Herrmann Staudinger: From Organic to Macromolecular Chemistry

R
O
R = CH 3; CO 2CH 3
O
O
Herrmann Staudinger:
From Organic to
Macromolecular Chemistry
April, 11, 2011
Christian Grünanger
η sp
c
= K m • M
R 1
O
R 2
H H
R3 R4

International Historic Landmark of Chemistry
Origin of Polymeric Sciences
review: Mühlhaupt, R. Angew. Chem. Int. Ed. 2004, 43, 1054-1063.

1903:
1903-1907:
1907-1912:
* March 23, 1881 in Worms
Overview
PhD from University of Halle
Habilitation with J. Thiele at
University of Strasbourg
Asstistant Professor at
Technical University of Karlsruhe
1912-1926: Professor at ETH Zürich
1926-1956:
Professor at Albert-Ludwigs-
University, Freiburg
+ September 8, 1965 in Freiburg
malonate addition to
unsaturated compounds
ketene chemistry
oxalyl chloride,
aliphatic diazo compounds,
carbene reactions,
new organophosphorus compounds,
biofunctional small molecules,
preparation and polymerization of
isoprene and butadiene
development of the concept
of macromolecules

1905:
1907:
Ketenes: Isolation and Identification
Ph
Cl
Ph
O
Cl
Zn
Staudinger, H. Ber. Dtsch. Chem. Ges. 1905, 38, 1735 - 1739.
Ph
Ph
C O
Ph
N
Ph
Ph
Ph
C O
also describes !-lactones and cyclobutanones
Staudinger, H. Justus Liebigs Ann. Chem. 1907, 356, 51-123.
Ph
Ph
Ph
N
O
Ph
ZnCl 2

Ketenes: Importance for !-Lactam Synthesis
1928: A. Fleming: Discovery of Penicillin
R
O
H
N
O
H
N
S
Me
Me
COOH
Penicilin core structure
S
Me
O N Me
O
COOH
Benzylpenicillin, Penicillin G
O
H
N
H
N
H
S
Me
O N Me
O
COOH
Phenoxymethylpenicillin, Penicillin V
H
R 2
O
H
N
O
H
N
S
COOH
R 1
Cephalosporin core structure
NC
O
H
N
H
S
N
O
COOH
Cefacetril
NH 2
O
H
N
O
Cefradine
H
N
S
O
COOH
O

Ph
First synthetic penicillin structure
O
N
N
O
S
O
Cl
Me
Me
COOMe
Et 3N
(13% yield)
!-Lactams in Total Synthesis
O
N
O
O
Ph
S
N
(rac.)
Me
Me
1) H 2O
2) CH 2N 2
COOMe
KMnO4 AcOH/dioxane/H2O (82% yield)
MeO
O
O
N
O
O
O
H
N
O
Ph
S
Me
O O
N
Ph
S
N
biologically inactive
Me
COOMe
biologically inactive
Sheehan, J. C.; Buhle, E. L.; Corey, E. J.; Laubach, G. D.; Ryan, J. J. J. Am. Chem. Soc. 1950, 72, 3828-3829.
Me
Me
COOMe

Me
MeO
!-Lactams in Total Synthesis
Synthetic Studies on Ecteinascidin-743
OMe
OBn
DBU, THF
CHO
75%
(25% start. mat.)
1. BnNH 2, PhH
2. Et3N, CH2Cl2 Ph
O
Ph
N
O
COCl
(99% yield)
Me
MeO
OMe H
OBn
Bn
N
OMe H
Jin, W.; Metobo, S.; Williams, R. M.; Org. Lett. 2003, 5, 2095-2098.
Me
MeO
NH
CO 2Me
H
O
Ph
OBn
Bn
N
Ph
N
H
O
O
O
1. Pd(OH) 2, H 2 (60psi)
MeOH/THF
2. MeO 2CCHO, MeOH
(84% yield)
Me
MeO
HO
MeO
Me
O
O
OMe H
OBn
AcO
O
O
Bn
N
N
NH
S
H
Me
MeO
H
O
H
N
O
OBn
H
HO
H
OH
NHMe
NMe
H
OMe H
OBn
OMe
Bn
N
NH
CO 2Me
Me OMe
OH
Me
H
O

!-Lactams in Total Synthesis
Synthetic Studies on Ecteinascidin-743
Me
MeO
H 2O work-up
-BnNH 2
OMe H
OBn
Bn
N
N
H
O
O
OBn
H
Me
MeO
NHMe
MeO
Me OMe
OBn
OH
LiBEt 3H, THF
0°C, 10 min.
(49% yield)
Jin, W.; Metobo, S.; Williams, R. M.; Org. Lett. 2003, 5, 2095-2098.
N
O
O
OBn
NHMe
OMe
HO Me
Me
MeO
-H 2O
MeO
HO
MeO
OBn
Me
O
Li
BnN O
Me
MeO
O
AcO
N
O
O
OBn
H
MeO
O
OBn
NH
S
H
H
N
NHMe
Me OMe
N
O
OBn
HO
H
OH
NMe
H
NMe
OMe
OH
OMe
Me
HO Me

H
O
!-Lactams in Total Synthesis
Synthetic Studies on Ecteinascidin-743 - Origin of Diastereoselectivity
Ar
BnNH 2
Me
MeO
Bn
H
N
Ar
OMe
OBn
CHO
O
C
H N
O
1. BnNH 2, PhH
2. Et3N, CH2Cl2 Ph
O
Ph
N
O
COCl
Ph
O
(99% yield)
Ph
Bn
H
N
Me
MeO
Ar H
O
OMe H
Ph
OBn
O
N
4 " conrotatory
for mechanistic studies: Venturini, A.; González, J. J. Org. Chem. 2002, 67, 9089-9092.
Ph
O
Bn
N
Ph
N
Ph
H
O
O
O
Bn O
N
Ar
Ph
N
O
O
Ph

Me
I
I
Me
Cl 3C
O
Cyclobutanones in Total Synthesis
Cl
Zn-Cu
POCl 3, Et 2O, 20 °C
(80% yield)
RuO 2 (cat), NaIO 4,
CH 3CN/CCl 4/H 2O (1.5:1:1), 20 °C
Me
Me
H
(93% yield over 2 steps)
O
O
OTBDMS
DME/HMPA,
LHMDS (2x), -60 °C
(68% yield)
Cl
Cl
O
HOOC
HOOC
TBDMSO
Me
Me
H
Me
Me
H
MeO 2C
n-BuLi, THF, -78 °C,
then Ac 2O, -78 °C ! 20 °C
LiAlH 4,
THF, "
(91% yield)
Me
Me
H
(2.5:1)
HO
HO
Me
Me
H
HF, CH 3CN, 20 °C
(79% yield)
Cl
AcO
Me
Me
H
not isolated
TMSI,
CHCl 3, 20 °C
O
(75% yield)
O
Me
Me
H
(+)-Bakkenolide A
Brocksom, T. J.; Coelho, F.; Deprés, J.-P.; Greene, A. E.; Freire de Lima, M. E.; Hamelin, O.; Hartmann, B.; Kanazawa, A. M.;
Wang, Y. J. Am. Chem. Soc. 2002, 124, 15313-15325.

R 1 R 2
Reactivity of Ketenes with Alkenes
R 3
O
C
Huisgen, R.; Mayr, H. Tet. Lett., 1975, 16, 2969-2972.
R 4
R 1
O
R 2
H H
R3 R4 LUMO of ketene: antarafacial
HOMO of alkene: suprafacial
R 1
R 2
H
H
O
R3 R4

Coffee break?

Isolation of Coffee and Pepper flavors
!1914-1918 due to shortage of coffee during WWI
Coffee: Isolation of 70 compounds
O
SH
O
Reichstein, T.; Staudinger, H. Angew. Chem. 1950, 62, 292.
Johnston, W. R.; Frey, C. N.; J. Am. Chem. Soc. 1938, 60, 1624-1627.
OH
Pepper: Search for surrogates
O
N
O
piperine (!10% in natural pepper)
a) Staudinger, H.; Schneider, H. Ber. Dtsch. Chem. Ges. 1923, 56, 699-711.
b) Staudinger, H.; Müller, F.; Ber. Dtsch. Chem. Ges. 1923, 56, 711-715.
O
O
O
O
N
O
O
N
N
O
H 2S
Staudinger's surrogates

MeO
Identification of Pyrethrins as active ingredients of
Dalmatian insect-powder
O
O
OH
HO
R
O
R = CH 3; CO 2CH 3
O
O
OH
a) Staudinger, H.; Ruzicka, L. Helv. Chim. Acta 1924, 7, 201-211.
b) Staudinger, H.; Ruzicka, L. Helv. Chim. Acta 1924, 7, 212-235.
O
NaOH (aq.)
O
O
OH
HO
O

OH
O
chrysanthemic acid
Identification of Pyrethrins
H 2 (only 1 mol consumed!),
O
m.p.: 132-132.5 °C
not known
OH
O
chrysanthemic acid
NH 2
Pd
NH 3
Br 2 (only 1 mol consumed)
Br Br
a) Staudinger, H.; Ruzicka, L. Helv. Chim. Acta 1924, 7, 201-211.
b) Staudinger, H.; Ruzicka, L. Helv. Chim. Acta 1924, 7, 212-235.
O
SOCl 2
O
OH
Cl
O
OH
H 2N
KMnO 4
Br 2
O
H
N
m.p.: 82-83 °C
not known

OH
O
chrysanthemic acid
Identification of Pyrethrins
OMe
O
chrysanthemic acidmethyl
ester
a) Staudinger, H.; Ruzicka, L. Helv. Chim. Acta 1924, 7, 201-211.
b) Staudinger, H.; Ruzicka, L. Helv. Chim. Acta 1924, 7, 212-235.
O 3
16 h, CH 2Cl 2
O 3
16 h, CH 2Cl 2
O
BnOH
OBn
OBn
O
HO
OH
O O
trans-caronic acid
known
charactarized
from acetal structure
HO
O
O
OMe
trans-caronic acidmethyl
ester
known

1919:
The Staudinger reaction: early development
Ph3P + N2C Ph3P N N C
Ph 3P + N 3
+
N 2
Ph 3P N
a) Staudinger, H.; Meyer, J. Helv. Chim. Acta., 1919, 2, 619-635.
b) Staudinger, H.; Meyer, J. Helv. Chim. Acta., 1919, 2, 635-646.
c) Staudinger, H.; Hauser, E. Helv. Chim. Acta., 1921, 4, 861-886.
+
N 2
-N 2
H 2O
Ph 3P C
Ph 3P O +
H 2N

The Staudinger reaction: mechanism and applications
R 1 N N N
N PX 3
R 1
Iminophosphorane
(aza-ylide)
R 1 N N N
PX 3 R 1 N N N
PX 3
phosphazide
H2O - X3P O R1 NH staudinger
2
R 2
O
OH
- X3P O
R 2
O
X
- X3P O
-
R 2
O
R 3
X 3P O
O R 2
NH
R1 X R 2
N
R1 R 3 R 2
N
R1 reduction
aza-Wittig
reaction
R 1
N
N N
PHX 3
electrophilic trap
O
Ph
N R
P
1
Ph Ph
O
P
Ph
-N 2 N PX 3
R 1
H 2O
OMe
N R 1
staudinger
ligation
Iminophosphorane
(aza-ylide)
- CH 3O -
O
N
H
P O
Ph Ph
R 1

O
TsO
MeI, CaCO 3,
aq. CH 3CN
(74% yield)
Ph
PMBO
Staudinger reduction: Synthetic application
O
a) n-BuLi, 1,3-dithiane, THF;
b) vinylmagnesium bromide,
CuI, THF
PMBO
TMSOTf, Et 3N
CH 2Cl 2
(96% yield)
O
O
(63% yield)
CHO
OTMS
Ph
Ph
BF 3•OEt 2
CH 2Cl 2, -78°C
(89% yield)
PdCl 2, Cu(OAc) 2•H 2O,
AcNMe 2/H 2O (7:1)
(77% yield)
Yokokawa, F.; Asano, T.; Shioiri, T. Org. Lett. 2002, 2, 4169-4172.
OH
S
S
PMBO
O
PMBO
KH, PMBCl,
n-Bu 4NI, THF
(86% yield)
OH
dr: 88:12
O
O
O
PMBO
S
a) Et2BOMe, NaBH4, THF;
Ph
Ph
S
b) 2,2 - dimethoxy propane,
PPTs
(59% yield)
+ (9% all syn)

O
PMBO
Staudinger reduction: Synthetic application
O
O
a) OsO 4, NMO, aq. acetone;
b) NaIO 4, pH 7, buffer, THF;
c) Cp 2TiCH 2AlClMe 2, THF
(72% yield)
a) MsCl, Et 3N, DMAP, CH 2Cl 2
b) n-Bu 4NN 3, DMF, 100 °C
(68% yield)
Ph
PPTs, MeOH
OPMB
O
MeO H
OPMB
O
MeO H
(85% yield)
OPMB
O
MeO H
OMe
OMe
OMe
O
MeO H
Yokokawa, F.; Asano, T.; Shioiri, T. Org. Lett. 2002, 2, 4169-4172.
N
N 3
OTBDPS
O
OPMB
OH
Ph
a) OsO 4, NMO, aq. acetone;
NaH, MeI,
THF
(98% yield)
b) TBDPSCl, Et 3N, DMAP, CH 2Cl 2
N
Ph 3P,
(94% yield)
aq. THF, 55°C
(68% yield)
O
(!)-Hennoxazole A
OPMB
O
MeO H
O
MeO H
OMe
OPMB
O
MeO H
OPMB
NH 2
OTBDPS
OMe
OMe
OH
Ph
OTBDPS

R 2
Ph
O
P
Ph
OMe
The Staudinger Ligation: Introduction
N 3 R 1
electrophilic trap
O
OMe
P N R1 N R
P
Ph
Ph
1
- CH3O Ph Ph
-
H2O R2 R2 R2 Clue: Coupling of abiotic reagents (phosphines and azides)
under biocompatible conditions
Phosphine oxide and R 2 is only present and
covalently bound at reaction position
Allows examination of biological processes
O
O
N
H
P O
Ph Ph
R 1

HN
HN
O
S
S
NH
H
N
H
N
O
Biotin water soluble linker
NH
Staudinger ligation on cell surfaces
introduced by unnatural
sialic acid biosynthesis
O
3
N 3
O
Ph 2P
O O
O
H
N
Ph 2P
Saxon, E.; Bertozzi, C. R. Science 2000, 287, 2007-2010.
O
3
H
N
O
HO
H
N
O
OH
OMe
HN
HO
O
O
OH
O
HO
H
N
O
CO 2 -
OH
HO
O
OH
O
CO 2 -
O

Staudinger ligation on cell surfaces
Saxon, E.; Bertozzi, C. R. Science 2000, 287, 2007-2010.

Pyrolysis of 6-membered rings: one of the first
industrial routes to 1,3-dienes
! (Pt wire)
2-3 mbar
(60% yield)
Staudinger, H.; Klever, H. W. Ber. Dtsch. Chem. Ges. 1911, 44, 2212-2215.

efore ca. 1920-1930:
Definition of the word "polymer"
1833: Berzelius [a] : compounds of the same chemical composition
that exhibit very different properties. = isomers, homologues
a) Berzelius, J. Jahresber. Fortsch. Phys. Wissensch. 1833, 12, 63.
b) Berthelot, P. E. M. Bull. Soc. Chim. Fr. 1866, 6, 268.
1866: Berthelot [b] reports the formation of the "polymers"
benzene and styrene upon heating acetylene
The concept of macromolecules was not accepted
ca. 1930: The community accepted Staudingers concept of macromolecules
polymers = macromolecules

natural rubber:
bakelite:
OH
1920: known polymers - structure unknown
n
OH
OH
n
vulcanized rubber:
S
S
S
S
n
S S
n
and others

Proposed wrong structures and misleading experiments
1902: Harries' proposal for natural rubber. [a] self-assembly of dimethylcyclooctadiene
O 3
1914: Pickles' bromination of natural rubber. [b] First proposal of covalent bonds
between isoprene monomer molecules. Underestimation of molecular weight.
n
1923: Brills cristallographic work on silk fibroin [c] :
protein molecules M = 500 - 600 g/mol
a) Harries, C. Ber. Dtsch. Chem. Ges. 1902, 35, 3256.
b) Pickles, S. S. J. Chem. Soc. 1910, 97, 1085.
c) Brill, R. Justus Liebigs Ann. Chem. 1923, 434, 204.
Br 2
O
Br
Br
O
n

1922 [a] :
First experimental evidence
H 2 (100 bar)
Pt, 270 °C
n n
n ?
a) Staudinger, H.; Fritschi, J. Helv. Chim. Acta 1922, 5, 785-806.
H
H
similar characteristics

Final evidence: Staudingers viscosity law
for molecules in highly diluted solution (no interaction of molecules):
Einsteins viscosity law: ! sp = K c • N L
M
for one and the same substance in different concentrations:
! sp
c
= K'
Staudinger, H.; Heuer, W. Ber. Dtsch. Chem. Ges. 1930, 63, 222-234.
"
! sp = specific viscosity
K = constant (depending on solvent, substance)
N L = Avogadro (Loschmidt) - constant
" = volume of particle
Glucose
NL M " K = K'
c (g/mol) ! sp ! sp/c
1.00
2.11
4.63
10.20
15.72
20.14
24.03
0.027
0.062
0.131
0.316
0.619
0.901
1.216
0.027
0.029
0.028
0.031
0.039
0.045
0.056
association
of
molecules

Final evidence: Staudingers viscosity law
for polystyrene (polymerized by heating, M W > 10000:
! sp
c
= K'
Staudinger, H.; Heuer, W. Ber. Dtsch. Chem. Ges. 1930, 63, 222-234.
polystyrene
c (g/mol) ! sp ! sp/c
0.125
0.25
0.5
0.75
1.0
1.5
2.0
Einsteins viscosity law: ! sp = K c • N L
M
"
0.54
1.21
3.05
5.69
9.25
31.00
59.5
4.32
4.84
6.10
7.58
9.25
20.66
29.75
association ?
! sp = specific viscosity
K = constant (depending on solvent, substance)
N L = Avogadro (Loschmidt) - constant
" = volume of particle
what is the volume of a macromolecule?

Final evidence: Staudingers viscosity law
r
h
h = length of molecule
r = "radius" of chain
1/2 h
2r
Staudinger, H.; Heuer, W. Ber. Dtsch. Chem. Ges. 1930, 63, 222-234.
macromolecule considered to be a cylinder:
" = r 2 # h ! sp = K c • N L • r 2 # h
M
! sp = K c • N L
M
! sp = K' c does not apply!
macromolecule allowed to move in volume:
" = 1
2 r # h2 ! sp = K c • NL • r # h2
2 M
! sp = K' c h = K m • c • M
! sp
c
= K m • M does apply!
"

Final evidence: Staudingers viscosity law
polystyrenes, polymerized by heating
n
polymerization
conditions
6 h 260 °C
12 h 150 °C
53 d 100 °C
17 d 65 °C
cold
Staudinger, H.; Heuer, W. Ber. Dtsch. Chem. Ges. 1930, 63, 222-234.
! sp
c
3.365
12.26
22.6
30.3
56.0
! sp
c
M
(K m = 0.25 • 10 -3 )
13400
49000
90500
121000
200000
= K m • M

1953: Nobel prize in Chemistry

for help with this talk: Marina
Acknowledgements
for the exciting time at Caltech: Brian, Stoltz Lab, Reisman Lab