The uncatalyzed direct amide formation reaction - Mechanism studies and the key role of carboxylic acid h-bonding

Article abstract of DOI:10.1002/ejoc.201100714

Calorimetric studies of the mixing of a series of carboxylic acids and amines have been carried out to measure heat output, which has been compared with their ability to react to form carboxylate ammonium salts and amides. In order to identify which species (salt or H-bonded species) were formed, ¹H NMR studies were also carried out by mixingcarboxylic acids and amines in [D₈]toluene and monitoring the resulting reactions. These experiments were also compared to DFT computational studies, from which the relative merits of different mechanistic schemes for direct amide formation could be assessed. A reaction mechanism involving zwitterionic intermediates could be eliminated on the basis of calculated energies in toluene, however, a neutral intermediate pathway, involving carboxylic acid dimerization by mutual hydrogen bonding was found to be accessible and may explain how the direct amide formation reaction occurs. Such a mechanism is not inconsistent with kinetic modelling of direct amide formation under different reactions conditions. It Takes Two to Amide: Direct amide formation between carboxylic acids andamines has attracted a lot of curiosity, but there is little clarification on the interplay between ammonium carboxylate salt formation vs. amide bond formation. These studies shed light on these competing processes and a new mechanism is proposed for direct amide formation, elucidating the key role of carboxylic acid dimers.

Full text of DOI:10.1002/ejoc.201100714

FULL PAPER
DOI: 10.1002/ejoc.201100714
The Uncatalyzed Direct Amide Formation Reaction – Mechanism Studies and
the Key Role of Carboxylic Acid H-Bonding
Hayley Charville,[a] David A. Jackson,[b] George Hodges,[c] Andrew Whiting,*[a] and
Mark R. Wilson[d]
Keywords: Reaction mechanisms / Carboxylic acids / Amines / Amides / Hydrogen bonds
Calorimetric studies of the mixing of a series of carboxylic
acids and amines have been carried out to measure heat out-
put, which has been compared with their ability to react to
form carboxylate ammonium salts and amides. In order to
identify which species (salt or H-bonded species) were
formed, 1H NMR studies were also carried out by mixing
carboxylic acids and amines in [D8]toluene and monitoring
mation could be assessed. A reaction mechanism involving
zwitterionic intermediates could be eliminated on the basis
of calculated energies in toluene, however, a neutral inter-
mediate pathway, involving carboxylic acid dimerization by
mutual hydrogen bonding was found to be accessible and
may explain how the direct amide formation reaction occurs.
Such a mechanism is not inconsistent with kinetic modelling
the resulting reactions. These experiments were also com- of direct amide formation under different reactions condi-
pared to DFT computational studies, from which the relative
merits of different mechanistic schemes for direct amide for-
tions.
and the commonly taught assumption that the lack of reac-
tion between an amine and carboxylic acid is the result of
unreactive ammonium carboxylate salt formation as in
Equation (1).
Introduction
Amide bond formation between amines and carboxylic
acids is generally promoted by the use of stoichiometric
coupling reagents such as carbodiimides, or by the use of
other activated carboxylic acid derivatives such as acid
chlorides or anhydrides.[1] However, the use of condensing
and activating agents is increasingly undesirable as environ-
mentally benign alternatives to standard chemical transfor-
mations are sought.[2] In particular, catalytic solutions to
many chemical reactions are being developed, aiming for
high yielding processes coupled with high atom efficiency
and minimising the associated E-factor for the transforma-
tion.[3] To that end, the most desirable way to construct an
amide bond would be the direct condensation of an amine
with a carboxylic acid. However, despite the fact that direct
amide formation was reported as early as 1858,[4,5] there
have been relatively few reports in the literature referring to
direct condensation[5,6] and it remains an understudied and
misunderstood reaction. These misconceptions largely de-
rive from early reports of relatively forcing conditions[4,5]
(1)
A rennaisance in the direct reaction of an amine with a
carboxylic acid has been triggered by the discovery of a
number of catalysts (Figure 1), which allow direct amide
formation to proceed at lower temperatures[7–12] making the
more general synthetic application much more appealing.
However, it has not always been appreciated to what extent
the direct amide formation competes with the catalyzed re-
action, though it is known that certain combinations of car-
boxylic acid and amine can provide the corresponding
amide in good yield in the absence of catalysis.[10] In ad-
dition, relatively little is understood regarding the kinetics
and mechanistic details of the direct amide formation reac-
[a] Centre for Sustainable Chemical Processes, Department of tion.[13] Mechanistic investigations into the spontaneous
Chemistry, Science Laboratories, Durham University,
formation of lactams from ortho-aminophenylpropionic ac-
South Road, Durham DH1 3LE, UK
ids under aqueous conditions have been carried out,[14]
[b] Syngenta AG, Process Technology,
Muenchwilen, Switzerland
however, the mechanism described in this type of intramo-
lecular reaction does not necessarily provide a suitable basis
for explaining how intermolecular direct amide formation
occurs, particularly under nonpolar and nonaqueous reac-
tion conditions. In order to advance the development of
amide bond formation reactions, a comprehensive under-
[c] Syngenta, Jealott’s Hill International Research Centre,
Bracknell, Berkshire, RG42 6EY, UK
[d] Department of Chemistry, Science Laboratories, Durham
University,
South Road, Durham DH1 3LE, UK
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100714.
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FULL PAPER
standing of the mechanism(s) operating is essential. In this reaction. In contrast, phenylbutyric acid (pKa 4.76) gave a
paper, we report our investigations into the mechanistic as- much reduced heat output with benzoic acid (pKa 4.19) giv-
pects of this reaction.
ing intermediate heat output with the different amines, to-
gether with gradation of the heat output. It is clear, and not
surprising, that heat output is strongly related to pKa, which
is demonstrated by the relative order of reactivity of the
three carboxylic acids. Bromoacetic acid also interacts with
all the amines examined in an exothermic manner and,
interestingly, fails to react under either thermal or the stan-
dard boronic or boric acid catalyzed reaction conditions.
Phenylbutyric acid in contrast is more reactive and amide
formation occurs to some extent with all the amines exam-
ined, whereas benzoic acid shows reactivity intermediate
between that of the other two carboxylic acids. This shows
that there is some level of correlation between the carbox-
ylic acid pKa and the ability to undergo direct amide forma-
tion, i.e. higher pKa equates to higher reactivity, which con-
trasts with previous claims.[15]
Figure 1. Boron based catalysts for direct amide formation.
Results and Discussion
Reaction Calorimetry
In order to establish whether ammonium carboxylate salt
Examining the amine reactivity is similarly intriguing.
formation occurs upon mixing carboxylic acids and amines There was no major difference in heat output between the
in a nonpolar, aprotic solvent, the heat output of several amines, with the exception of aniline (ammonium
combinations of amines and carboxylic acids were followed pKa 4.63), which was universally considerably less reactive
over time in toluene solution. The range of amines and car- with all three carboxylic acids. This lower reactivity clearly
boxylic acids used was selected on the basis of their pKa results from the lower basicity of aniline in comparison to
values in water (it has been claimed that there is not a direct the other amines, resulting in diminished susceptibility
relationship between amine and carboxylic acid pKa values towards protonation. However, and in stark contrast, lower
and their ability to undergo direct amide formation)[15] and basicity does not extrapolate to lower reactivity towards di-
solubility in toluene. The total heat outputs were also deter- rect amide formation. In fact, the least reactive amine was
mined (Table 1) and direct amide formation reactions were tert-butylamine (ammonium pKa 10.83), which failed to re-
carried out under both thermal and catalytic conditions to act with any of the carboxylic acids under any of the reac-
determine if there was a correlation between the propensity tion conditions. These results show that the amine reactivity
for amide formation and experimentally determined heat contribution to amide formation is not a simple function of
output (see Table 1).
amine basicity; steric and electronic effects must play a part.
The results shown in Table 1 demonstrate that the high- This conclusion is reinforced by examining the reactivity
est heat outputs were derived from the reactions of bro- of benzylamine (ammonium pKa 9.33) compared with other
moacetic acid (pKa 2.69) with the different amines and the amines, which is the most reactive amine under all condi-
rate of heat output was also similarly rapid for each amine tions with the two reactive carboxylic acids, despite being
Table 1. Results from calorimetry and yields for direct amide formation.
Carboxylic acid
Amine
Total heat output
[kJ/mol]
Yields [%] of direct amide formation
Uncat.[a]
Cat.[b]
Cat.[c]
benzylamine
tert-butylamine
2-methoxyethylamine
piperidine
79[d]
75[d]
79
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
Bromoacetic acid
74[d]
43[d]
aniline
benzylamine
tert-butylamine
2-methoxyethylamine
piperidine
24
30[d]
21
19
0
60[d]
56[d]
65[d]
51
64
Ͻ 1
54
24
4
89
3
70
80
74
76
Ͻ 1
49
1
Phenylbutyric acid
Benzoic acid
aniline
16
benzylamine
tert-butylamine
2-methoxyethylamine
piperidine
14
0
5
10
0
86
0
24
49
35
2
0
5
0
aniline
0
20
[a] Uncatalyzed in toluene at 120 °C with Dean–Stark water removal over 48 h. [b] Boric acid catalyzed in toluene at 120 °C with Dean–
Stark water removal over 48 h. [c] o-Iodophenylboronic acid catalyzed in toluene at 50 °C using 3 Å molecular sieves over 48 h. [d]
Crystallization of salt occurred on mixing carboxylic acid and amine.
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The Uncatalyzed Direct Amide Formation Reaction
neither the most basic (see proton affinities below in a simu- Table 2. Yields of ammonium carboxylate salt precipitated from
combinations of carboxylic acids and amines (all precipitates were
lated nonpolar solvent) nor the least sterically hindered
confirmed by CHN analysis).
amine. We[10] and others[15] have observed this enhanced re-
activity of benzylamine previously, and hence, understand-
Yield [%]
precipitate
ing this “benzylic effect” (with respect to amine reactivity)
would be an important consequence of studying how direct
amide formation works.
Carboxylic acid
Amine
Analysis
benzylamine
tert-butylamine
2-methoxyethylamine
piperidine
CHN
CHN
NMR
CHN
CHN
50
48
–
13
46
Bromoacetic acid
Ammonium Carboxylate Salt Formation and Solution
NMR Studies
aniline
benzylamine
tert-butylamine
2-methoxyethylamine
piperidine
NMR
CHN
NMR
NMR
NMR
–
100
–
–
–
The high heat output from certain carboxylic acid–amine
combinations (Table 1) leads to the obvious conclusion that
this results from exothermic salt formation. However, solid
products were not always produced, and in cases where heat
output was lower, it was not immediately obvious which
resulting species are likely to be responsible for the lower
exothermicity. In order to probe this question further, it was
necessary to establish exactly what species were produced
Phenylbutyric acid
Benzoic acid
aniline
benzylamine
tert-butylamine
2-methoxyethylamine
piperidine
CHN
CHN
CHN
NMR
NMR
64
100
72
–
aniline
–
1
Figure 2. H NMR spectra obtained from mixing selected carboxylic acids and amines.
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FULL PAPER
upon mixing the carboxylic acids and amines. Hence, each amine, tuned by steric vs. electronic (conjugation) effects. In
carboxylic acid and amine was mixed at room temperature order to understand exactly how the direct amide formation
in toluene, and for those combinations that produced a pre- actually occurs, a detailed computational study was carried
cipitate (Table 2), this was removed by filtration and ana- out.
lysed to confirm that ammonium carboxylate salt formation
had taken place. For those combinations that failed to pro-
duce a precipitate (Table 2), the solutions (in [D8]toluene)
were examined by NMR up to 24 h after mixing in order
Calculated Proton Affinities
to identify what species were present in solution and how
they changed.
In order to get a measure of the relative basicity or acid-
ity of the substrates used throughout the study, proton af-
For the combinations of amines and carboxylic acids that finities were obtained in the gas phase and using an approx-
remained in solution upon mixing, the solutions remained imate (polarization continuum model, PCM) solvation
homogeneous and it was reasonably straightforward to fol- model for toluene by DFT calculations. This study was car-
low the reactions over time. NMR revealed the presence of ried out in order to ascertain that calculated proton affin-
three different types of species being formed: 1) complete ities reflected experimental pKa values and, more import-
salt formation (for example Figure 2, a); 2) H-bonding be- antly, to provide a better picture of the susceptibility of the
tween ammonium and carboxylate (for example Figure 2, different amine derivatives towards protonation by carbox-
b); 3) and H-bonding between amine and carboxylic acid ylic acids in a simulated nonpolar solvent. The values ob-
(for example Figure 2, c). In contrast, in the case of phen- tained using a B3LYP functional, 6-31G** and 6-31+G**
ylbutyric acid with benzylamine (Figure 2, d), the spectrum basis sets are given in Table 3.
obtained just after mixing showed the presence of an am-
Although the calculated proton affinity values are con-
monium salt, however, H-bonding between ammonium and sistently slightly higher than the experimental values, these
carboxylate was also observed in a 2:1 ratio. The benzyl results provide a useful trend showing relative basicity,
CH2 peak was also split (2:1) suggesting the presence of which enables us to compare one compound with another.
two different species. It is noteworthy that this combination The trend for five experimentally known affinities is exactly
of carboxylic acid and amine seems to be one of the most reproduced, and a plot of experimental vs. calculated affin-
reactive for direct amide formation, with or without a cata- ities yields a straight line fit with an R2 coefficient of 0.998.
lyst (see Table 1) and hence, presumably this association ob- Hence, the DFT results can be used to provide a reasonable
served between the ammonium and carboxylate, and associ- estimate for the unknown bases (including the conjugate
ation between the free amine and carboxylic acid, are im- bases of the three acids in this study). It should be noted
portant for assisting direct amide formation is some way. In that none of the bases used in Table 1 are predicted to be
order to ensure that all of the reactions carried out in the as basic as triethylamine.
NMR tube had finished, each sample was re-examined after
The calculated proton affinities are in good agreement
24 h. The results from this second set of NMR spectra with the five experimentally measured affinities in Table 3
showed that, for the three combinations of different amines at the 6-31G** level (mean error of 2%). With the further
reacting with phenylbutyric acid (i.e., benzylamine, 2-me- addition of diffuse functions using 6-31+G** basis sets
thoxyethylamine and piperidine), the presence of ammo- (which give a better representation of soft anions), the pre-
nium salt, H-bonded salt or just H-bonding became less dicted values improve further to a mean error of 0.2%. The
clear. These samples were, therefore, heated at 50 and 85 °C proton affinities were also estimated in toluene using an
to see if this resulted in simplification of the spectra, which approximate PCM solvation treatment. Here, as expected,
it did. In all three cases the ammonium salt was the only proton affinities for the neutral bases in toluene are slightly
species present after this process. It should also be noted higher because of the dielectric effects of the solvent stabi-
that for all three cases, increasing the temperature from 50– lizing the charged conjugate acid. Although the trend in
85 °C resulted in a higher field shift ammonium salt forma- proton affinities does not change with solvation, the range
tion, though notably at different rates depending the of values is significantly reduced by the presence of the sol-
amine–carboxylic acid combination. Rerunning the same vent. However, the dielectric effect of the solvent is fairly
NMR samples after cooling to room temperature showed weak (compared to more polar solvents) and the basicity
the presence of the ammonium salt in all three cases, with of the three carboxylic acid anions is such that we do not
broad ammonium N–H peaks observed at δ = 7.58 (3 H) expect salt formation in toluene for any of the combinations
for phenylbutyric acid + benzylamine, δ = 8.32 (3 H) for in Table 1, at least without an additional contribution from
phenylbutyric acid + 2-methoxyethylamine and δ = 9.72 the lattice energy assisting precipitation, and/or interactions
(2 H) for phenylbutyric acid + piperidine. Hence, from the with water (or water molecules) stabilising an ion pair.
evidence obtained from calorimetry, NMR studies and the These results are intriguing especially in contrast to the re-
yields of direct amide formation it can be concluded that sults reported in Table 1 and Table 2. From the pKa values
several factors influence the reactivity of carboxylic acid– and energy differences calculated, we do not expect proton
amine partners for direct amide formation, i.e. 1) the sta- transfer to form salts to be enthalpically favored. It is,
bility of the ammonium carboxylate salt, 2) the pKa of the therefore, likely that the heat output measured (Table 1) in
carboxylic acid, and 3) the nucleophilicity vs. basicity of the many of the amine–carboxylic acid reactions results from
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The Uncatalyzed Direct Amide Formation Reaction
Table 3. Proton affinities in the gas phase and in the toluene solvation model.
Gas phase
Toluene solution
Exp. affinity
(kJ/mol)[a]
Calcd. (6-31G**)
Affinity (kJ/mol)
Calcd. (6-31+G**)
Affinity (kJ/mol)
Calcd. (6-31G**) Calcd. (6-31+G**)
Affinity (kJ/mol)
Affinity (kJ/mol)
Ammonia
Aniline
Methylamine
2-Methoxyethylamine
Ethylamine
Dimethylamine
Benzylamine
tert-Butylamine
Trimethylamine
Diethylamine
854
873
900
916
923
931
941
946
955
957
967
969
991
1439
1469
1495
803
854
830
849
879
896
901
910
925
924
934
942
942
951
976
1386
1412
1428
777
828
807
1050
1043
1076
1072
1084
1085
1085
1089
1086
1099
1106
1110
1313
1344
1359
947
1019
1006
1049
1040
1057
1065
1052
896
923
942
972
[b]
–
1072
1074
1077
1090
1263
1283
1298
891
Piperidine
Triethylamine
Bromoacetic acid ion
Benzoic acid ion
Phenylbutyric acid ion
Bromoacetic acid
Benzoic acid
977
958
937
[b]
Phenylbutyric acid
–
[a] For experimental proton affinities, see ref.[16] [b] Convergence not obtained for 6-31+G** basis set with PCM.
precipitation of the ammonium carboxylate salt rather than
proton transfer from acid to amine. In solution, where there
is no precipitation, but where NMR studies indicate forma-
tion of the ammonium carboxylate salt, we expect the for-
mation of solvent stabilized ion pairs. However, the latter is
difficult to model without the use of explicit solvent mole-
cules.
Kinetic Evidence for Acid or Base Catalysis in Direct
Amide Formation
Having examined proton affinities and how these are re-
flected in the observed interactions and reactions between
carboxylic acids and amines, we turned to investigate the
viability of possible alternative mechanisms for direct amide
formation with the aim of establishing the viability of dif-
ferent intermediates and transition states along different re-
action pathways. To start, a mechanism analogous to the
acid-catalyzed esterification reaction was investigated, i.e.
Scheme 1. Initial proposed mechanism for direct amide formation
based on acid-catalyzed esterification.
where the electrophilicity of the carboxylic acid is increased
by protonation of the carbonyl oxygen atom, facilitating at-
tack of an amine. If direct amide formation can be cata-
lyzed by a general acid, then the acid source could derive hence, although this difference may be a real effect, it is
from an ammonium salt NH or from excess carboxylic acid clearly not significant, and we can therefore conclude that
as shown in Scheme 1. In order to investigate this possibil- it is unlikely that direct amide formation is particularly
ity, direct amide formation reactions between phenylbutyric amenable to either acid or base catalysis. If it was amenable
acid and benzylamine in the presence of either a 20% excess to such general catalysis, a more significant increase in rate
of carboxylic acid or a 20% excess of amine were followed would have been expected.
over time. The results are shown in Figure 3.
In light of the direct amide formation reaction not being
The addition of excess carboxylic acid or amine pro- enabled by general acid or base catalysis (vide supra), a sec-
duced very similar results (Figure 3) and indeed, both show ond reaction mechanism requiring consideration could in-
only a slight rate enhancement in comparison to the equi- volve attack of an amine directly on the carboxylic acid
molar reaction (for further experiments see Supporting In- as outlined in Scheme 2. Such a mechanism appears to be
formation). This slight increase in rate for the excess amine plausible when looking at the yields of direct amide forma-
and acid reactions is very close to the calculated ranges, tion (Table 1), as carboxylic acids attached to electron-with-
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H. Charville, D. A. Jackson, G. Hodges, A. Whiting, M. R. Wilson
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of bromoacetic acid with tert-butylamine does not undergo
direct amide formation because the only species present in
solution is the carboxylate salt. If direct amide formation
were to proceed by the direct attack of the amine on the
carboxylic acid (Scheme 2) then an amine that is a good
nucleophile is required, followed by formation of a stable
zwitterionic intermediate species (7 in Scheme 2). Carbox-
ylic acid–amine combinations that form stable carboxylate
ions, where the ammonium salt cannot reprotonate the
carboxylate back to the neutral acid form, are predicted
to be unreactive. In order to probe this mechanistic theory
further, additional computational studies were carried out.
Computational Studies on Possible Direct Amide Formation
Mechanisms
Initially, DFT calculations were used to investigate the
structure and energies of possible intermediate compounds
as outlined in Scheme 2. Calculations were carried out for
all combinations of carboxylic acids and amines that were
used in the calorimetry and NMR studies (see above and
Supporting Information). These investigated the possibility
of various species being either stable intermediates (energy
minima) or transition states on the reaction surface in a
simulated toluene solvent. The results clearly showed that
the zwitterion 7, formed from the attack of the free amine
on a free carboxylic acid, was unstable in all cases and
would rapidly dissociate to give back the starting materials.
Species 7 (Scheme 2) is, therefore, not involved as a transi-
tion state or intermediate in direct amide formation and can
be discounted from Scheme 2. However, in the process of
investigating plausible intermediates, neutral species 8 was
found to be stable in all cases (see Supporting Information),
which raises the question as to how such an intermediate
could be generated. If 8 is formed, it clearly does not result
from zwitterion 7 by deprotonation; therefore, what other
mechanism could be operating to account for its formation?
Mutual dimerisation of carboxylic acids through inter-
molecular hydrogen bonding (to give 9, Scheme 3) is well
documented.[17,18] Indeed, not only are such dimerisations
Figure 3. Results following the reaction between phenylbutyric acid
and benzylamine over time.
drawing groups are likely to be largely in the form of the
ammonium salt due to their lower pKa values. Considering
the amine, electron-donating groups stabilize ammonium
salt formation, and this would explain why the combination
Scheme 2. Alternative proposed mechanism for direct amide for-
mation through zwitterion 7.
Scheme 3. New proposed mechanism for direct amide formation supported by DFT calculations.
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The Uncatalyzed Direct Amide Formation Reaction
particularly efficient in nonpolar solvents (such as toluene),
but these dimers can be observed at elevated temperatures
and even persist into the gas phase, where they compete
with linear hydrogen-bonded dimers. We, therefore, theo-
rized that such species might be important as the poten-
tially reactive form of the carboxylic acid, which might be
sufficiently activated to enable a nucleophilic attack by an
amine. Examining this possibility by DFT showed that the
mechanism for direct amide formation could proceed
through a carboxylic acid dimer 9, which could form readily
in toluene. Subsequent attack on this species by the amine
results in the formation of a transition state 10 as shown in
Figure 4, in which the reacting amine is able to attack one
carboxylic acid of the carboxylic acid dimer 9 and the sec-
ond carboxylic acid acts as the proton acceptor (see Sup-
porting Information). The result of a concerted proton
transfer from amine to acid and release of the second car-
boxylic acid is the neutral intermediate 8, from which water
is readily lost (see Scheme 3). Importantly, a mechanism
that proceeds in this manner avoids the formation of zwit-
terion 7, which had been shown to collapse back to the
starting materials from previous calculations (vide supra).
An overall calculated energy profile using benzoic acid and
benzylamine is shown in Figure 5.
Figure 5. Calculated energy profile for species contributing to di-
rect amide formation by a hydrogen bonded acid dimer, for the
reaction of benzoic acid with benzylamine. Relative energies ob-
tained from gas phase DFT calculations (B3LYP/6-31g**). Calcu-
lated relative energies are shown as an approximate guide to the
suggested reaction pathway and are quoted as the sum of uncor-
rected electronic and zero point energies in the absence of solvent.
(A = amine 5 + carboxylic acid dimer 9, TS = transition state 10,
I = dihydroxy intermediate 8 hydrogen-bonded to acid 4, B = amide
3 + acid 4 + water.).
formed.[18] Hence, active water removal becomes essential in
order to maintain a sufficient dimer 9 concentration to en-
able carboxylic acid activation and hence, amine nucleo-
philic addition.
In further support of the new mechanistic proposal out-
lined in Scheme 3, it is worth noting that investigations car-
ried out by Kirby et al.[14] on the kinetics and mechanism
of intramolecular direct amide formation discussed the im-
portance of the formation of a similar neutral intermediate
to 8. Although this work differs from our investigations
(due to aqueous conditions and intramolecularity), the role
of the carboxylic acid dimer 9 necessarily orchestrates the
intermolecular reaction, especially under nonaqueous con-
ditions (in toluene for example). In many other respects, the
mechanism in Scheme 3 is similar and one can explain this
Figure 4. Structure of proposed transition state supported by DFT
calculations in simulated toluene. The transition state shown is
formed from the attack of benzylamine on a carboxylic acid dimer.
In order to achieve efficient direct amide formation, the on the basis of how, for example, acids with low pKa values
removal of water from the reaction is essential, typically prevent direct amide formation due to forcing the equilib-
by azeotropic distillation at higher temperature[11] or using rium betweeen acid 4 and amine 5 fully in the direction
activated molecular sieves under more ambient condi- of ammonium carboxylate salt 6 and hence, direct amide
tions.[12] Without efficient water removal, direct amide for- formation kinetics are most heavily influenced by this equi-
mation is markedly slowed but does not stop.[11] If direct librium. In addition, one can understand the possible origin
amide formation does indeed proceed by carboxylic acid of the “benzylic effect” of amine reactivity (vide supra) in
dimers of type 9, why is it necessary to remove water? This terms of the balance required between amine nucleophilic-
can be explained by observations that the addition of even ity (to enable formation of 8) and to minimise competing
small amounts of water causes hydration of the mutually salt 6 formation by the amine not being too basic. If the
H-bonded cyclic carboxylic acid dimer (i.e. 9), resulting in mechanistic analysis in Scheme 3 is correct, then it would be
the incorporation of the water molecules into the dimer expected that the addition of either excess carboxylic acid 4
structure leading to water separated structures. Quantum or excess amine 5 would have only a small effect on the rate
chemical calculations[18] carried out on acetic acid, for ex- of direct amide formation as addition of excess of either
ample, show that with the addition of even one molecule of would cause increased salt 6 formation. However, compared
water to 9 causes the hydrogen bonds to break. Addition of with the equimolar reaction, if the step from 9 + 5 to give
a second water molecule will break the second hydrogen 8 through 10 were rate determining, then one would expect
bond of the dimer and as more water molecules are added, some sign of an increased rate of reaction. Indeed, Figure 3
more water separated complexes of the acetic acid dimer are does suggest that this might be the case. Hence, in addition
Eur. J. Org. Chem. 2011, 5981–5990
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5987

H. Charville, D. A. Jackson, G. Hodges, A. Whiting, M. R. Wilson
FULL PAPER
to these data, the direct amide formation reaction of phen- reaction[14] in that the formation of a similar neutral inter-
ylacetic acid and benzylamine was carried out with much mediate is required for the direct amide formation reaction
greater (and varying) excesses of amine and carboxylic acid. in aqueous conditions, from which water loss is rapid to
When Micromath Scientist® software was employed to give the amide. In our current proposed mechanism, the
model the mechanism represented in Scheme 3, it was reaction in organic solvents of course differs considerably,
found to reproduce the observed data (see Supporting In- and especially with respect to the likelihood that carboxyl-
formation), and hence, did not contradict the potential via- ate ammonium salt formation may well have the greatest
bility of the mechanism as represented in Scheme 3.
effect upon the rate of direct amide formation.
Further studies are underway to examine direct amide
formation in more detail and to develop improved catalysts
for carboxylic acid–amine combinations that are less reac-
tive.
Conclusions
We previously postulated[10] the intervention of anhy-
drides from the thermolysis of carboxylic acids as the
mechanism by which direct amide formation might occur. Experimental Section
However, we have no direct evidence that this process oc-
Calorimetry Studies: Microcalorimetry was carried out at using an
curs in the presence of amines to result in amide formation.
The studies reported herein clearly show that amines and
carboxylic acids generally do react to some extent to give
ammonium carboxylate salts. However, this reaction only
Omnical reaction calorimeter and Omnical WinCRC 2000 for MS
Windows software. The appropriate carboxylic acid (2 mL of a 1 m
solution in toluene) was added to a calorimetry vial equipped with
a stirrer bar. This was placed inside the calorimeter, which was set
seems to proceed to completion with combinations involv- at 30 °C and once the heat flow had stabilised the appropriate
amine was added (2 mL of a 1 m solution in toluene). Once the
heat flow had stabilised following an exotherm the vial was re-
moved from the calorimeter and the heat output recorded. The
data were processed using Excel. Due to the solubility of benzoic
acid in toluene, a 0.5 m solution was made and all amines used in
combination with benzoic acid were diluted to achieve 0.5 m solu-
tions keeping the combination equimolar.
ing acids with lower pKa values and basic amines, and com-
pletion of the reaction is likely to be driven by the forma-
tion of a salt precipitate. NMR studies clearly show that a
number of species can be formed in solution upon mixing
carboxylic acids and amines, ranging from hydrogen-
bonded amine–acid species, through to hydrogen-bonded
ammonium carboxylate species, and essentially noninter-
acting ammonium carboxylate ions. These types of species
most likely act to diminish (to varying extents) the potential
for direct amide formation, which explains the very low of
reactivity of α-amino acids on direct amide formation.[19]
The process of amide formation is likely to proceed through
another equilibrium species, i.e. the carboxylic acid hydro-
gen-bonded dimer 9, especially under nonaqueous and non-
intramolecular circumstances.[14] There is little evidence for
general acid- or base-catalyzed direct amide formation un-
der these conditions, though as hydrogen bonding and pro-
ton transfer processes are key to this reaction, it not sur-
prising that there is only a minor effect from the addition
of excess acid or amine (though it not clear at this point
exactly how this occurs). More importantly, it is clear that
highly charged zwitterionic species are not involved in the
direct amide formation reaction, and indeed, this may even
extrapolate to the boronic acid-catalyzed reaction vari-
ants.[20] DFT calculations suggest that a plausible mecha-
nism for intermolecular direct amide formation proceeds
through the existence of carboxylic acid hydrogen-bonded
dimers, which are not only known to persist even at elevated
temperatures but are likely to be highly favourable in non-
polar solvents. The role of such hydrogen-bonded dimers,
as demonstrated in Scheme 3, is to enable both carboxylic
acid activation towards nucleophilic attack by the amine,
and to allow the reaction to proceed through to a neutral
intermediate such as 8, which, according to the calculations,
is energetically accessible. This new mechanistic proposal
has important similarities with kinetic and mechanistic
NMR Studies: Solutions of the amines and carboxylic acids in [D8]-
1
toluene were mixed in an NMR tube and submitted for H NMR
immediately. After 24 h the same sample was resubmitted.
Procedure for Following Reactions Over Time: 4-Phenylbutyric acid
(3 mmol or 3.6 mmol) was weighed into each reaction vessel, fol-
lowed by the addition of naphthalene (0.35 mmol) and assembly of
a micro-Soxhlet apparatus loaded with activated molecular sieves
(3 Å) under argon. Toluene (10 mL) and benzylamine (3 mmol or
3.6 mmol) were then added to each reaction vessel. Reactions were
sampled (50 μL) at 6 h intervals (48 h reaction time). Samples were
diluted once (50 μL in 450 μL MeCN) mixed and analysed by
HPLC [gradient MeCN (0.05% TFA)/water (0.05% TFA) 50:50
over 15 min; 1 mLmin–1]. Naphthalene was used as an internal
standard. Data was analysed using Micromath Scientist® version
2.01.
General Procedure for the Preparation of Amides at 120 °C: The
appropriate carboxylic acid (3.05 mmol) was dissolved in toluene
(30 mL) and amine (1 equiv.) was added, followed by the addition
of catalyst (5 mol-%). The reaction mixture was heated to 120 °C
and azeotropic removal of water was performed using a Dean–
Stark condenser. The mixture was allowed to stir with heating to
reflux for 48 h before being concentrated in vacuo. The residue was
then redissolved in ethyl acetate (25 mL), washed with brine
(25 mL), 5% HCl (25 mL), brine (25 mL), 5% NaOH (25 mL),
brine (25 mL), dried (MgSO4) and the solvent evaporated.
General Procedure for the Preparation of Amides at 55 °C: The ap-
propriate carboxylic acid (3.05 mmol) was dissolved in toluene
(30 mL) and amine (1 equiv.) was added, followed by the addition
of catalyst (5 mol-%) and activated 3 Å molecular sieves. The reac-
tion mixture was heated to 55 °C and allowed to stir at this tem-
perature for 48 h before being filtered and concentrated in vacuo.
studies carried out on the intramolecular amide formation The residue was then redissolved in ethyl acetate (25 mL), washed
5988 Eur. J. Org. Chem. 2011, 5981–5990
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

The Uncatalyzed Direct Amide Formation Reaction
with brine (25 mL), 5% HCl (25 mL), brine (25 mL), 5% NaOH
(25 mL), brine (25 mL), dried (MgSO4) and the solvent evaporated.
solid. Spectroscopic details were the same as those reported in the
literature.[7]
N-(2-Methoxyethyl)benzamide: The general procedure for the prep-
aration of amides was followed. Yield in the presence of B(OH)3:
0.13 g (24%), yield in the presence of o-iodophenylboronic acid:
0.027 g (5%), yield in the absence of catalyst: 0.028 g (5%) as a
Quantum Chemical Calculations: The quantum chemical calcula-
tions used DFT, employing Becke’s three-parameter hybrid ex-
change functional (B3)[21] combined with the correlation functional
of Lee, Yang and Parr (LYP),[22] together with 6-31G** or 6-
31+G** basis sets for all atoms within the Gaussian 03 program.[23]
Single-molecule calculations were fully optimized at this level of
theory, with stationary points confirmed by vibrational analysis.
Some calculations employed an implicit solvation model for tolu-
ene provided by a PCM.[24]
pale yellow oil. ν
(ATR): 694, 1018, 1299, 1533, 1638, 2927,
˜
max
3309 cm–1. H NMR (700 MHz, CDCl3): δ = 3.39 (s, 3 H, CH3),
3.56 (t, 2 H, J = 5.6 Hz, CH2), 3.65 (m, 2 H, CH2), 6.54 (s, 1 H,
NH), 7.43 (m, 2 H, 2ArH), 7.49 (m, 1 H, ArH), 7.79 (d, 2 H, J =
7 Hz, 2ArH) ppm. 13C NMR (175 MHz, CDCl3): δ = 39.7 (CH2),
59.8 (OCH3), 71.2 (CH2), 126.9 (2 ArC), 128.5 (2 ArC), 131.4
(ArC), 134.5, 167.4 (C=O) ppm. HRMS: calcd. for C10H14O2N [M
+ H]+ 180.1019; found 180.1020.
1
N-Benzyl-4-phenylbutyramide: The general procedure for the prepa-
ration of amides was followed. Yield in the presence of B(OH)3:
0.69 g (89%), yield in the presence of o-iodophenylboronic acid:
0.59 (76%), yield in the absence of catalyst: 0.49 g (64%) as a white
solid. Spectroscopic details were the same as those reported in the
literature.[7,8]
N-Benzoylpiperidine: The general procedure for the preparation of
amides was followed. Yield in the presence of B(OH)3: 0.28 g
(49%), yield in the absence of catalyst: 0.058 g (10%) as a white
solid. Spectroscopic details were the same as those reported in the
literature.[27]
N-(tert-Butyl)-4-phenylbutanamide: The general procedure for the
preparation of amides was followed. Yield in the presence of
Benzanilide: The general procedure for the preparation of amides
was followed. Yield in the presence of B(OH)3: 0.21 g (35%), yield
in the presence of o-iodophenylboronic acid: 0.12 g (20%) as a
B(OH) : 0.017 g (3%) as a yellow oil. νmax (ATR): 696, 1221, 1543,
˜
3
1644, 2927, 3301 cm–1. H NMR (400 MHz, CDCl3): δ = 1.3 (s, 9
1
H, 3CH3), 1.93–1.99 (m, 2 H, CH2), 2.09 (2 H, J = 7 Hz, CH2),
2.63–2.68 (m, 2 H, CH2), 5.19 (s, 1 H, NH), 7.17–7.21 (m, 3 H,
3ArH), 7.26–7.30 (m, 2 H, 2ArH) ppm. 13C NMR (100 MHz,
CDCl3): δ = 14.6 (CH3), 20.9 (CH2), 21.4 (CH2), 28.8 (CH2), 60.3
[C(CH3)3], 125.3 (ArC), 128.2 (ArC), 128.3 (ArC), 128.5 (ArC),
129 (ArC), 137.8(ArC), 171.1 (C=O) ppm. HRMS: calcd. for
C14H24NO [M + H]+ 220.1701; found 220.1704.
1
white solid. H NMR: (400 MHz, CDCl3): δ = 7.14–7.19 (m, 1 H,
ArH), 7.35–7.40 (m, 2 H, ArH), 7.46–7.52 (m, 2 H, ArH), 7.54–
7.58 (m, 1 H, ArH), 7.64 (m, 2 H, ArH), 7.82 (br., 1 H, NH), 7.86–
7.89 (m, 2 H, ArH) ppm. 13C NMR (100 MHz, CDCl3): δ = 120.2
(2 ArC), 124.6 (ArC), 127.0 (2 ArC), 128.8 (2 ArC), 129.1 (2 ArC),
131.9 (ArC), 135.1 (ArCCO), 137.9 (ArCNH), 165.7 (C=O) ppm.
Other spectroscopic details were the same as those reported in the
literature.[26]
N-(2-Methoxyethyl)-4-phenylbutanamide: The general procedure for
the preparation of amides was followed. Yield in the presence of
B(OH)3: 0.47 g (70%), yield in the presence of o-iodophenylboronic
acid: 0.33 g (49%), yield in the absence of catalyst: 0.36 g (54%) as
Supporting Information (see footnote on the first page of this arti-
cle): General experimental, experimental, calorimetry data, compu-
tational chemistry experimental, amide formation reactions, NMR
data, computational chemistry data.
a pale yellow oil. ν
(ATR): 700, 1132, 1542, 1550, 2942,
˜
max
3289 cm–1. 1H NMR (700 MHz, CDCl3): δ = 1.94–1.98 (m, 2 H,
CH2), 2.17 (t, 2 H, J = 7.7 Hz CH2), 2.64 (t, 2 H, J = 7.7 Hz, CH2),
3.33 (s, 3 H, CH3), 3.43 (m, 4 H, 2CH2), 5.82 (s, 1 H, NH), 7.16–
7.18 (m, 3 H, 3ArH), 7.25–7.72 (m, 2 H, 2ArH) ppm. 13C NMR
(175 MHz, CDCl3): δ = 27.1 (CH2), 35.1 (CH2), 35.8 (CH2), 39.1
(OCH3), 58.7 (CH2), 71.2(CH2), 126.9 (2 ArC), 128.2 (ArC), 128.3
(ArC), 128.5 (ArC), 141.5, 172.7 (C=O) ppm. HRMS: calcd. for
C13H20O2N [M + H]+ 222.1489; found 222.1490.
Acknowledgments
We thank Syngenta AG for funding (studentship to H. C.), the
Royal Society of Chemistry (RSC) for a Journals Grant (to A. W.)
and the EPSRC Mass Spectrometry Service at the University of
Wales, Swansea.
1-(4-Phenylbutanoyl)piperidine: The general procedure for the prep-
aration of amides was followed. Yield in the presence of B(OH)3:
0.56 g (80%), yield in the presence of o-iodophenylboronic acid:
0.008 g (1%), yield in the absence of catalyst: 0.17 g (24%) as a
colourless oil. 13C NMR (175 MHz, CDCl3): δ = 24.5 (CH2), 26.5
(CH2), 26.6 (CH2), 26.8 (CH2), 32.5 (CH2), 36.4 (CH2), 42.6 (CH2),
46.6 (CH2), 125.8 (2 ArC), 128.3 (ArC), 128.5 (2 ArC), 141.8, 170.9
(C=O) ppm. All other spectroscopic details were consistent with
those reported in the literature.[25]
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Eur. J. Org. Chem. 2011, 5981–5990
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5989

H. Charville, D. A. Jackson, G. Hodges, A. Whiting, M. R. Wilson
FULL PAPER
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Published Online: August 23, 2011
5990
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 5981–5990