Theoretical study of aminoalkylation in the Mannich reaction of furan ...

Introduction
Theoretical Study of Aminoalkylation in
the Mannich Reaction of Furan with
Methyleneimminium Salt
UKO MARAN, 1 ALAN R. KATRITZKY, 2 MATI KARELSON1 1
Department of Chemistry, University of Tartu, 2 Jakobi Str., Tartu EE2400, Estonia
2
Florida Center for Heterocyclic Compounds, Department of Chemistry, University of Florida,
Gainesville, Florida 32611-7200
Received 30 July 1997; revised 13 October 1997; accepted 24 October 1997
ABSTRACT: The potential energy surface for the reaction of furan and
methyleneimminium cation with formation of a Mannich base has been studied using
AM1 and PM3 semiempirical calculations. Nonspecific solvent effects were taken account
of in the framework of the multicavity self-consistent reaction field approach.
Characteristics of the reaction path elucidated for various media are discussed.
Key words: semiempirical calculations; solvent effects; Mannich reaction; reaction
mechanism
T he Mannich reaction is a three-component
condensation in which an active hydrogen
atom containing compound reacts with formaldehyde
and an NH derivative with the elimination
of a water molecule 1 .
As shown in Scheme 1, the Mannich reaction
product Ž the Mannich base. has the N-atom of the
nitrogen functionality linked to the substrate R
through a methylene group. This transformation
was first discovered by Carl Mannich in 1912 when
Correspondence to: M.Karelson.
he treated a salicylantipyrine pharmaceutical preparation
and urotropine with acid 2 .
Since then,
and especially during recent decades, Mannich reactions
and their Mannich base products have
gained significant importance, especially as pharmaceuticals
and pesticides and in the preparation
of natural and synthetic macromolecules. The relatively
mild conditions of the Mannich reaction and
its application to the synthesis of a large variety of
compounds Ž Scheme 1. has been recently reviewed
by Tarmontini and Angiolini 1 .
Two different pathways Ž I and II in Scheme 2.
have been proposed for the sequence in which
three components in the Mannich reaction become
linked Ž Scheme 1. 1 .
According to the first path-

SCHEME 1
way I, formaldehyde and the amine initially form
an equilibrium with the corresponding aminomethyl
carbocation or methyleneimminium salt 3 ,
which further reacts with the CH substrate. In the
second pathway II Ž Scheme 2 . , a C-hydroxymethylene
derivative is first generated, and this gives the
Mannich base by reaction with amine. Instead of
using three-component reaction mixtures, in an
alternative procedure Ž based on pathway I . , the
imminium salt is preformed and mixed thereafter
with the substrate 3 .
This procedure separates the
three-component reaction into two steps and enables
deeper insight into the mechanism of the
formation of Mannich bases. Accordingly, we restricted
our theoretical treatment to a study of the
interaction of the imminium salt and substrate.
The imminium salt formed from formaldehyde
and dimethylamine Žlong
considered as an intermediate.
4, 5 ,
has been developed as a Mannich
reagent 69 ,
and extensively used in synthetic
work where it shows advantages in yield and rate
of reaction 3 in comparison to conventional Mannich
reactions. The methyleneimminium salt is
considered to be the key intermediate in the Mannich
reaction by initiating electrophilic attack on
the substrate Ž Scheme 2 . . Such Mannich reactions
occur under mild conditions, in the presence of
anhydrous acetonitrile as a solvent Žother
aprotic
solvents have also been used. 1 .
The present study was directed to the second
step of pathway I, i.e., to the reaction between
360
SCHEME 2
SCHEME 3
preformed methyleneimminium chloride and furan
as the active hydrogen substrate Ž Scheme 3 . .
The relative simplicity of the species involved allows
direct quantum chemical modeling of the
reaction potential energy surface Ž PES . . Scheme-3type
reactions have been experimentally realized
for imminium salts with various five-membered
heterocycles including furan 1017 ,
thiophene
18a , and N-methylpyrrole 18b .
Moreover, N-
Ž 2-aminoalkyl. benzotriazoles, which are in equilibrium
with imminium cations, have been widely
used as aminoalkylating reagents 19 .
Previous somewhat fragmented theoretical work
on Mannich reactions has included: Ž. i a study of
the stereoselectivity of zinc halides on the Mannich-type
cyclization 20 using AM1 and PM3
parameterizations and frontier orbital analysis; Ž ii.
an investigation of intermediates in Mannich reaction
between N-hydroxymethylamines and methyleneimminium
ions using MNDO parameterization
21 ; Ž iii. frontier-orbital interaction analysis of
Mannich reactions with polynitromethanes using
the CNDO2 method 22, 23 ; Ž iv. a study of
various unstable N-methylolamines and their imminium
cations as intermediates during the Mannich
reaction by the CNDO2 24 method; and Ž v.
formation of intramolecular hydrogen bonds in
Mannich bases using AM1 parameterization 25 .
To the best of our knowledge, only two theoretical
studies consider reaction potential energy surfaces:
the reactions of imminium salts with ethylene 26 and with furan 27 .
Computational Details
The stationary points* on the reaction PES and
paths connecting them were calculated using the
MOPAC semiempirical program package 28 with
AM1 29 and PM3 30 parameterizations. The
stationary points were initially located using
path-following grid calculations and the SADDLE
* The geometries of stationary points are available upon
request from Uko Maran: uko@chem.ut.ee.

point search method, starting from the minima
corresponding to the initial and product complexes
of the reaction, respectively. The geometries of the
stationary points were subsequently refined using
the eigenvector following Ž EF. method 31, 32 ,
together with the requirement that the gradient
norm should not be higher than 0.01 kcalA. ˚ The
stationary points were verified using frequency
calculations to confirm a single negative element
in the Hessian matrix for each transition state and
all positive elements for each of the local energy
minima. The existence of a sole transition state
Ž TS. between each two minima was verified using
the intrinsic reaction coordinate Ž IRC. and dynamic
reaction coordinate Ž DRC. methods.
The self-consistent reaction field method 33 using the multicavity approach Ž MCa SCRF. 34 was applied to model the potential energy surface
of the reaction in a solvent 35 .
Two different
conditions for the reaction were considered, with
38.8 and 1.88, which correspond to the
macroscopic dielectric permittivity of acetonitrile
at 20C and n-hexane at 25C, respectively. The
SCRF model assumes that the reaction complex is
in equilibrium with the medium at any point on
the reaction path.
The chlorine ion was assumed to be dissociated
from the cation throughout the reaction ŽScheme
3 . , and the geometries of the reactant, intermediates,
TS, and product complexes were all calculated
without its presence Žunless
indicated to the
contrary . . The chloride ion is not expected to influ-
ence directly the electrophilic attack of the positively
charged carbon of the imminium ion at the
furan -carbon, which is known to be the most
favored for such attack 1, 18, 36, 37 .
Results and Discussion
INTERACTION BETWEEN IMMINIUM CATION
AND FURAN
The PES gas-phase calculations indicate a relatively
low activation energy for the reaction, 7.0
and 8.4 kcalmol using the AM 1 and PM3 parameterizations,
respectively Ž Table I and Figs. 12 . .
The reaction proceeds via transition state TS
Ž Scheme 4. to the product minimum P Ž Scheme 4 . .
The shape of the minimum potential energy
path Ž MPEP. depends somewhat on the parameterization
used. The AM1 parameterization produces
an additional transition state ŽTS0
as indicated
in Fig. 1. in the reactant side of the MPEP,
which is geometrically very similar to the local
minimum P0 Žsee
C2C10 bond distance on
Scheme 5 . . Attempts to find a path to TS without
proceeding through TS0 and P0 were unsuccessful.
The difference in the energy of the two abovementioned
stationary points Ž TS0 and P0. is small
Ž 0.2kcalmol, cf. Table I. and insignificant bearing
in mind the overall precision of the semiempirical
calculations. Structures TS0 and P0 formally correspond
to a transition state and to a minimum. The
structural characteristics of the other stationary
points calculated for the gas phase using AM1 are
all similar to those obtained with the PM3 parameterization.
Nonspecific solvent effects on the reaction were
modeled using the MCa SCRF approach 34 employing
separate cavities for the two reactants
Ž furan and imminium ion . . The AM1 and PM3
calculations each found high activation energies
TABLE I
AM1 and PM3 calculated heats of formation for the stationary points, H ( kcal/mol )
f
, activation energies,
( ) ( ) a
E kcal/mol , and reaction energies, E kcal/mol .
a
H H
f f
R TS P E E TS0 P0 E E
a a
AM1 / gas 170.1 177.1 169.8 7.0 0.3 173.5 173.3 3.4 3.2
AM1 / CH3CN AM1 / n-hexane
101.0
137.1
133.9
156.1
125.0
148.9
32.9
19.0
24.0
11.8
PM3 / gas 176.7 185.1 174.4 8.4 2.3
PM3 / CH3CN PM3 / n-hexane
107.0
143.5
142.8
164.5
129.6
154.5
35.8
21.0
22.6
11.0
a ( ) ( )
The following notation is used: R stands for reactants complex, TS for transition state, P for products, E = H P H R .
f f
361

FIGURE 1. AM1 calculated minimum potential energy
path in different media.
for the reaction in acetonitrile ŽTable
I and Figs.
12: . EŽ AM1. 32 kcalmol and E Ž PM3. a a 35
kcalmol, respectively. Similar stationary points
geometries were obtained by both parameterizations,
but with somewhat greater difference than
those for the gas phase. Notably, the calculated
bond lengths between the C2 atom of furan and
the C10 atom of the salt are somewhat shorter in
solution Ž Scheme 4 . . The modeling of the MPEP in
nonpolar n-hexane gives substantially lower activation
energies E Ž AM1. a 19.0 kcalmol and
E Ž PM3. 21.0 kcalmol a
than in acetonitrile. The
geometries of stationary points calculated in two
condensed media remain similar to those in the
gas phase.
Although Mulliken population analysis is often
not appropriate for quantitative predictions, the
calculated Mulliken charges in the reactant com-
362
SCHEME 4
FIGURE 2. PM3 calculated minimum potential energy
path in different media.
plex indicate that the carbon Ž C10. in the salt
moiety acquires an excess positive charge, and the
-carbon Ž C2. of the furan ring an excess negative
charge Ž Table II . . In the reaction intermediate positive
charge is already transferred to the furan ring
Ž C3 and C5. Ž Scheme 4; P. Ž Table II . . Minimum P
corresponds to a stable intermediate.
TRANSFER OF THE ACTIVE H FROM THE
REACTION INTERMEDIATE
Additional supermolecular complexes in the gas
phase were studied to investigate the stability of
the reaction intermediate and the mode of cleavage
of the furan ring hydrogen atom. Modeling the
reaction paths in such complexes is known to be
difficult due to the conformational flexibility of the

TABLE II
Calculated Mulliken atomic partial charges.
SCHEME 5
O1 C2 C3 C4 C5 C10 N11 H6
AM1 / gas / R 0.2345 0.1102 0.1467 0.1466 0.1103 0.1113 0.1364 0.1900
AM1 / gas / TS0 0.1720 0.2072 0.1229 0.1850 0.0700 0.1241 0.1456 0.1889
AM1 / gas / P0 0.1398 0.2332 0.1142 0.2010 0.0495 0.1283 0.1688 0.2004
AM1 / gas / TS 0.0905 0.2616 0.0103 0.2404 0.0940 0.1230 0.3118 0.2207
AM1 / gas / P 0.0937 0.1066 0.0147 0.2470 0.2229 0.0026 0.3725 0.2093
AM1 / CH CN / R 0.2377 0.1204 0.1396 0.1466 0.1056 0.1107 0.1334 0.1852
3
AM1 / CH CN / TS 0.0983 0.2423 0.1000 0.2388 0.1436 0.1154 0.3559 0.2127
3
AM1 / CH CN / P 0.1056 0.0657 0.0143 0.2373 0.2413 0.0657 0.3288 0.2066
3
AM1 / n-hexane / R 0.2354 0.1138 0.1446 0.1474 0.1076 0.1113 0.1355 0.1852
AM1 / n-hexane / TS 0.0933 0.7500 0.0032 0.2414 0.1236 0.1186 0.3385 0.2176
AM1 / n-hexane / P 0.0987 0.0887 0.0134 0.2428 0.2315 0.0304 0.3524 0.2315
PM3 / gas / R 0.1853 0.0747 0.1238 0.1238 0.0747 0.0759 0.6009 0.1443
PM3 / gas / TS 0.0545 0.2441 0.0515 0.2283 0.1755 0.0286 0.2407 0.1726
PM3 / gas / P 0.0431 0.0143 0.0630 0.2383 0.3345 0.0851 0.0156 0.164
PM3 / CH CN / R 0.1842 0.0833 0.1191 0.127 0.0685 0.0895 0.6191 0.1408
3
PM3 / CH CN / TS 0.0796 0.0182 0.0780 0.2319 0.3590 0.1324 0.0118 0.1532
3
PM3 / CH CN / P 0.0647 0.2129 0.0752 0.2279 0.2404 0.0379 0.1449 0.1641
3
PM3 / n-hexane / R 0.1844 0.0788 0.1220 0.1265 0.0703 0.0805 0.6075 0.1427
PM3 / n-hexane / TS 0.0593 0.2231 0.0693 0.2310 0.2170 0.0361 0.1766 0.1689
PM3 / n-hexane / P 0.0734 0.0073 0.0783 0.2356 0.3511 0.1088 0.0204 0.1538
363

system and the long-range interactions involved,
and in such cases AM1 and PM3 parameterizations
may lead to different results.
By considering intramolecular proton transfer in
the intermediate as one possible mechanism for
the hydrogen abstraction from the furan ring a
well-defined transition state Ž
Hf 196.17 kcal
mol. TS( H) Ž Scheme 6. with a calculated activation
energy of 26 kcalmol was found with AM1
parameterization. Proceeding from TS( H) the
product PH ( ) Ž Scheme 6. was formed ŽHf
157.37 kcalmol. with reaction energy 12.4
kcalmol.
Our recent comparison 38 of AM1 and ab
initio quantum chemical calculations suggests that
the AM1 parameterization is sufficiently accurate
to predict the PES characteristics of C—H N
proton transfers and therefore should be applicable
for the present reaction. A similar transition
state was obtained for the same reagents by Y. Li
et al. 27 and discussed as the main barrier in the
reaction between furan and methylene imminium
salt. However, our attempts to find transition state
( )
TS H using PM3 parameterization failed as no
stationary points could be detected in this part of
364
SCHEME 6
SCHEME 8
the calculated PES. The calculated reaction barriers
in solution using the AM1 MCa SCRF model indicate
a much higher activation energy in comparison
with the results for the gas phase. However,
efforts to obtain the precise location of the transition
state in solution was unsuccessful, possibly
due to the complex representation of the reaction
field in the MCa SCRF Hamiltonian.
Placing a chlorine anion in the vicinity of intermediate
P in the gas phase causes dissociation of
the active hydrogen from the furan ring and formation
of HCI Ž Scheme 7 . . In solution, a lone pair
SCHEME 7

SCHEME 9
of electrons of a solvent molecule is more likely to
act as the proton acceptor. The influence of such
lone pair was modeled by placing a NH 3 molecule
in the vicinity of intermediate P, which is also a
model for intermolecular proton transfer in
N—H N system. The formation of a stable com-
plex PNH ( ) between ammonia and P was pre-
3
dicted by using both AM1 and PM3 parameterizations.
The scission of the proton from the furan
ring resulted in the formation of the NH ion
4
( PNH ) without any activation barrier Ž
4
Scheme
8 . . This indicated that intermolecular proton transfer
is a possible pathway to cleave the active
hydrogen from furan. This observation is still consistent
with the overall reaction scheme including
the formation of a stable intermediate with the
active H connected to the furan ring.
Therefore, our results indicate that transfer of
the active H from the furan ring, either to an
adjacent chlorine ion or to a solvent lone pair, are
energetically more favorable than the intramolecular
H transfer. Consequently, the present results
indicate that the stability of the intermediate and
the loss of the active H from furan in Mannich
reaction can he facilitated by such nucleophiles in
different media.
Conclusions
On the basis of the present results we suggest
Scheme 9 as the detailed mechanism for the Mannich
reaction of furan with an imminium salt. The
reaction involves a stable intermediate and is predicted
to occur more easily in nonpolar media and
also in aprotic basic solvents where an active hydrogen
is easily abstracted from furan by interaction
with the lone pair of electrons of the solvent.
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