 20
α D
= -22.2 (c = 1.2, acetone); yield: 41.8 g (67%).
1 H NMR: δ = 7.3 (m, 2 H), 7.2 (m, 1 H), 7.1 (m, 2 H), 7.03 (dd, J = 3.3, 1.9 Hz, 1 H),
6.18 (t, J = 3.5 Hz, 1 H), 6.15 (dd, J = 3.5, 1.9 Hz, 1 H), 5.56 (q, J = 7.1 Hz, 1 H), 1.80
(d, J = 7.1 Hz, 3 H) ppm.
13 C NMR: δ = 143.5, 128.9, 127.7, 126.4, 119.7, 111.1, 109.5, 101.5, 56.8, 21.7 ppm.
MS: 251 (5%, M + + 1), 249 (5%, M + - 1), 145 (65%), 105 (100%).
D
4

78
C12H12BrN (250.13) calcd. C 57.62% H 4.84%
found C 57.63% H 4.72%.
(+)-(1R)-2-Bromo-N-(1-phenylethyl)pyrrole (R-17): Analogously prepared from
(-)-(1S)-N-(1-phenylethyl)pyrrole (9; 43 g, 0.25 mol) and N-bromosuccinimide (44 g,
20
20
0.25 mol); colorless needles; m.p. -24 to -20 °C; n = 1.5761; d = 1.329; [ α ] = +22.0
(c = 1.2, acetone); yield: 43.0 g (69%).
(-)-(1S)-2-Chloro-N-(1-phenylethyl)pyrrole (S-20): N-Chlorosuccinimide (42 g, 0.30 mol)
was added portionwise to a solution of (+)-(1S)-N-(1-phenylethyl)pyrrole (14; 51 g, 0.30 mol)
in toluene (0.50 L) at 25 °C. Once the reagent was completely dissolved, the solvent was
removed and the pale yellow oil was suspended in diethyl ether (0.20 L). The solid (21) was
collected by filtration. Gas chromatography (30 m, DB-1, 175 °C) of the ethereal mother
liquor revealed the presence of 20% of pyrrole (21). After evaporation of the solvent, the
yellow residue was distilled under reduced pressure to afford a colorless liquid; b.p. 78 -
20
20
80 °C/0.3 Torr; n = 1.563; = 1.134;
(74%).
D
d [ ] 20
4
D
D
4
α = -13.7 (c = 1.11, acetone); yield: 46.4 g
1 H NMR: δ = 7.31 (tt, J = 6.4, 1.3 Hz, 2 H), 7.25 (tt, J = 7.4, 1.3 Hz, 1 H), 7.1 (m,
2 H), 6.74 (dd, J = 3.2, 1.6 Hz, 1 H), 6.16 (t, J = 3.5 Hz, 1 H), 6.08 (dd, J = 3.5,
1.6 Hz, 1 H), 5.52 (q, J = 7.0 Hz, 1 H), 1.80 (d, J = 7.0 Hz, 3 H) ppm.
13 C NMR: δ = 142.3, 128.6, 127.4, 126.2, 117.4, 116.0, 108.0, 106.7, 54.9,
21.7 ppm.
MS: 205 (18%, M + ), 105 (100%), 106 (76%).
C12H12ClN (205.68) calcd. C 70.07% H 5.88%
found C 70.02% H 5.93%.
(+)-(1R)-2-Chloro-N-(1-phenylethyl)pyrrole (R-20): Analogously prepared from
(-)-(1S)-N-(1-phenylethyl)pyrrole (14; 51 g, 0.30 mol) and N-chlorosuccinimide (42 g, 0.30
20
20
mol); colorless liquid; b.p 86 - 88 °C/0.4 Torr; n = 1.560; d = 1.133; [ α
] = +11.0
(c = 1.11, acetone); yield: 48.9 g (79%).
D
4
20
D
20
D

79
(-)-N-{1-[(1S)-Phenylethyl]pyrrol-2-yl}succinimide (S-21): The amorphous solid formed
along with chloropyrrole (S-21) was collected by filtration and recrystallized from diethyl
ether to afford colorless needles; m.p. 148 - 149 °C; [ ] 20
α D = -143.0 (c = 1.0, tetrahydrofuran);
yield: 48.9 g (79%).
1 H NMR: δ = 7.3 (m, 3 H), 7.1 (m, 2 H), 6.89 (dd, J = 3.2, 1.9 Hz, 1 H), 6.28 (t,
J = 3.6 Hz, 1 H), 6.13 (dd, J = 3.8, 1.9 Hz, 1 H), 5.05 (q, J = 7.0 Hz, 1 H), 2.6 (m,
4 H), 1.77 (d, J = 7.0 Hz, 3 H) ppm.
13 C NMR: δ = 164.0, 142.4, 128.8, 127.7, 125.7, 118.8, 118.6, 108.0, 107.6, 55.4,
28.0, 22.2 ppm.
MS : 268 (23%, M + ), 164 (100%), 136 (12%), 105 (28%).
C16H16N2O2 (268.32) calcd. C 71.62% H 6.01%
found C 71.63% H 6.00%.
(+)-N-[(1R)-Phenylethyl]pyrrole-2-carboxylic acid (R-22): Potassium (7.6 g, 0.19 mol),
anhydrous magnesium chloride (9.7 g, 0.10 mol) and potassium iodide (5.3 g, 32 mmol) were
heated in refluxing tetrahydrofuran (0.15 L) for 90 min. A solution of
(+)-(1R)-2-chloro-N-(1-phenylethyl)pyrrole (R-20; 6.6 g, 32 mmol) in tetrahydrofuran
(5.0 mL) was then rapidly added and the mixture was heated for a further 3 h until gas
chromatography (30 m, DB-1, 175 °C) of an hydrolyzed sample did not show any trace of
starting material. At 25 °C, the resulting black slurry was poured on an excess of freshly
crushed dry ice and acidified to pH 1 with 2.0 M hydrochloric acid (50 mL). After decantation
of the reaction mixture and extraction with ethyl acetate (2 × 40 mL), the combined organic
layers were dried with sodium sulfate, filtered and concentrated to leave a brown oil which
slowly crystallized upon storage at -10 °C overnight. The obtained compound was sublimed
to give colorless needles; m.p. 89 - 91 °C (ref.
(c = 0.96, acetone); yield: 2.04 g (74%).
[ ]
[ ] 20
229 : m.p. 83.5 - 84.5 °C); α = 131.2
1 H NMR: δ = 7.3 (m, 3 H), 7.1 (m, 3 H), 7.03 (t, J = 2.2 Hz, 1 H), 6.56 (q,
J = 7.0 Hz, 1 H), 6.21 (dd, J = 3.9, 2.4 Hz, 1 H), 1.80 (d, J = 7.0 Hz, 3 H) ppm.
13 C NMR: δ = 165.9, 142.6, 128.6, 127.4, 126.7, 126.3, 121.3, 120.5, 108.8, 55.4, 22.0
ppm.
D

80
C13H13NO2 (215.25) calcd. C 72.54% H 6.09%
found C 71.55% H 6.03%.
Ethyl bis{N-[(1S)-phenylethyl]pyrrol-2-yl}phosphinite (19): At -75 °C, butyllithium
(20 mmol) in hexanes (13 mL) was added to a solution of (-)-(1S)-2-bromo-
N-(1-phenylethyl)pyrrole (17; 5.0 g, 20 mmol) in toluene (20 mL). The reaction mixture was
kept at - 10 °C for 20 min. Triethyl phosphite (1.7 mL, 1.7 g, 10 mmol) was then added over a
period of 20 min and the solution was kept at 25 °C for 3 h. The volatiles were then
evaporated to leave an orange oil. Purification by column chromatography on silica (0.16 kg)
eluted with a 5 : 95 (v/v) mixture of ethyl acetate and hexanes afforded a pale yellow liquid;
yield: 1.89 g (47%).
1 H NMR: δ = 7.2 (m, 6 H), 7.1 (m, 4 H), 7.01 (dd, J = 3.6, 2.1 Hz, 1 H), 6.8 m,
1H), 6.41 (symm. m, 1 H), 6.30 (dd, J = 3.0, 1.5 Hz, 1 H), 6.20 (symm. m, 1 H),
6.2 (m, 1 H), 5.92 (qd, J = 6.6, 5.1 Hz, 1 H), 5.49 (quint, J = 6.6 Hz, 1 H), 3.55
(symm. m, 2 H), 1.73 (d, J = 6.6 Hz, 3 H), 1.61 (d, J = 6.6 Hz, 3 H), 0.94 (t, J =
6.7 Hz, 3 H) ppm.
31 P NMR: δ = 143.5 ppm.
MS : 416 (23%, M + +1), 105 (100%), 77 (24%).

3 The Alkaline Decomposition of Quaternary
Tetraalkylphosphonium Salts
3.1 Preparation of Trialkyl Phosphines and Corresponding
Trivalent Phosphorus Compounds
81
The trivalent phosphorus compounds described below are common intermediates in the
preparation of most of the phosphine oxides and phosphonium salts. Since all of those
compounds were highly pyrophoric, their preparation was carried out following Schlenk
techniques and their purification consisted in a direct filtration/distillation step of the crude
reaction mixture under inert atmosphere, using the apparatus represented below.
Apparatus used for direct distillation under inert atmosphere

82
3.1.1 Dialkyl-N,N-diethylaminophosphines
Dichloro-N,N-diethylaminophosphine (23): Diethylamine (0.20 L, 0.15 kg, 2.0 mol) was
added dropwise to a solution of phosphorus trichloride (88 mL, 0.14 kg, 1.0 mol) in diethyl
ether (0.60 L) at -75 °C. After the end of addition, the mixture was allowed to reach 25 °C and
the salts were removed by filtration through a pad of celite (0.20 kg). The solvent was
stripped off and the residue distilled under vacuum to afford a colorless liquid; b.p. 41 –
42 °C/4.6 Torr (ref. [147] 20
b.p. 73 - 74 °C/13 Torr); n D = 1,4939 ; yield: 147 g (85%).
General procedure: The appropriate organolithium or Grignard reagent (0.20 mol) was
added dropwise to a solution of dichloro-N,N-diethylaminophosphine (23; 0.10 mol) in
tetrahydrofuran (0.20 L) at -75 °C. The reaction mixture was then allowed to warm up to
25 °C and solvents were removed at atmospheric pressure to be replaced by hexanes (0.10 L).
The salts were removed by filtration under inert atmosphere and the filtrate transferred via a
canula, to the addition funnel of the distillation apparatus described above. The solution was
then continuously added during distillation of the solvent at atmospheric pressure, and the
residual yellowish liquid was distilled under high reduced pressure.
Di-tert-butyl-N,N-diethylaminophosphine (24a): Prepared by addition of tert-butyllithium
in pentane (0.13 L); colorless liquid; b.p. 52 - 53 °C/0.77 Torr (ref. [148] b.p. 74 -75 °C/1 Torr);
20 n = 1,4806 (ref.
D
[148] 20 n D = 1,4885); yield: 19.8 g (89%).
1 H NMR: δ = 3.13 (qd, J = 8.7, 7.0 Hz, 4 H), 1.19 (d, J = 12.1 Hz, 18 H), 1.04 (t,
J = 7.0 Hz, 6 H) ppm.
13 C NMR: δ = 43.7 (d, J = 13.5 Hz), 27.6 (d, J = 17.0 Hz), 16.4 (d, J = 2.9 Hz)
31 P NMR: δ = 99.7 ppm.
Dibutyl-N,N-diethylaminophosphine (24b): Prepared by addition of butyllithium in hexane
(0.13 L); colorless liquid; b.p. 51 - 53 °C/0.73 Torr (ref. [147] b.p. 121 °C/16 Torr);
20 n D = 1,4576; yield: 19.4 g (88%).
1 H NMR: δ = 2.91 (dq, J = 8.6, 7.0 Hz, 4 H), 1.5 (m, 2 H), 1.4 (m, 8 H), 1.2 (m,
2 H), 1.01 (t, J = 7.0 Hz, 6 H), 0.90 (t broad, J = 7.0 Hz, 6 H) ppm.

83
13 C NMR: δ = 43.8 (d, J = 14 Hz), 30.7 (d, J = 13 Hz), 28.8 (d, J = 15 Hz), 25.3
(d, J = 12 Hz), 16.4 (d, J = 3 Hz), 14.9 ppm.
31 P NMR: δ = 56.9 ppm.
Diethyl-N,N-diethylaminophosphine (24c): Prepared following the procedure described by
K. Issleib and W. Seidel [147] ; colorless liquid; b.p. 44 - 47 °C/12 Torr (ref. [147] b.p. 181°C);
yield: 13.0 g (81%).
1 H NMR: δ = 2.93 (symm. m, 4 H), 1.5 (m, 2 H), 1.2 (m, 2 H), 1.02 (symm. m,
12 H) ppm.
13 C NMR: δ = 42.8 (d, J = 13.3 Hz), 22.2 (d, J = 10.9 Hz), 15.5 (d, J = 2.8 Hz),
9.7 (d, J = 16.1 Hz) ppm.
31 P NMR: δ = 65.2 ppm.
Dimethyl-N,N-diethylaminophosphine (24d): Prepared by addition of methyllithium in
diethyl ether (0.14 L); colorless liquid; b.p. 46 - 49 °C/59 Torr (ref. [149] b.p. 48 °C/35 Torr);
20 n D = 1,4492 (ref.
[149] n 20 = 1.4472); yield: 6.51 g (49%).
D
1 H NMR: δ = 2.80 (qd, J = 9.6, 7.0 Hz, 4 H), 1.01 (d, J = 6.0 Hz, 6 H), 0.94 (t,
J = 7.0 Hz, 6 H) ppm.
13 C NMR: δ = 22.5 (d, J = 11.9 Hz), 16.1 (d, J = 2.6 Hz), 9.9 (d, J = 16.4 Hz)
ppm.
31 P NMR: δ = 34.7 ppm.
3.1.2 Dialkylchlorophosphines
Di-tert-butylchlorophosphine (25a): A 5.8 M hydrogen chloride solution in diethyl ether
(0.10 L) was slowly added to a solution of di-tert-butyl-N,N-diethylaminophosphine (24a;
43 g, 0.20 mol) in diethyl ether (0.10 L) at -75 °C. The salts were removed by filtration under
inert atmosphere and the mother liquors transferred via a canula to the usual distillation

84
apparatus. The solution was added continuously during removal of the solvent under
atmospheric pressure, and the residual liquid was distilled under vacuum to afford a colorless
liquid; b.p. 57 - 58 °C/12 Torr (ref. [150] b.p. 70 - 72 °C/13 Torr); yield: 28.5 g (79%).
1 H NMR: δ = 1.22 (d, J = 12.2 Hz, 18 H) ppm.
13 C NMR: δ = 27.8 (d, J = 17) ppm.
31 P NMR: δ = 149.6 ppm.
Dibutylchlorophosphine (25b): Analogously prepared from dibutyl-N,N-diethylaminophosphine
(24b; 43 g, 0.20 mol); colorless liquid; b.p. 60 - 61 °C/3.4 Torr (ref. [147] b.p. 91 -
92 °C/12 Torr); yield: 31.0 g (86%).
1 H NMR: δ = 1.5 (m, 2 H), 1.4 (m, 8 H), 1.2 (m, 2 H), 0.90 (t broad, J = 7.0 Hz,
6 H) ppm.
13 C NMR: δ = 36.9 (d, J = 28.5 Hz), 26.6 (d, J = 14.2 Hz), 23.7 (d, J = 11.7 Hz),
13.7 (d, J = 0.5 Hz) ppm.
31 P NMR: δ = 119.1 ppm
Chlorodiethylphosphine (25c): Analogously prepared from diethyl-N,N-diethylaminophosphine
(24c; 32 g, 0.20 mol); colorless liquid; b.p. 34 - 37 °C/40 Torr (ref. [151] b.p. 131 - 132 °C); yield:
15.9 g (64%).
1 H NMR: δ = 1.5 (m, 2 H), 1.2 (m, 2 H), 1.0 (m, 6 H) ppm.
13 C NMR: δ = 26.7 (d, J = 27.3 Hz), 8.4 (d, J = 12.7 Hz) ppm.
31 P NMR: δ = 118.0 ppm.
Chlorodimethylphosphine (25d): Analogously prepared from dimethyl-N,N diethylaminophosphine
(24d; 27 g, 0.20 mol); colorless liquid; b.p. 62 - 65 °C (ref. [152] b.p. 72 -75 °C); yield: 9.07 g (47%).

85
1 H NMR: δ = 0.97 (d, J = 6.1 Hz, 6 H) ppm.
13 C NMR: δ = 23.0 (d, J = 27.6 Hz) ppm.
31 P NMR: δ = 93.1 ppm.
Chlorodicyclohexylphosphine (25e): Prepared following the procedure described by
W. Voskuil and J.F. Arens [153] , starting from cyclohexyl chloride (35 mL, 35 g, 0.30 mol),
magnesium (7.0 g, 0.30 mol) and phosphorus trichloride (26 mL, 41 g, 0.15 mol); colorless
liquid; b.p. 100 - 102 °C/0.45 Torr (ref. [153] b.p. 85 - 87 °C/0.001 Torr); yield: 18.0 g (53%).
Chlorodiisopropylphosphine (25f): Prepared following the procedure described by
W. Voskuil and J.F. Arens [153] , starting from isopropyl chloride (27 mL, 23 g, 0.30 mol),
magnesium (7.0 g, 0.30 mol) and phosphorus trichloride (13 mL, 21 g, 0.15 mol); colorless
liquid; b.p. 55 - 57 °C/18 Torr (ref. [153] b.p. 46 - 47 °C/10 Torr); yield: 8.96 g (37%).
3.1.3 Trialkylphosphines
Butyldi-tert-Butylphosphine (26a): Analogously prepared from chlorodi-tert-
butylphosphine (25a; 22 g, 0.12 mol) and butyllithium (0.12 mol) in hexane (82 mL);
[ ]
colorless liquid; b.p. 75 - 76 °C/7.4 Torr (ref. 230 b.p. 88 - 90 °C/8 Torr); yield: 20.5 g (83%).
1 H NMR: δ = 1.5 - 1.2 (m, 6 H), 1.12 (d, J = 10.6 Hz, 18 H), 0.90 (t, J = 7.4 Hz,
3 H) ppm.
13 C NMR: δ = 32.8 (d, J = 24 Hz), 31.1 (d, J = 20 Hz), 29.6 (d, J = 13 Hz), 24.6
(d, J = 13 Hz), 20.7 (d, J = 19 Hz), 13.9 ppm.
31 P NMR: δ = 31.6 ppm.
C12H27P (202.32) calcd. C 71.24% H 13.45%
found C 70.90% H 13.41%.

86
Di-tert-butylisopropylphosphine (26b): Analogously prepared from Chlorodi-tert-
butylphosphine (25a; 18 g, 0.10 mol) and freshly prepared isopropylmagnesium chloride
(0.10 mol) in tetrahydrofuran (50 mL); colorless liquid; b.p. 41 - 43 °C/4.9 Torr (ref. [154] b.p.
81 - 83 °C/11 Torr); yield: 9.85 g (52%).
1 H NMR: δ = 1.4 (m, 1 H), 1.12 (d, J = 11.0 Hz, 18 H), 1.02 (d, J = 11.2 Hz, 6 H)
ppm.
13 C NMR: δ = 35.9 (d, J = 40 Hz), 30.8 (d, J = 13 Hz), 27.8 (d, J = 17 Hz), 23.2
(d, J = 12 Hz) ppm.
31 P NMR: δ = 31.6 ppm.
Di-tert-butylmethylphosphine (26c): A solution of methyllithium (90 mmol) in diethyl ether
(59 mL) was added slowly to a solution of di-tert-butylchlorophosphine (25a; 16 g, 90 mmol)
in diethyl ether (90 mL) at -75 °C. The salts were removed by filtration under inert
atmosphere and the direct distillation protocol was applied to give a colorless liquid; b.p. 50 -
52 °C/13 Torr (ref. [155] b.p. 58 °C/12 Torr); yield: 8.99 g (63%).
1 H NMR: δ = 0.83 (d, J = 4.5 Hz, 3 H), 1.04 (d, J = 10.6 Hz, 18 H) ppm.
13 C NMR: δ = 30.5 (d, J = 21.0 Hz), 29.5 (d, J = 14.1 Hz), 3.2 ppm.
31 P NMR: δ = 11.2 ppm.
Dibutylneopentylphosphine (26d): Analogously prepared from dibutylchlorophosphine
(25b; 22 g, 0.12 mol) and freshly prepared neopentylmagnesium bromide (0.12 mol) in
diethyl ether (0.10 L); colorless liquid; b.p. 84 - 85 °C/1.1 Torr; yield: 16.8 g (65%).
1 H NMR: δ = 1.5 - 1.3 (m, 10 H), 1.2 (s, 2 H), 0.98 (s, 9 H), 0.9 (m, 8 H) ppm.
13 C NMR: δ = 31.5 (d, J = 6 Hz), 30.9 (d, J = 9 Hz), 30.1 (d, J = 64 Hz), 24.3 (d,
J = 14 Hz), 24.2 (d, J = 4 Hz), 13.7 (d, J = 20 Hz) ppm.
31 P NMR: δ = 50.1 ppm.

87
Dibutyl-tert-butylphosphine (26e): Analogously prepared from chlorodibutylphosphine
(25b; 20 g, 0.11 mol) and tert-butyllithium (0.11 mol) in pentane (79 mL); colorless liquid;
b.p. 72 - 73 °C/2.8 Torr; yield: 13.0 g (58%).
1 H NMR: δ = 1.4 (m, 9 H), 1.2 (m, 3 H), 1.02 (d, J = 11.2 Hz, 9 H), 0.9 (m, 6 H)
ppm.
13 C NMR: δ = 42.9 (d, J = 14 Hz), 30.1 (d, J = 18 Hz), 27.4 (d, J = 13 Hz), 24.2
(d, J = 16 Hz), 15.5 (d, J = 3 Hz), 13.9 (d, J = 8 Hz) ppm.
31 P NMR: δ = 0.8 ppm.
C12H27P (202.32) calcd. C 71.24% H 13.45%
found C 71.32% H 13.35%.
Dibutylmethylphosphine (26f): Analogously prepared from dibutylchlorophosphine (25b;
16 g, 90 mmol); colorless liquid; b.p. 63 - 64 °C/15 Torr; yield: 12.0 g (84%).
1 H NMR: δ = 1.3 - 0.9 (m, 18 H), 0.81 (d, J = 3.7 Hz, 3H) ppm.
13 C NMR: δ = 32.6 (d, J = 12.0 Hz), 28.4 (d, J = 13.8 Hz), 24.6 (d,
J = 10.9 Hz), 14.4 (d, J = 16.1 Hz), 13.8 ppm.
31 P NMR: δ = -43.7 ppm.
C9H21P (160.24) calcd. C 67.46% H 13.21%
found C 67.41% H 13.13%.
Butyldiethylphosphine (26g): A solution of butyllithium (0.13 mol) in hexane (0.11 mL)
was added slowly to a solution of diethylchlorophosphine (25g; 16 g, 0.13 mol) in diethyl
ether (50 mL) at -75 °C. The salts were then filtered under inert atmosphere and the usual
direct distillation protocol was applied to give a colorless liquid; b.p. 65 - 66 °C/46 Torr (ref.
[156] b.p. 106 - 107 °C/100 Torr); yield: 9.49 g (51%).
1 H NMR: δ = 1.7 (m, 1 H), 1.4 (m, 9 H), 1.17 (dt, J = 15.6, 7.6 Hz, 1 H), 1.06 (symm.
m, 5 H), 0.9 (m, 3 H) ppm.

88
13 C NMR: δ = 32.9 (d, J = 12 Hz), 27.6 (d, J = 14 Hz), 24.4 (d, J = 11 Hz), 14.3
(d, J = 16 Hz), 11.9 (d, J = 13 Hz), 12.9 ppm.
31 P NMR: δ = 54.0 ppm.
tert-Butyldimethylphosphine (26h) [156] : Analogously prepared from chlorodimethylphosphine
(25d; 24 g, 0.25 mol) and tert-butyllithium (0.25 mol) in pentane (0.16 L); colorless liquid; b.p.
38 - 39 °C/140 Torr; yield: 19.7 g (67%).
1 H NMR: δ = 0.81 (d, J = 4.7 Hz, 6 H), 1.03 (d, J = 10.7 Hz, 9 H) ppm.
13 C NMR: δ = 26.5 (d, J = 10.6 Hz), 26.4 (d, J = 13.3 Hz), 9.5 (d, J = 19.8 Hz)
ppm.
31 P NMR: δ = -28.7 ppm.
Butyldimethylphosphine (26i): Analogously prepared from chlorodimethylphosphine (25d;
14 g, 0.15 mol) and butyllithium (0.15 mol) in hexane (0.10 L); colorless liquid; b.p. 45 -
48 °C/31 Torr (ref. [38] b.p. 56 - 60 °C/72 Torr); yield: 19.7 g (68%).
1 H NMR: δ = 1.3 - 0.9 (m, 9 H), 0.83 (d, J = 3.7 Hz, 6H) ppm.
13 C NMR: δ = 32.9 (d, J = 12.1 Hz), 27.6 (d, J = 13.7 Hz), 24.4 (d,
J = 11.3 Hz), 14.3 (d, J = 16.0 Hz), 12.9 ppm.
31 P NMR: δ = -53.5 ppm.
Butyldicyclohexylphosphine (26j): Analogously prepared from Chlorodicyclohexylphosphine
(25e; 24 g, 0.11 mol) and butyllithium (0.11 mol) in hexane (68 mL); colorless liquid; b.p. 107 -
108 °C/0.39 Torr; yield: 20.8 g (82%).
13 C NMR: δ = 33.3 (d, J = 12 Hz), 30.7 (d, J = 18 Hz), 30.4 (d, J = 14 Hz), 29.1
(d, J = 8 Hz), 27.4 (d, J = 10 Hz), 27.3 (d, J = 6 Hz), 26.6, 24.6 (d, J = 12 Hz),
21.0 (d, J = 16 Hz), 13.9 ppm.
31 P NMR: δ = -1.3 ppm.

89
C16H31P (254.39) calcd. C 75.54% H 12.28%
found C 75.52% H 12.26%.
Methyldiisopropylphosphine (26k): Prepared following the procedure described by A.H.
Cowley and J.L. Mills [158] starting from chlorodiisopropylphosphine (25f; 12 g, 80 mmol)
and methyllithium (80 mmol) in diethyl ether (66 mL); colorless liquid; b.p. 47 - 48 °C/63
Torr (ref. [158] b.p. 150 - 151 °C); yield: 7.24 g (69%).
3.2 Trialkylphosphine Oxides
Butyldi-tert-butylphosphine oxide (27a): Analogously prepared from butyldi-tert-
butylphosphine (26a; 8.5 g, 42 mmol) and 30% hydrogen peroxide solution (10 mL);
[ ]
colorless liquid; b.p. 78 - 79 °C/0.5 Torr (ref. 231 b.p. 73 °C/0.025 Torr); yield: 7.96 g (87%).
1 H NMR: δ = 1.7 (m, 4 H), 1.4 (m, 2 H), 1.26 (d, J = 12.8 Hz, 18 H), 0.94 (t,
J = 7.4 Hz, 3 H) ppm.
13 C NMR: δ = 35.7 (d, J = 59 Hz), 26.7, 25.3 (d, J = 5 Hz), 24.9 (d, J = 12 Hz),
21.5 (d, J = 57 Hz), 13.7 ppm.
31 P NMR: δ = 62.4 ppm.
C12H270P (218.32) calcd. C 66.02% H 12.47%
found C 65.95% H 12.34%.
Di-tert-butylisopropylphosphine oxide (27b): Analogously prepared from
di-tert-butylisopropylphosphine (26b; 3.2 g, 17 mmol) and 30% hydrogen peroxide solution
(5 mL); white needles after sublimation; m.p. 64 - 66 °C (ref. [231] b.p. 63 - 65 °C); yield:
3.05 g (88%).
1 H NMR: δ = 2.37 (symm. m, 1 H), 1.41 (d, J = 17 Hz, 18 H), 1.32 (d, J = 13 Hz, 6 H)
ppm.

90
13 C NMR: δ = 41.5 (d, J = 61 Hz), 27.1 (d, J = 86 Hz), 26.7, 18.7 (d, J = 2 Hz)
ppm.
31 P NMR: δ = 97.7 ppm.
Dibutylneopentylhposphine oxide (27c)
[81] : Analogously prepared from
dibutylneopentylphosphine (26d; 5.0 g, 23 mmol) and 30% hydrogen peroxide solution
(9 mL); colorless liquid; b.p. 113 - 118 °C/0.25 Torr; yield: 4.59 g (86%).
1 H NMR: δ = 1.7 (m, 6 H), 1.64 (d, J = 10.0 Hz, 2 H), 1.5 (m, 7 H), 1.16 (s, 9 H),
0.94 (t, J = 7.0 Hz, 6H) ppm.
13 C NMR: δ = 40.9 (d, J = 63 Hz), 31.5 (d, J = 7 Hz), 30.1 (d, J = 64 Hz), 24.3 (d,
J = 14 Hz), 24.2 (d, J = 4 Hz), 24.2, 13.6 ppm.
31 P NMR: δ = 50.1 ppm.
Dibutyl-tert-butylposphine oxide (27d): Analogously prepared from dibutyl-tert-
butylposphine (26e; 10 g, 51 mmol) and 30% hydrogen peroxide solution (15 mL); colorless
liquid; b.p. 95 - 96 °C/0.38 Torr; yield: 8.29 g (75%).
1 H NMR: δ = 1.6 (m, 8 H), 1.4 (m, 4 H), 1.17 (d, J = 14.0 Hz, 9 H), 0.94 (t, J =
7.4 Hz, 6 H) ppm.
13 C NMR: δ = 32.4 (d, J = 66 Hz), 24.8, 24.7 (d, J = 6 Hz), 24.5 (d, J = 22 Hz),
24.3 (d, J = 27 Hz), 13.7 ppm.
31 P NMR: δ = 57.9 ppm.
C12H27OP (218.32) calcd. C 66.02% H 12.47%
found C 66.01% H 12.43%.
Butyldiethylphosphine oxide (27e): Analogously prepared from butyldiethylphosphine (26g;
6.0 g, 41 mmol) and 30% hydrogen peroxide solution (17 mL); colorless liquid; b.p. 93 -
94 °C/2.5 Torr (ref. [37] b.p. 160 °C/3.1 Torr); yield: 5.17 g (78%).

91
1 H NMR: δ = 1.7 (m, 6 H), 1.5 (m, 2 H), 1.4 (m, 2 H), 1.17 (dt, J = 15.6, 7.7 Hz,
6 H), 0.94 (t, J = 7.2 Hz, 3 H) ppm.
13 C NMR: δ = 26.2 (d, J = 65 Hz), 24.2 (d, J = 14 Hz), 23.5 (d, J = 4 Hz), 19.8 (d,
J = 66 Hz), 13.6, 5.7 (d, J = 5 Hz) ppm.
31 P NMR: δ = 58.1 ppm.
Butyldimethylposphine oxide (27f): A 30% aqueous hydrogen peroxide solution (3.5 mL,
29 mmol) was added dropwise to a solution of butyldimethylphosphine (26i; 2.3 g, 19 mmol)
in diethyl ether (38 mL) at 0 °C. After the exothermic reaction has ceased, phases were
separated and the organic layers was washed with a saturated sodium sulfite solution (10 mL)
and dried with sodium sulfate. Removal of the solvent and distillation of the residue afforded
a colorless liquid; b.p. 81 - 82 °C/0.35 Torr (ref. [38] b.p. 70 - 73 °C/0.25 Torr; yield: 2.18 g
(84%).
1 H NMR: δ = 1.7 (m, 2 H), 1.6 (m, 2 H), 1.48 (d, J = 12.3 Hz, 6 H), 1.45
(symm. m, 2 H), 0.95 (t, J = 7.2 Hz, 3 H) ppm.
13 C NMR: δ = 31.5 (d, J = 69 Hz), 24.1 (d, J = 20 Hz), 24.0, 16.1 (d, J = 68 Hz),
13.6 ppm.
31 P NMR: δ = 45.6 ppm.
Butyldicyclohexylphosphine oxide (27g): Analogously prepared from
butyldicyclohexylphosphine (26j; 2.7 g, 15 mmol) and 30% hydrogen peroxide solution
(5 mL); white needles after sublimation; m.p. 57 - 59 °C; yield: 3.77 g (93%).
1 H NMR: δ = 2.0 (m, 3 H), 1.8 (m, 6 H), 1.7 (m, 3 H), 1.6 (m, 4 H), 1.4 (m, 6 H),
1.2 (m, 6 H), 0.93 (t, J = 7.3 Hz, 3 H) ppm.
13 C NMR: δ = 36.3 (d, J = 64 Hz), 26.6 (d, J = 3 Hz), 26.6 (d, J = 3 Hz), 26.0 (d, J = 1
Hz), 26.0 (d, J = 2 Hz), 25.7 (d, J = 3 Hz), 24.7 (d, J = 13 Hz), 24.1 (d, J = 4 Hz), 23.6
(d, J = 61 Hz), 13.7 ppm.

31 P NMR: δ = 53.4 ppm.
92
C16H31OP (270.39) calcd. C 71.07% H 11.56%
found C 71.01% H 11.53%.
Methyldiisopropylphosphine oxide (27h): Analogously prepared from
Methyldiisopropylphosphine (26k; 4.8 g, 36 mmol) and 30% hydrogen peroxide solution
(10 mL); colorless liquid; b.p. 70 - 71 °C/3.1 Torr (ref. [161] b.p. 116 - 117 °C/20 Torr); yield:
4.63 g (86%).
1 H NMR: δ = 1.98 (symm. m, 2 H), 1.31 (d, J = 11.5 Hz, 3 H), 1.23 (dd, J = 14.9,
7.4 Hz, 6 H), 1.16 (dd, J = 15.5, 7.2 Hz, 6 H) ppm.
13 C NMR: δ = 25.6 (d, J = 67 Hz), 16.0 (d, J = 2 Hz), 15.1 (d, J = 3 Hz), 7.6 (d,
J = 62 Hz) ppm.
31 P NMR: δ = 60.6 ppm.
Di-tert-butylmethylphosphine oxide (27i): In a two necked flask equipped with a reflux
condenser, iodomethane (0.3 mL, 0.7 g, 4.0 mmol) was added at 25 °C, to a solution of
methyldi-tert-butylphosphinite (7.0 g, 40 mmol) in tetrahydrofuran (20 mL). The mixture was
then vigorously stirred until the white precipitate redisolved. After 1 h, the solvent and excess
of reagent were evaporated and the residue directly distilled to afford a colorless liquid which
spontaneously crystallized into white needles; b.p. 72 - 73 °C/0.85 Torr (ref. [162] b.p.
57 °C/0.02 Torr); m.p. 23 - 25 °C; yield: 5.50 g (79%).
1 H NMR: δ = 3.72 (d, J = 10 Hz, 3 H), 1.17 (d, J = 16 Hz, 18 H) ppm.
13 C NMR: δ = 51.3 (d, J = 7 Hz), 24.2, 8.5 (d, J = 85) ppm.
31 P NMR: δ = 58.4 ppm.
Dibutylmethylphosphine oxide (27j): Prepared following a procedure described by G.M.
Kosolapoff and R.F. Struck [163] , starting from methylphosphonic dichloride ( 6.7 g, 50 mmol)
and butylmagnesium bromide (0.11 mol) in tetrahydrofuran (45 mL); white needles; b.p. 133
- 135 °C/0.49 Torr; m.p. 32 - 34 °C (ref. [163] m.p. 34 - 35 °C); yield: 7.45 g (84%).

93
1 H NMR: δ = 1.7 (m, 4 H), 1.6 (m, 4 H), 1.4 (m, 4 H), 1.42 (d, J = 12.1 Hz, 3 H),
0.94 (t, J = 7.0 Hz, 6 H) ppm.
13 C NMR: δ = 29.7 (d, J = 67 Hz), 24.2 (d, J = 14 Hz), 23.9 (d, J = 4 Hz), 13.9 (d,
J = 66 Hz), 13.6 ppm.
31 P NMR: δ = 48.8 ppm.
tert-Butyldimethylposphine oxide (27k): A solution of tert-butylphosphonic dichloride (8.7
g, 50 mmol) in diethyl ether (50 mL) was added dropwise to methylmagnesium bromide (0.10
mol) in diethyl ether (35 mL) at 10 °C. The brown mixture was then stirred at 25 °C for 1 h
until it became homogeneous and solvent was removed and replaced by hexanes (50 mL).
Filtration of the salts and evaporation of the solvent gave a brown oil which was distilled
under vacuum to afford a colorless liquid; b.p. 58 - 61 °C/0.33 Torr (ref. [162] b.p. 90 -
94 °C/2 Torr); yield: 4.55 g (68%).
1 H NMR: d = 2.13 (d, J = 11.8 Hz, 6 H), 1.49 (d, J = 15.2 Hz, 9 H) ppm.
13 C NMR: d = 51.5 (d, J = 7 Hz), 24.4, 8.4 (d, J = 85) ppm.
31 P NMR: d = 48.9 ppm.
3.3 Tetraalkylphosphonium Halides
Dibutyldimethylphosphonium iodide (28a): Iodomethane (0.40 mL, 1.0 g, 7.0 mmol) was
added dropwise to a solution of dibutylmethylphosphine (26f; 1.1 g, 7.0 mmol) in diethyl
ether (6.0 mL) at 0 °C. The reaction mixture was allowed to warm up to 25 °C and the
precipitate formed was filtered under inert atmosphere. The solid obtained was recrystallized
from diethyl ether to afford white prisms; m.p. 168 - 169 °C; yield: 2.10 g (99%).
1 H NMR: δ = 2.5 (m, 4 H), 2.18 (d, J = 13.6 Hz, 6 H), , 1.5 (m, 8 H), 0.98 (t, J =
7.1 Hz, 6 H) ppm.

94
13 C NMR: δ = 40.8 (d, J = 3 Hz), 23.8 (d, J = 16 Hz), 23.7 (d, J = 14 Hz), 23.7 (d,
J = 4 Hz), 23.6 (d, J = 3 Hz), 7.5 (d, J = 53 Hz) ppm.
31 P NMR: δ = 31.7 ppm.
C10H24IP (302.18) calcd. C 39.75% H 8.01%
found C 39.72% H 8.02%.
Di-tert-butyldimethylphosphonium iodide (28b): Analogously prepared from
di-tert-butylmethylphosphine (26c; 1.9 g, 12 mmol) and iodomethane (0.7 mL, 1.7 g, 12
mmol); white needles (from diethyl ether); m.p. > 320 °C (ref. [164] m.p. 338 - 346 °C); yield:
3.57 g (99%).
1 H NMR: δ = 2.13 (d, J = 11.8 Hz, 6 H), 1.48 (d, J = 15.3 Hz, 18 H) ppm.
13 C NMR: δ = 27.2, 26.1 (d, J = 4 Hz), 29.7 (d, J = 11 Hz) ppm.
31 P NMR: δ = 50.0 ppm.
Dibutyldi-tert-butylphosphonium bromide (28c): Analogously prepared from
butyldi-tert-butylphosphine (26a; 1.7 g, 8.4 mmol) and butyl bromide (2.3 mL, 2.9 g, 21
mmol); white prisms (from ethyl acetate); m.p. 105 - 106 °C; yield: 2.79 g (98%).
1 H NMR: δ = 2.52 (symm. m, 4 H), 1.7 (m, 4 H), 1.65 (symm. m, 4 H), 1.55 (d,
J = 14.4 Hz, 18 H), 1.00 (t, J = 7.0 Hz, 6 H) ppm.
13 C NMR: δ = 35.0 (d, J = 37 Hz), 28.2, 26.1 (d, J = 6 Hz), 24.8 (d, J = 14 Hz),
17.8 (d, J = 40 Hz), 13.7 ppm.
31 P NMR: δ = 47.6 ppm.
C16H36BrP (339.33) calcd. C 56.63% H 10.69%
Tributylneopentylphosphonium iodide (28d)
found C 56.08% H 10.56%.
[ ] 232 : Butyl iodide (1.9 mL, 3.1 g, 17 mmol)
was quickly added to a solution of dibutylneopentylphosphine (26d; 2.4 g, 11 mmol) in

95
hexanes (15 mL) and the reaction mixture was heated to reflux for 12 h. At 25 °C, the
precipitate was filtered under inert atmosphere and recrystallized from ethyl acetate to afford
white needles; m.p. 173 - 175 °C; yield: 4.40 g (98%).
1 H NMR: δ = 2.55 (d, J = 13.4 Hz, 2 H), 2.5 (m, 6 H), 1.6 (m, 12 H), 1.23 (s,
9 H), 0.99 (t, J = 7.0 Hz, 9 H) ppm.
13 C NMR: δ = 33.3 (d, J = 42 Hz), 32.3 (d, J = 5 Hz), 31.8 (d, J = 7 Hz), 24.1 (d, J
= 5 Hz), 24.0 (d, J = 15 Hz), 21.2 (d, J = 46 Hz), 13.5 ppm.
31 P NMR: δ = 34.9 ppm.
Butyltriethylphosphonium iodide (28e) [167] : Analogously prepared from triethylphosphine
(3.1 g, 26 mmol) and butyl iodide (4.3 mL, 7.0 g, 39 mmol); white needles (from ethyl
acetate); m.p. 194 - 196 °C; yield: 7.44 g (96%).
1 H NMR: δ = 2.53 (dq, J = 13.0, 7.7 Hz, 6 H), 1.6 (m, 6 H), 1.33 (dt, J = 18.0,
7.7 Hz, 9 H), 0.99 (t, J = 7.2 Hz, 3 H) ppm.
13 C NMR: δ = 24.0 (d, J = 15 Hz), 23.7 (d, J = 5 Hz), 18.2 (d, J = 47 Hz), 13.5,
12.7 (d, J = 49 Hz), 6.3 (d, J = 6 Hz) ppm.
31 P NMR: δ = 41.1 ppm.
3.4 Alkaline Decomposition of Phosphonium Salts
General procedure: The phosphonium salt (1.0 mmol) was suspended in butanol (5 .0 mL) and a 6.0
M aqueous potassium hydroxide solution (1.0 mL) was added. Tributylphosphine oxide or
triisopropylphosphine oxide (1 mmol), depending on the expected reaction products, was immediately
added as internal standard. The reaction mixture was then heated at 110 °C until no trace of starting
phosphonium remained. The gases formed during the decomposition were bubbled into a solution of
bromine (0.2 mL, 0.5 g, 3 mmol) in chloroform (5 mL). After the gas evolution ceased, cyclohexane
(20 mL) was added and the solvents were removed under reduced pressure. The residue was dissolved
in diethyl ether (15 mL), dried with sodium sulfate and evaporated to dryness. 31 P NMR experiment
was directly run on the crude mixture without any further purification.

96
31 P NMR settings: It is known that the Nuclear Overhauser Effect (NOE) causes change in the
integration intensity during 1 H decoupling. Thus, all spectra were recorded in a 1 H-nondecoupling
mode. Furthermore, pulse delay time must be long enough to allow complete relaxation of the nuclei
and thus quantitative measurements. Hence, a typical experiment based on the progressive saturation
[ , ]
and saturation recovery 233 234 was applied to the phosphonium salts in order to determine the
minimum spin-lattice relaxation time T1(min.). To insure complete relaxation of all nuclei considered,
the experimental relaxation time T1(exp.) was then set to 5T1(min.). The effective NMR settings used
were data points 32K, spectral width 19000 Hz, pulse width 12.0 µsec (pulse angle 90°), pulse delay
time 30 sec, and number of FID accumulation 256.
In order to evaluate the standard error on the measurements, a calibration was
performed by recording several spectra, in the conditions described above. Twelve sample
mixtures of di-tert-butylmethylphosphine oxide and dibutylmethylphosphine oxide were
prepared by accurate weighting in ratios ranging from 48.7 : 51.3 to 99.3 : 0.7. The accuracy
of the 31 P-NMR quantification was hence checked for ratios close to 1 : 1 mixture, as well as
extreme 99 : 1 cases, by comparing the theoretical ratios to thoses obtained by NMR
integration of the peaks (see Figure 10 – 14 for typical examples). Each sample of phosphine
oxides mixture was recorded three times and an average integration value was used to obtain a
linear regression with a good correlation factor (r² = 0.99):
Theoretica l ratio = 1.01×
Experimental
ratio - 0.50
Theoretical ratio: (48.7:51.3)
Experimental ratio: (48.0:52.0)
Figure 10. Calibration 31 P-NMR spectrum of a (tert-C4H9)2P(O)CH3 / (C4H9)2P(O)CH3

97
Theoretical ratio: (50.3:49.7)
Experimental ratio: (51.0:49.0)
Figure 11. Calibration 31 P-NMR spectrum of a (tert-C4H9)2P(O)CH3 / (C4H9)2P(O)CH3
Theoretical ratio: (94.0:6.0)
Experimental ratio: (93.4:6.6)
Figure 12. Calibration 31 P-NMR spectrum of a (tert-C4H9)2P(O)CH3 / (C4H9)2P(O)CH3

98
Theoretical ratio: (96.1:3.9)
Experimental ratio: (95.7:4.3)
Figure 13. Calibration 31 P-NMR spectrum of a (tert-C4H9)2P(O)CH3 / (C4H9)2P(O)CH3
Theoretical ratio: (99.3:0.7)
Experimental ratio: (98.6:1.4)
Figure 14. Calibration 31 P-NMR spectrum of a (tert-C4H9)2P(O)CH3 / (C4H9)2P(O)CH3

99
To illustrate the experimental method for the quantification of the phosphine oxides
resulting from alkaline decomposition of phosphonium halides, a detailed protocole is given
for tributylneopentylphosphonium iodide degradation:
Tributylneopentylphosphonium iodide (0.40 g, 1.0 mmol) was suspended in butanol (5.0 mL) and
a 6.0 M aqueous potassium hydroxide solution (1.0 mL) was added. Triisopropylphosphine oxide
(0.13 g, 0.76 mmol) was immediately added as internal standard. The reaction mixture was then
heated at 110 °C in a thermostated bath until no trace of starting phosphonium remained. The gases
formed during the decomposition were bubbled into a solution of bromine (0.2 mL, 0.5 g, 3 mmol) in
chloroform (5.0 mL). After the gas evolution ceased, the bromine solution was treated with a sodium
sulfite solution, phases were decantated. The organic layer was dried with sodium sulfate and the
presence of brominated adduct was immediately checked by gas chromatography (30 m, DB-1,
70 °C). Cyclohexane (20 mL) was added to the reaction slurry and the solvents were removed under
reduced pressure. The residue was dissolved in diethyl ether (15 mL), dried with sodium sulfate and
evaporated to dryness. 31 P NMR experiment was directly run on the crude mixture without any further
purification (See Figure 15). Yield: 98% according to triisopropylphosphine oxide (internal standard).
This experiment was repeated three times in the same conditions to afford an average phosphine oxide
ratio by comparison with the spectra of each individual original phosphine oxide. The average
tributylphosphine oxide/dibutylneopentylphosphine oxide was calculated of 17:83.
Figure 15. Alkaline decomposition of tributylneopentylphosphonium iodide with potassium hydroxide in a
butanol/water (8:2) mixture at 110 °C

101
4 The Preparation and Racemate Resolution of
Biphenyls and Biphenylbisphosphines
4.1 Preparation of 6,6’-Dibromobiphenyl-2,2’-diol and
Derivatives Thereof
1,3-Dibromo-2-iodobenzene (29): Butyllithium (1.0 mol) in hexane (0.50 L) was added to a
solution of diisopropylamine (0.15 L, 0.11 kg, 1.1 mol) in tetrahydrofuran (2.0 L) at 0 °C. The
solution was then cooled to -75 °C and 1,3-dibromobenzene (0.12 L, 0.24 kg, 1.0 mol) was
added dropwise over 90 min, so that temperature stayed below -70 °C. The slightly yellow
suspension was stirred for 2 h before a solution of iodine (0.25 kg, 1.0 mol) in tetrahydrofuran
(0.40 L) was added all at once. The reaction mixture was allowed to warm up to 25 °C and a
saturated aqueous sodium sulfite solution (0.20 L) was added. The volatiles were removed
under reduced pressure and the aqueous phase was extracted with ethyl acetate (2 × 0.25 L)
and washed with 1.0 M hydrochloric acid (0.10 L; 0.10 mol) to afford a slightly yellow solid
which was recrystallized from ethanol to give colorless prisms; m.p. 99 - 101 °C; yield:
0.35 kg (96%).
1 H NMR: δ = 7.56 (d, J = 8.0 Hz, 2 H), 7.06 (t, J = 8.0 Hz, 1 H) ppm.
13 C NMR: δ = 131.2, 131.0, 130.2, 109.2 ppm.
C6H3Br2I (361.8) calcd. C 19.92% H 0.84%
found C 19.97% H 0.80%.
2,2’,6,6’-Tetrabromobiphenyl (30): Butyllithium (0.75 mol) in hexane (0.49 L) was added
dropwise over 2 h to a solution of 1,3-dibromo-2-iodobenzene (29; 0.27 kg, 0.75 mol) in
diethyl ether (1.4 L) at -75 °C. Copper(II) bromide (0.17 kg, 0.75 mol) was then added all at
once and the black slurry was kept at the same temperature for 45 min before nitrobenzene
(77 mL, 93 g, 0.75 mol) was added. At 25 °C, a 12% ammonium hydroxide solution (0.40 L)

102
was added and the phases were separated. The aqueous layer was extracted with ethyl acetate
(2 × 0.30 L), the combined organic phases were dried with sodium sulfate and the solvent was
evaporated. The black residue was triturated with cold methanol and filtered to afford the
[ ]
product as colorless crystals; m.p. 215 - 217 °C (ref. 235 m.p. 215 °C); yield: 113 g (64%).
1 H NMR: δ = 7.66 (d, J = 8.0 Hz, 4 H), 7.16 (t, J = 8.0 Hz, 2 H) ppm.
13 C NMR: δ = 142.3, 132.0, 131.0, 124.7 ppm.
(±)-(PM)-6,6’-Dibromobiphenyl-2,2’-diol (31): At -75 °C, butyllithium (0.14 mol) in
hexane (64 mL) was added to a solution of 2,2’,6,6’-tetrabromo-1,1’-biphenyl (30; 33 g, 70
mmol) in tetrahydrofuran (0.35 L) at -75 °C. The mixture was then consecutively treated with
fluorodimethoxyborane diethyl etherate [177] (39 mL, 35 g, 0.21 mol) and at 0 °C, with a 2.0 M
aqueous sodium hydroxide solution (0.15 L, 0.30 mol). After 30 min, a 35% aqueous
hydrogen peroxide solution (18 mL, 0.21 mol) was added and the white slurry was stirred for
1 h. Phases were decanted and extracted with ethyl acetate (2 × 0.10 L), and the combined
organic layers washed with a saturated aqueous sodium sulfite solution. Drying with sodium
sulfate and removal of the solvent left a dark brown paste which was precipitated in hexanes
an recrystallized from toluene to afford the expected product as white prisms; m.p. 165 -
166 °C; yield: 18.2 g (76%).
1 H NMR: δ = 7.31 (dd, J = 8.2, 1.2 Hz, 2 H), 7.25 (t, J = 8.1 Hz, 2 H), 7.01 (dd,
J = 8.2, 1.2 Hz, 2 H), 4.8 (s broad, 2 H) ppm.
13 C NMR: δ = 155.1, 132.0, 125.7, 125.5, 122.5, 115.2 ppm.
C12H8Br2O2 (344.00) calcd. C 41.90% H 2.34%
found C 41.98% H 2.30%.
Optical resolution of (±)-(PM)-6,6’-Dibromobiphenyl-2,2’-diol (31): Racemic
6,6’-dibromobiphenyl-2,2’-diol (31; 15 g, 44 mmol) and (-)-(1R,2R)-1,2-diaminocyclohexane
(33; 5.1 g, 44 mmol) were heated in boiling ethanol (0.10 L) for 10 min and the solution was
stirred for 3 h while slowly decreasing the temperature to 25 °C. Hexanes was then added
(10 mL) and the solution was kept a 5 °C for 24 h until crystallisation occurred. The solid was
collected by filtration and directly recrystallized from ethanol to afford colorless prisms
(6.91 g). Decomposition of the complex with 10% hydrochloric acid (30 mL) and the usual

103
extraction protocol with ethyl acetate (2 × 20 mL) afforded the enriched (P)-(-)-(3)
enantiomer. This protocol was repeated until optical rotatory power remained constant;
colorless prisms; m.p. 180 - 181 °C; [ ] 20
α D = -42.9 (c = 1.0, ethanol); ee > 99% [determined by
conversion to (+)-MeO-BIPHEP]; yield: 5.80 g (39%).
The residue obtained after evaporation of the combined mother liquor was decomposed the
same way. The whole procedure was then applied to the enriched (M)-(+)-(31) enantiomer
obtained, using (1S,2S)-1,2-diaminocyclohexane. Filtration of the complex and decomposition
afforded colorless prisms; m.p. 178 - 180 °C; [ ] 20
α D = +42.0 (c = 1.0, ethanol); ee > 98%
[determined by conversion to (-)-MeO-BIPHEP]; yield: 6.31 g (42%).
C12H8Br2O2 (344.00) calcd. C 41.90% H 2.34%
found C 41.84% H 2.33%.
(±)-(PM)-2,2’-Dibromo-6,6’-bis(methoxymethoxy)biphenyl (34): A solution of
6,6’-dibromobiphenyl-2,2’-diol (31; 26 g, 76 mmol) in tetrahydrofuran (75 mL) was added
dropwise to a 60% suspension of sodium hydride in mineral oil (6.1 g, 0.15 mol) in
tetrahydrofuran (75 mL) at 25 °C. After 30 min, a solution of freshly prepared chloromethyl
methyl ether (13 mL, 13 g, 0.17 mol) in tetrahydrofuran (35 mL) was added dropwise at 0 °C.
After the end of addition, the reaction mixture was warmed up to 25 °C and water was added
(0.10 L). Phases were decanted, the aqueous one was extracted with ethyl acetate (2 × 75 mL)
and the combined organic layers were dried with sodium sulfate. After removal of the solvent,
the white solid left was recrystallized from methanol to afford tiny colorless platelets; m.p.
153 - 155 °C; yield: 30.8 g (94%).
1 H NMR: δ = 7.34 (dd, J = 7.9, 1.3 Hz, 2 H), 7.22 (t, J = 8.0 Hz, 2 H), 7.17 (dd,
J = 8.3, 1.3 Hz, 2 H), 5.07 (d, J = 6.7 Hz, 2 H), 5.05 (d, J = 6.7 Hz, 2 H), 3.36 (s,
6 H) ppm.
13 C NMR: δ = 157.6, 130.0, 129.1, 125.8, 124.9, 113.7, 94.5, 56.0 ppm.
C16H16Br2O4 (432.10) calcd. C 44.47% H 3.73%
found C 44.38% H 3.87%.
(-)-(P)-2,2’-Dibromo-6,6’-bis(methoxymethoxy)biphenyl (P-34): Prepared following the
same protocol, starting from (-)-(P)-6,6’-dibromobiphenyl-2,2’-diol (31); m.p. 66 - 68 °C;
[ ] 20
α
D
= -29.7 (c = 1.03, acetone).

104
(+)-(M)-2,2’-Dibromo-6,6’-bis(methoxymethoxy)biphenyl (M-34): prepared following the
same protocol, starting from (+)-(M)-6,6’-dibromobiphenyl-2,2’-diol (31); m.p. 67 - 68 °C;
[ ] 20
α D
= +29.4 (c = 1.0, acetone).
(±)-(PM)-2,2’-Dibromo-6,6’-dimethoxybiphenyl (35): Iodomethane (3.4 mL, 7.8 g,
55 mmol) was added to a suspension of 6,6’-dibromobiphenyl-2,2’-diol (31; 8.6 g, 25 mmol)
and finely powdered potassium hydroxide (3.1 g, 55 mmol) in dimethylsulfoxide (25 mL) at
25 °C. After vigorous for 90 min, water (7.0 mL) was added and the precipitate was filtered to
give a white solid. Recrystallization from diethyl ether afforded colorless prisms; m.p. 221 -
223 °C; yield: 8.55 g (90%).
1 H NMR: δ = 7.28 (dd, J = 8.0, 1.2 Hz, 2 H), 7.23 (t, J = 8.0 Hz, 2 H), 6.92 (dd,
J = 8.0, 1.2 Hz, 2 H), 3.74 (s, 6 H) ppm.
13 C NMR: δ = 158.3, 129.9, 128.1, 125.3, 124.6, 110.0, 56.4 ppm.
C14H12Br2O2 (372.05) calcd. C 45.20% H 3.25%
found C 45.55% H 2.96%.
(-)-(P)-2,2’-Dibromo-6,6’-dimethoxybiphenyl (P-35): Prepared following the same
protocol, starting from (-)-(P)-6,6’-dibromobiphenyl-2,2’-diol (31); m.p. 173 - 174 °C;
[ ] 20
α D
= -51.5 (c = 1.0, acetone).
C14H12Br2O2 (372.05) calcd. C 45.20% H 3.25%
found C 45.20% H 3.21%.
(+)-(M)-2,2’-Dibromo-6,6’-dimethoxybiphenyl (M-35): Prepared following the same
protocol, starting from (+)-(M)-6,6’-dibromobiphenyl-2,2’diol (31); m.p. 172 - 174 °C;
[ ] 20
α D
= +51.1 (c = 1.0, acetone).
(±)-(PM)-2,2’-Dibromo-6,6’-diethoxybiphenyl (36): A solution of 6,6’-dibromobiphenyl-2,2’-diol
(31; 8.6 g, 25 mmol) in tetrahydrofuran (25 mL) was added dropwise to a 60% suspension of
sodium hydride in mineral oil (2.0 g, 50 mmol) in tetrahydrofuran (25 mL) at 25 °C. After 30
min, ethyl bromide (5.6 mL, 8.2 g, 75 mmol) was added and the reaction mixture was stirred
for 1 h. Water was then added (50 mL) and phases were decanted. The aqueous layer was

105
extracted with ethyl acetate (2 × 25 mL) and the combined organic layers were dried with
sodium sulfate and evaporated. The white solid obtained was recrystallized from ethanol to
afford colorless prisms; m.p. 116 - 118 °C; yield: 7.54 g (92%).
1 H NMR: δ = 7.26 (dd, J = 8.0, 1.0 Hz, 2 H), 7.20 (t, J = 8.0 Hz, 2 H), 6.90 (dd,
J = 8.0, 0.8 Hz, 2 H), 4.00 (symm. m, 4 H), 1.21 (t, J = 7.0 Hz, 6 H) ppm.
13 C NMR: δ = 157.5, 130.4, 129.8, 125.5, 124.6, 111.4, 64.9, 14.7 ppm.
C16H16Br2O2 (400.11) calcd. C 48.03% H 4.03%
found C 48.03% H 3.81%.
(-)-(P)-2,2’-Dibromo-6,6’-diethoxybiphenyl (P-36): Prepared following the same protocol,
starting from (-)-(P)- 6,6’-dibromobiphenyl-2,2’-diol (31); m.p. 83 - 84 °C; [ ] = -46.3
(c = 1.0, acetone).
(+)-(M)-2,2’-Dibromo-6,6’-diethoxybiphenyl (M-36): Prepared following the same
protocol, starting from (+)-(M)- 6,6’-dibromobiphenyl-2,2’-diol (31); m.p. 81 - 83 °C; [ ] 20
α D
= +45.9 (c = 1.03, acetone).
4.2 Preparation of 6,6’-Dibromobiphenyl-2,2’-dicarboxylic
Acid and Derivative Thereof
(±)-(PM)-6,6’-Dibromobiphenyl-2,2’-dicarboxylic acid (37): At -75 °C, butyllithium (43
mmol) in hexane (29 mL) was added dropwise to a solution of 2,2’,6,6’-tetrabromobiphenyl
(30; 10 g, 21 mmol) in tetrahydrofuran (0.10 mL). The resulting white suspension was then
poured on an excess of freshly crushed dry ice before being treated, at 25 °C, with 2.0 M
hydrochloric acid (50 mL, 0.10 mol). The volatiles were removed and the beige solid residue
was recrystallized from methanol to afford colorless prisms; m.p. 279 - 281 °C "decomp.";
yield: 7.70 g (90%).
1 H NMR (DMSO-d6): δ = 7.90 (dd, J = 8.0, 1.0 Hz, 2 H), 7.82 (dd, J = 8.0, 1.3 Hz, 2
H), 7.34 (t, J = 8.0 Hz, 2 H), 3.10 (s, 2H) ppm.
α
20
D

106
13 C NMR (DMSO-d6): δ = 167.2, 143.3, 137.0, 133.5, 130.7, 130.5, 125.8 ppm.
C14H8Br2O4 (400.02) calcd. C 42.04% H 2.02%
found C 42.26% H 2.03%.
Optical resolution of (±)-(PM)-6,6’-Dibromobiphenyl-2,2’-dicarboxylic acid (37):
Racemic diacid (37; 8.2 g, 21 mmol) was dissolved in boiling ethanol (40 mL) and quinine
(6.7 g, 21 mmol) was added. The mixture was heated for a further 30 min until it became a
clear yellow solution and the temperature was slowly brought to 25 °C where crystallization
occurred. The diastereoisomeric salt was filtered and recrystallized from ethanol to give
colorless crystals (7.03 g). Decomposition with 10% hydrochloric acid (40 mL, 80 mmol) and
the usual extraction protocol with ethyl acetate (2 × 30 mL) afforded the enriched (-)-(P)-(37)
enantiomer. This protocol was repeated until optical rotatory power remained constant;
colorless prisms; m.p. 234 - 236 °C; [ ] 20
α D = -7.3 (c = 1.02, ethanol); yield: 6.26 g (42%).
The residue obtained after evaporation of the combined mother liquor was decomposed the
same way to afford colorless prisms of the (+)-(M)-(37) enantiomer; m.p. 232 - 234 °C;
[ ] 20
α D
= +7.1 (c = 1.0, ethanol); yield: 5.81 g (39%).
C14H8Br2O4 (400.02) calcd. C 42.04% H 2.02%
found C 42.20% H 2.04%.
(±)-(PM)-Dimethyl-6,6’-dibromobiphenyl-2,2’-dicarboxylate (38): (±)-(PM)-6,6’-
Dibromobiphenyl-2,2’-dicarboxylic acid (37; 4.0 g, 10 mmol) was dissolved in methanol
(0.10 mL) with a catalytic amount of 96% sulfuric acid and heated at 60 °C for 7 h. The
mixture was then cooled down to 25 °C and crystallyzation occurred spontaneously. The solid
was collected by filtration and washed with water and cold methanol to afford white prisms;
m.p. 169 - 171 °C (ref. [15] m.p. 173 - 174 °C); yield: 3.77 g (88%).
1 H NMR: δ = 8.08 (dd, J = 7.8, 1.0 Hz, 2H), 7.86 (dd, J = 7.8, 1.0 Hz, 2 H), 7.37
(t, J = 7.9 Hz, 2 H), 3.66 (s, 6 H) ppm.
13 C NMR: δ = 166.0, 142.8, 136.6, 131.3, 129.7, 129.1, 125.2, 52.4 ppm.
(-)-(P)-Dimethyl-6,6’-dibromobiphenyl-2,2’-dicarboxylate (P-38): Prepared following the
same protocol, starting from (-)-(P)-6,6’-dibromobiphenyl-2,2’-dicarboxylic acid (37); m.p.
20
D
104 - 105 °C; [ α
] = -6.2 (c = 0.54, acetone).

107
(+)-(M)-Dimethyl-6,6’-dibromobiphenyl-2,2’-dicarboxylate (M-38): Prepared following
the same protocol, starting from (+)-(M)-6,6’-dibromobiphenyl-2,2’-dicarboxylic acid (37);
20
D
m.p. 103 - 105 °C; [ α ] = +5.8 (c = 0.51, acetone).
C16H12Br2O4 (428.07) calcd. C 44.89% H 2.83%
found C 44.65% H 2.67%.
(±)-(PM)-(6,6’-Dibromobiphenyl-2,2’-diyl)dimethanol (39): Prepared following the
procedure described by R. Schmid et al. [15] , starting from (±)-(PM)-dimethyl-6,6’-
dibromobiphenyl-2,2’-dicarboxylate (38; 3.0 g, 7.0 mmol); colorless prisms; m.p. 130 -
132 °C (ref. [15] m.p. 134 - 136 °C); yield: 2.19 g (84%).
(-)-(P)-(6,6’-Dibromobiphenyl-2,2’-diyl)dimethanol (P-39): Prepared following the same
protocol, starting from (-)-(P)-dimethyl-6,6’-dibromobiphenyl-2,2’-dicarboxylate (38); m.p.
[ ] 20
19
107 - 108 °C; α = -43.2 (c = 0.5, ethanol); ee > 99% (determined by F NMR analysis of
D
the enantiomerically pure Mosher ester derivative, in comparison with a racemic mixture of
the ester).
(+)-(6,6’-Dibromobiphenyl-2,2’-diyl)dimethanol (M-39): Prepared following the same
protocol, starting from (+)-(M)-dimethyl-6,6’-dibromobiphenyl-2,2’-dicarboxylate (38); m.p.
[ ] 20
19
105 - 107 °C; α = +41.9 (c = 0.51, ethanol). ee ≥ 98% (determined by F NMR analysis
D
of the enantiomerically pure Mosher ester derivative, in comparison with a racemic mixture of
the ester).
Preparation of Mosher ester derivative of (-)-(P)-(39) and (+)-(M)-(39): Under inert
atmosphere, the diol (39, 0.17 g, 0.45 mmol) was dissolved in a mixture of carbon
tetrachloride (2.0 mL) and pyridine (2.0 mL) at 25 °C and (R)-(-)-α-methoxy-α-
(trifluoromethyl)-phenylacetyl chloride (0.25 mL, 0.34 g, 1.35 mmol) was added. The
mixture was stirred for 20 h and the completion of the reaction was monitored by TLC.
N,N-dimethylethanolamine (0.1 mL, 9.0 mg, 1.0 mmol) and the mixture was stirred for a
further 30 min. Dichloromethane (5.0 mL) and 1.0 M hydrochloric acid (5.0 mL) were
added and phases were decanted. The organic layer was washed with brine, dried with
sodium sulfate and evaporated to dryness to afford a slightly yellow oil; yield: 347 mg
(96%).

108
(R)-(-)-MTPA ester from (-)-(P)-(39): prepared as described above; yield: 347 mg (96%).
1 H NMR: δ = 7.6 (m, 3 H), 7.4 - 7.2 (m, 13 H), 5.04 (d, J = 13.5 Hz, 2 H), 4.80 (d,
J = 13.5 Hz, 2 H), 3.50 (s, 6 H) ppm.
19 F NMR: δ = -71.5 ppm.
(R)-(-)-MTPA ester from (+)-(M)-(39): Prepared as described above; yield: 340 mg (94%).
1 H NMR: δ = 7.6 (m, 3 H), 7.4 - 7.2 (m, 13 H), 4.95 (d, J = 13.3 Hz, 2 H), 4.80 (d,
J = 13.3 Hz, 2 H), 3.45 (s, 6 H) ppm.
19 F NMR: δ = -71.9 ppm.
(±)-(PM)-2,2’-Dibromo-6,6’-bis(methoxymethyl)biphenyl (41): At 0 °C, a solution of
(±)-(PM)-(6,6’-dibromobiphenyl-2,2’-diyl)dimethanol (39; 2.5 g, 6.7 mmol) in
tetrahydrofuran (15 mL) was added to a suspension of sodium hydride (0.41 g, 17 mmol) in
tetrahydrofuran (5.0 mL). After the end of hydrogen emission, iodomethane (0.5 mL, 1.1 g,
8.0 mmol) was added at 25 °C to the reddish suspension which slowly faded to beige. Water
(10 mL) was added and the solvent was removed under reduced pressure and replaced by
ethyl acetate (10 mL). Phases decantation and extraction with ethyl acetate (2 × 7 mL) gave,
after drying and evaporation, an analytically pure colorless oil which resisted to all
crystallization attempts; yield: 0.93 g (93%).
1 H NMR: δ = 7.62 (d, J = 8.0 Hz, 2 H), 7.54 (d, J = 7.8 Hz, 2 H), 7.32 (t,
J = 7.9 Hz, 2 H), 4.09 (d, J = 13.0 Hz, 2 H), 4.02 (d, J = 13.0 Hz, 2 H), 3.26 (s,
6 H) ppm.
13 C NMR: δ = 139.6, 138.3, 131.9, 129.9, 126.5, 124.3, 72.6, 59.0 ppm.
C16H16Br2O2 (400.11) calcd. C 48.03% H 4.03%
found C 47.91% H 3.91%.
(-)-(P)-2,2’-Dibromo-6,6’-bis(methoxymethyl)biphenyl (P-41): Prepared following the
same protocol, starting from (-)-(P)-(6,6’-dibromobiphenyl-2,2’-diyl)dimethanol (39; 1.5 g,
4.0 mmol); colorless prisms; m.p. 87 - 89 °C; [ ] 20
D
α = -38.9 (c = 1.0, ethanol); yield: 1.39 g
(86%).

109
(+)-(M)-2,2’-Dibromo-6,6’-bis(methoxymethyl)biphenyl (M-41): Prepared following the
same protocol, starting from (+)-(M)-(6,6’-dibromobiphenyl-2,2’-diyl)dimethanol (39; 1.5 g,
4.0 mmol); colorless prisms; m.p. 86 - 88 °C; [ ] 20
α D = -37.3 (c = 1.0, ethanol); yield: 1.37 g
(86%).
4.3 Preparation of Biphenylbisphosphines
(-)-(P)-(6,6’-Dimethoxybiphenyl-2,2’-diyl)bis(diphenylphosphine) (42) [(-)-(P)-MeO-BIPHEP]:
Butyllithium (5.4 mmol) in hexane (3.5 mL) was added dropwise to a solution of (+)-(M)-
2,2’-dibromo-6,6’-dimethoxybiphenyl (35; 1.0 g, 2.7 mmol) in toluene (8.0 mL) and diethyl
ether (2.0 mL) at -75 °C. After 30 min, a solution of chlorodiphenylphosphine (1.1 mL, 1.3 g,
6.0 mmol) in toluene (10 mL) was added dropwise in order to keep the temperature below
-70 °C. The mixture was then warmed up to 25 °C and water (10 mL) was added. The phases
were separated and the aqueous one was extracted with ethyl acetate (2 × 10 mL) to give,
after evaporation of the volatiles, a colorless solid which was recrystallized from ethanol to
afford colorless needles; m.p. 213 - 215 °C (ref. [16] m.p. 214 - 215 °C); [ α ] D = -42.4 (c = 1.0,
[16]
chloroform), ee > 99% [ref. [ ] = -42.5 (c = 1.0, chloroform), ee 99.7%]; yield: 1.01 g
20
α
(64%).
D
(+)-(M)-(6,6’-Dimethoxybiphenyl-2,2’-diyl)bis(diphenylphosphine) (42) [(+)-(M)-MeO-BIPHEP]:
Prepared following the same protocol starting from (-)-(P)-2,2’-dibromo-6,6’-
dimethoxybiphenyl (35; 1.0 g, 2.7 mmol); colorless needles; m.p. 213 - 215 °C (ref. [16] m.p.
20
D
214 - 215 °C); [ α ] = +41.7 (c = 1.0, chloroform), ee > 98.5% [ref.
chloroform), ee 98.5%]; yield: 1.12 g (66%).
20
[16] 20 [ α ] D = +41.3 (c = 1.0,
(±)-(PM)-(6,6’-Diethoxybiphenyl-2,2’-diyl)bis(diphenylphosphine) (43): tert-Butyllithium (30
mmol) in pentane (21 mL) was added dropwise to a solution of (±)-(PM)-2,2’-dibromo-6,6’-
diethoxybiphenyl (36; 3.0 g, 7.5 mmol) in tetrahydrofuran (30 mL) at -75 °C. After 30 min, the
reaction mixture was treated with a solution of chlorodiphenylphosphine (3.5 mL, 4.2 g, 19 mmol)
in tetrahydrofuran (20 mL) and immediately allowed to reach 25 °C. The solvents were removed,
the residue was dissolved in dichloromethane (35 mL) and water (20 mL) was added. The usual
extraction procedure with dichloromethane (2 × 20 mL) afforded a white solid which was
recrystallized from ethyl acetate to afford colorless prisms; m.p. 253 - 254 °C; yield: 3.89 g (85%).

110
1 H NMR (acetone-d6): δ = 7.3 (m, 11 H), 7.2 (m, 11 H), 6.79 (dd, J = 8.3, 1.0 Hz,
2 H), 6.65 (dm, 2 H), 3.72 (dq, J = 9.5, 7.0 Hz, 2 H), 3.38 (dq, J = 9.5, 7.0 Hz),
2 H), 0.92 (t, J = 6.8 Hz, 6 H) ppm.
13 C NMR (acetone-d6): δ = 135.1 (t, J = 10.5 Hz), 134.2 (t, J = 10.5 Hz), 129.2,
129.1, 129.0 (t, J = 2.8 Hz), 128.7 (m), 126.8, 112.6, 63.8, 15.1 ppm.
31 P NMR (acetone-d6): δ = - 10.8 ppm.
C40H36O2P2 (610.66) calcd. C 78.67% H 5.94%
found C 78.59% H 5.86%.
(-)-(M)-(6,6’-Diethoxybiphenyl-2,2’-diyl)bis(diphenylphosphine) (M-43): Prepared
following the same protocol starting from (+)-(M)-2,2’-Dibromo-6,6’-diethoxybiphenyl (36;
1.2 g, 3.0 mmol); colorless prisms; m.p. 211 - 213 °C; [ ] 20
α D = -39.4 (c = 0.5,
dichloromethane); ee > 98% [determined by chiral HPLC analysis on Chiracel OD-phase,
cyclohexane/ethanol (1 : 3), 1.0 ml/min]; yield: 1.52 g (83%). For crystallographic data see
Table 6, § 4.5.
(+)-(P)-(6,6’-Diethoxybiphenyl-2,2’-diyl)bis(diphenylphosphine) (P-43): Prepared
following the same protocol starting from (-)-(P)-2,2’-Dibromo-6,6’-diethoxybiphenyl (36;
1.2 g, 3.0 mmol); colorless prisms; m.p. 207 - 209 °C; [ ] 20
α D = +38.6 (c = 0.54,
dichloromethane); ee 99% [determined by chiral HPLC analysis on Chiracel OD-phase,
cyclohexane/ethanol (1 : 3), 1.0 ml/min]; yield: 1.41 g (77%).
(±)-(PM)-[6,6’-Bis(methoxymethoxy)biphenyl-2,2’-diyl]bis(diphenylphosphine) (44): To a
solution of (±)-(PM)-2,2’-dibromo-6,6’-bis(methoxymethoxy)biphenyl (34; 8.0 g, 19 mmol)
in tetrahydrofuran (0.10 L) at -75 °C, was added tert-butyllithium (76 mmol) in pentane
(52 mL) over 1 h. A solution of chlorodiphenylphosphine (8.3 mL, 9.9 g, 45 mmol) in
tetrahydrofuran (45 mL) was added dropwise so that temperature stayed below -70 °C. After
the end of addition, the mixture was allowed to reach 25 °C and water (0.10 L) was added.
Extraction with ethyl acetate (2 × 70 mL), drying with sodium sulfate and evaporation of the
volatiles gave an orange solid which was recrystallized from ethanol to afford colorless
prisms; m.p. 200 - 202 °C; yield: 10.2 g (84 %).

111
1 H NMR: δ = 7.2 (m, 20 H), 7.2 (m, 2 H), 7.05 (dd, J = 8.2, 0.9 Hz, 2 H), 6.84 (d,
J = 9.0 Hz, 2 H), 4.43 (d, J = 7.0 Hz, 2 H), 4.30 (d, J = 7.0 Hz, 2 H), 3.09 (s, 6 H)
ppm.
31 P NMR: δ = -10.8 ppm.
C40H36O4P2 (642.66) calcd. C 74.76% H 5.65%
found C 74.56% H 6.00%.
(-)-(M)[6,6’-Bis(methoxymethoxy)biphenyl-2,2’-diyl]bis(diphenylphosphine) (M-44):
Prepared following the same protocol starting from (+)-(M)-2,2’-dibromo-6,6’-
bis(methoxymethoxy)biphenyl (34; 2.0 g, 4.6 mmol); m.p.107 - 109 °C; [ α ] = -21.9 (c = 1.0,
acetone); ee > 98% [determined by chiral HPLC analysis on Chiracel OD-phase,
cyclohexane/ethanol (1 : 3), 1.0 ml/min]; yield: 1.97 g (66%). For crystallographic data see
Table 6, § 4.5.
(+)-(P)-[6,6’-Bis(methoxymethoxy)biphenyl-2,2’-diyl]bis(diphenylphosphine) (P-44):
Prepared following the same protocol starting from (-)-(P)-2,2’-dibromo-6,6’-
bis(methoxymethoxy)biphenyl (34; 2.0 g, 4.6 mmol); m.p.107 - 109 °C; [ α ] = +22.2
(c = 1.0, acetone); ee > 99% [determined by chiral HPLC analysis on Chiracel OD-phase,
cyclohexane/ethanol (1 : 3), 1.0 ml/min]; yield: 2.10 g (69%).
(±)-(PM)-[6,6’-Bis(methoxymethyl)biphenyl-2,2’-diyl]bis(diphenylphosphine) (45): tert-
Butyllithium (11 mmol) in pentane (7.4 mL) was added dropwise to a solution of (±)-(PM)-
2,2’-dibromo-6,6’-bis(methoxymethyl)biphenyl (41; 1.1 g, 2.7 mmol) in tetrahydrofuran (5.0
mL) at -75 °C. After 30 min, the reaction mixture was treated with a solution of
chlorodiphenylphosphine (1.0 mL, 1.2 g, 5.4 mmol) in tetrahydrofuran (6.0 mL) and
immediately allowed to reach 25 °C. Water was added and the usual extraction procedure
with ethyl acetate (2 × 10 mL) afforded a yellowish amorphous solid which gave colorless
needles after recrystallization from ethyl acetate/hexanes (9:1) mixture; m.p. 249 - 251 °C;
yield: 1.30 g (79%).
1 H NMR (acetone-d6): δ = 7.4 (m, 10 H), 7.3 (m, 10 H), 7.2 (m, 6 H), 3.62 (d, J = 6.5
Hz, 2 H), 3.13 (d, J = 6.5 Hz, 2 H), 2.88 (s, 6 H) ppm.
20
D
20
D

112
13 C NMR (acetone-d6): δ = 133.4 (d, J = 10.4 Hz), 133.1 (d, J = 9.0 Hz), 132.8 (d,
J = 12.4 Hz), 132.6 (d, J = 13.0 Hz), 132.3 (d, J = 3.0 Hz), 132.1 (d, J = 3.0 Hz),
130.3 (d, J = 3.1 Hz), 129.2 (d, J = 11.2 Hz), 128.9 (d, J = 12.2 Hz), 127.3, 71.8,
58.0 ppm.
31 P NMR (acetone-d6): δ = -13.0 ppm.
C40H36O2P2 (610.66) calcd. C 78.67% H 5.94%
found C 78.74% H 6.01%.
(-)-(M)-[6,6’-Bis(methoxymetyl)biphenyl-2,2’-diyl]bis(diphenylphosphine) (M-45): Prepared
following the same protocol starting from (+)-(M)-2,2’-dibromo-6,6’-
bis(methoxymethyl)biphenyl (41; 1.0 g, 2.5 mmol); colorless needles (from ethyl
acetate/hexane); m.p. 199 - 201 °C; [ ] 20
α D = -41.9 (c = 0.5, chloroform); ee > 98.5%
[determined by chiral HPLC analysis on Chiracel OD-phase, cyclohexane/ethanol (1 : 3),
1.0 ml/min]; yield: 1.08 g (71%). For crystallographic data see Table 6, § 4.5.
(+)-(P)-[6,6’-Bis(methoxymetyl)biphenyl-2,2’-diyl]bis(diphenylphosphine) (P-45): Prepared
following the same protocol starting from (-)-(P)-2,2’-dibromo-6,6’-bis(methoxymethyl)biphenyl
(41; 1.0 g, 2.5 mmol); colorless needles (from ethyl acetate/hexane); m.p. 198 - 199 °C;
[ ] 20
α D
= +41.0 (c = 0.49, chloroform); ee 99% [determined by chiral HPLC analysis on Chiracel
OD-phase, cyclohexane/ethanol (1 : 3), 1.0 ml/min]; yield: 1.13 g (74%).
4.4 Coalescence Studies of Dilithiobiphenyl Species
Sample preparation: The dibromobiphenyl (34 or 41; 0.70 mmol) in perdeuterated
tetrahydrofuran (3.0 mL) was added to a solution of tert-butyllithium (2.8 mmol) dissolved in
precooled (-75 °C) perdeuterated tetrahydrofuran (5.0 mL). By means of a precooled pipet, an
aliquot was withdrawn (1.0 mL) and transferred into a nitrogen purged 5 mm NMR tube,
which was plunged into liquid nitrogen before being sealed under vacuum.

113
2,2’-Dilithio-6,6’-bis(methoxymethoxy)biphenyl (47):
1 H NMR (-50 °C): δ = 7.3 - 7.1 (m, 4 H), 7.0 (m, 2 H), 5.15 (d, J = 6.9 Hz, 2 H),
4.93 (d, J = 6.9 Hz, 2 H), 3.57 (s, 6 H) ppm.
1 H NMR (-11 °C, coalescence temperature): δ = 7.3 - 7.1 (m, 4 H), 7.0 (m, 2 H),
5.02 (s broad, 4 H), 3.55 (s, 6 H) ppm.
2,2’-Dilithio-6,6’-bis(methoxymethyl)biphenyl (49):
1 H NMR (-50 °C): δ = 7.51 (d, 2 H), 7.3 (m, 2 H), 7.10 (d, 2 H), 4.13 (d,
J = 12.5 Hz, 2 H), 4.06 (d, J = 12.5 Hz, 2 H), 3.20 (s, 6 H) ppm.
1 H NMR (24 °C, coalescence temperature): δ = 7.51 (d, 2 H), 7.3 (m, 2 H), 7.09
(d, 2 H), 4.10 (s broad, 4 H), 3.18 (s, 6 H) ppm.

114
4.5 Seclected Crystallographic Data for Biphenylbisphosphines
(M)-43 (M)-44 (M)-45
Empirical formula C40H36O2P2 C40H36O4P2 C40H36O2P2
Crystal system Monoclinic Triclinic Orthorhombic
Space group P2(1)/n P1 Fdd2
Unit Cell dimension
a = 12.7416(17) Å,
α = 90°
b = 16.912(3) Å,
β = 96.113(11)°
c = 15.819(2) Å,
γ = 90°
Volume 3389.2(8) Å 3
Distances (Å)
a = 9.5032(10) Å,
α = 106.628(10)°
b = 13.4628(16) Å,
β = 95.321(8)°
c = 14.3427(15) Å,
γ = 93.138(9)°
a = 25.295(3) Å,
α= 90°
b = 28.389(3) Å,
β= 90°
c = 9.0567(9) Å,
γ = 90°
1744.3(3) Å 3 6503.8(12) Å 3
P(1)-C(1) 1.847(2) 1.844(4) 1.841(5)
P(2)-C(8) 1.848(2) 1.840(4) -
O(1)-C(5) 1.368(3) 1.378(4) -
O(2)-C(12) 1.368(3) - -
O(3)-C(12) - 1.389(4) -
C(6)-C(7) 1.497(3) 1.497(5) 1.513(5)
Angles (°)
C(2)-C(1)-P(1) 123.49(16) 124.8(3) 122.4(4)
C(6)-C(1)-P(1) 117.29(15) 116.5(3) 118.0(3)
C(9)-C(8)-P(2) 123.59(16) 124.2(3) -
C(7)-C(8)-P(2) 116.79(15) 116.4(3) -
O(1)-C(5)-C(4) 123.8(2) 124.2(4) -
O(1)-C(5)-C(6) 115.46(18) 114.9(4) -
O(2)-C(12)-C(11) 124.1(2) - -
O(3)-C(12)-C(11) - 123.5(4) -
O(2)-C(12)-C(7) 115.27(18) -
O(3)-C(12)-C(7) - 115.2(4) -
C(5)-C(6)-C(7) 119.25(18) 121.2(4)
C(5)-C(6)-C(6A) - - 119.8(4)
C(1)-C(6)-C(7) 121.24(19) 119.4(4) -
C(1)-C(6)-C(6A) - - 119.6(4)
C(12)-C(7)-C(6) 119.79(18) 118.8(4) -
C(8)-C(7)-C(6) 120.92(19) 121.1(4) -
C(1)-C(6)-C(7)-C(8) -73.9(3) -84.4(5) -
C(1A)-C(6A)-C(6)-C(1) - - -88.3(4)

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PCl
25d:
p.26, 27, 72
C 2H 6ClP
PCl
25f: p.26, 27, 73
C 6H 14ClP
P
O
27k: p. 28, 81
C 6H 15OP
PCl
25b: p.26, 27, 72
C8H18ClP
PN
24c: p. 25, 26, 71
C 8H 20NP
125
Compounds Index
PCl
25c: p.26, 27, 72
C 4H 10ClP
P
26i: p. 27, 77
C 6H 15P
PN
24d: p. 25, 26, 71
C 6H 16NP
PCl
25a: p.26, 27, 71
C 8H 18ClP
P
26f: p. 27, 28, 75
C 9H 21P
Cl
PN
Cl
23: p. 25, 26, 70
C 4H 10Cl 2NP
P
26h: p. 27, 76
C 6H 15P
P
26k: p. 27, 77
C 7H 17P
P
26g: p. 27, 75
C 8H 19P
P
26c: p. 27, 28, 74
C 9H 21P
Br Br
I
29: p. 34, 35, 85
C 6H 3Br 2I
O
P
27f: p. 27,28, 79
C 6H 15OP
O
P
27h: p. 27, 28, 80
C 7H 17OP
O
P
27e: p. 27, 28, 29, 78
C 8H 19OP
P
O
27j: p. 29, 80
C 9H 21OP

O
P
27i: p. 30, 80
C 9H 21OP
P
26b: p. 27, 74
C 11H 25P
P
28a: p. 28, 29, 81
C 10H 24IP
O
P
27b: p. 27, 31, 77
C 11H 25OP
I
126
P I
28b: p. 28, 30, 82
C 10H 24IP
Br Br
Br Br
30: p. 33, 34, 35
36, 39, 85
C 12H 6Br 4
N N
Br
Br Br Cl N
18: p. 15
17: p. 15, 16, 65, 66
20: p. 16, 17, 66
C12H11Br2N
C12H12BrN C12H12ClN PCl
25e: p.26, 27, 73
C 12H 22ClP
O
P
27a: p. 27, 28, 30, 77
C 12H 27OP
P
26e: p. 27, 75
C 12H 27P
PN
24b: p. 25, 26, 70
C 12H 28NP
P
26a: p. 27, 28, 73
C 12H 27P
PN
24a: p. 25, 26, 70
C 12H 28NP
P I
28e: p. 29, 83
C 10H 24IP
Br OH
Br OH
31: p. 35, 36, 37, 38
39, 40, 44, 51, 86
C 12H 8Br 2O 2
N
14: p. 14, 15, 16, 65
C 12H 13N
P
O
27d: p. 27, 28, 30, 78
HOOC
C 12H 27OP
N
(S)-22: p. 17, 67
C 13H 13NO 2

Br COOH
Br COOH
37:
p. 35, 39, 40
41, 42, 89, 90
C14H8Br2O 4
P
O
3
8:
p. 13, 62
Br O
Br O
35: p. 38, 39, 42
44, 88
C14H12Br2O 2
P
O
OH
13: p. 13, 14, 64
C15H15O3P
C15H15O6P Br
Br
N
15: p. 14, 15
C 13H 15N
41: p. 42, 46, 53
92, 93
C16H16Br2O 2
P
O
O
O
27g: p. 27, 28, 30, 79
C 16H 31OP
N
16: p. 15
C 13H 15N
Br O
Br O
3
O
O
34: p. 38, 45, 51
87, 88
C16H16Br2O 4
127
Br
Br
OH
OH
39: p. 41, 42, 46
53, 91
C14H12Br2O 2
Br COOCH 3
Br COOCH 3
38: p. 41, 90, 91
O
C 16H 12Br 2O 4
N
O
P
26d: p. 27, 28, 74
C 13H 29P
N
(S)-21: p. 16, 17, 67
C 16H 16N 2O 2
P
O
P
27c: p. 27, 28, 29, 78
C 13H 29OP
H
O
12: p. 14, 64
C 15H 9O 6P
Br O
Br O
3
36: p. 38, 39, 44
88, 89
C16H16Br2O 2
P
O
26j: p. 27, 77
C 16H 31P
P I
P I P O
28c: p. 28, 30, 82
C 16H 36IP
28d: p. 28, 29, 82
C 17H 38IP
1: p. 11, 59
C 21H 21O 3P
3

P
P
P
O
2: p. 11, 59
3
P
O
O
O
11: p. 14, 63
3
128
P
O
2
5: p. 11, 16, 61
P
O
9: p. 13, 62
C21H21O3P C21H21O9P C22H19OP C24H15O3P 3
7: p. 10, 11, 61
C 24H 27P
6: p. 11, 61
C 30H 21P
3
Ph2P O
Ph2P O
44: p. 45, 46, 94
95, 98
C40H36O4P 2
O
O
P N
3: p. 11, 60
C 24H 30N 3P
Ph2P O
Ph2P O
42: p. 44, 46, 93
C 38H 32O 2P 2
3
O P
N
2
(S)-19: p. 16, 17, 68
C 26H 29N 3OP
Ph2P O
Ph2P O
43: p. 44, 45, 46
93, 94, 98
C40H36O2P 2
P
Ph 2P
Ph 2P
3
4: p. 11, 60
C 30H 21P
3
O
O
45: p. 46, 47, 95
96, 98
C40H36O2P 2

Curriculum Vitae

Nom Maurin
Prénom Michaël
129
Curriculum Vitae
Date de Naissance 27 Juin 1976
Lieu de Naissance Thiais, France
Nationalité Française
Etat Civil Célibataire
ETUDES
1987 – 1991 Collège à Thiais, France.
1991 – 1994 Lycée à Thiais, France. Obtention du Baccalauréat
série C (Scientifique).
1994 – 1996 Préparation au Concours National Vétérinaire, Paris,
France.
1996 – 2000 Etudes de chimie à l'Université Paris XI, Orsay, France.
2000 – 2001 Stage de D.E.A. à l'Institut Curie, Orsay, France, sous
la responsabilité du Dr David Grierson: "Synthèse de
Nouveaux Fluorophores Utilisables dans la Technologie
des Puces à ADN".
Juin 2001 Diplôme d'Etude Approfondies (D.E.A.) en Chimie
Organique, Université Paris XI, Orsay, France.
Octobre 2001 Début d'un travail de doctorat à l'Ecole Polytechnique
Fédérale de Lausanne sous la responsabilité du
Professeur Manfred Schlosser; Assistant responsable
de la surveillance des travaux pratiques de chimie du
6 ème semestre.

130
Publication
F. Leroux, M. Maurin, N. Nicod, R. Scopelliti, "The Remarkable Configurational Stability of
Ortho,ortho'-tetrafluoro Substituted Biphenyls: 2,2',4,4',6,6'-Hexafluorobiphenyl-3,3'-
dicaboxylic as a Model", Tetrahedron Lett. 2004, 45, 1899 – 1902.