Rate and equilibrium constants for the addition of N-heterocyclic carbenes into benzaldehydes: A remarkable 2-substituent effect

Article abstract of DOI:10.1002/anie.201501840

Abstract Rate and equilibrium constants for the reaction between N-aryl triazolium N-heterocyclic carbene (NHC) precatalysts and substituted benzaldehyde derivatives to form 3-(hydroxybenzyl)azolium adducts under both catalytic and stoichiometric conditions have been measured. Kinetic analysis and reaction profile fitting of both the forward and reverse reactions, plus onwards reaction to the Breslow intermediate, demonstrate the remarkable effect of the benzaldehyde 2-substituent in these reactions and provide insight into the chemoselectivity of cross-benzoin reactions. It takes 2-: Measurement of rate and equilibrium constants for the reaction between N-aryl triazolium NHC precatalysts and substituted benzaldehydes under catalytic and stoichiometric conditions demonstrate the remarkable kinetic and thermodynamic effect of the benzaldehyde 2-substituent in these reactions, potentially providing insight into the chemoselectivity of cross-benzoin reactions.

Full text of DOI:10.1002/anie.201501840

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201501840
German Edition: DOI: 10.1002/ange.201501840
Reaction Mechanisms
Rate and Equilibrium Constants for the Addition of N-Heterocyclic
Carbenes into Benzaldehydes: A Remarkable 2-Substituent Effect**
Christopher J. Collett, Richard S. Massey, James E. Taylor, Oliver R. Maguire,
AnnMarie C. O’Donoghue,* and Andrew D. Smith*
Abstract: Rate and equilibrium constants for the reaction
between N-aryl triazolium N-heterocyclic carbene (NHC)
precatalysts and substituted benzaldehyde derivatives to form
3-(hydroxybenzyl)azolium adducts under both catalytic and
stoichiometric conditions have been measured. Kinetic analysis
and reaction profile fitting of both the forward and reverse
reactions, plus onwards reaction to the Breslow intermediate,
demonstrate the remarkable effect of the benzaldehyde 2-
substituent in these reactions and provide insight into the
chemoselectivity of cross-benzoin reactions.
reported the intramolecular cross-benzoin reaction between
an arylaldehyde and a tethered aliphatic aldehyde to effect
macrocyclization.[5b] Connon and co-workers found that N-
C6F5 triazolium NHC precatalyst 3 catalyzes intermolecular
cross-benzoin reactions between 2-substituted benzaldehydes
and aliphatic aldehydes with high levels of chemoselectivity
(Scheme 1a).[5c] A selective cross-benzoin reaction between
A
cyl anion equivalents generated from the reaction of N-
heterocyclic carbenes (NHCs) with aldehydes are important
catalytic intermediates that can undergo a range of carbon–
carbon bond forming processes.[1] In this regard, NHC-
catalyzed benzoin and Stetter reactions have been widely
studied, with a number of efficient catalytic asymmetric
methods available for both intra- and intermolecular reac-
tions.[1,2] However, the development of cross-benzoin reac-
tions has proven difficult in terms of the chemoselective
formation of a single reaction product.[3] While efficient
chemoselective NHC-catalyzed protocols for both intra- and
intermolecular cross-benzoin reactions between aldehydes
and ketones have been reported,[4] the reaction between two
distinct aldehydes remains a significant synthetic challenge.
As 2-substituted benzaldehydes are generally poor substrates
for homo-benzoin reactions they have been widely utilized in
cross-benzoin processes.[5] For example, Miller and Mennen
Scheme 1. Cross-benzoin reactions using 2-substituted benzaldehydes.
two benzaldehydes catalyzed by thiamine diphosphate de-
pendent benzaldehyde lyase (BAL) was reported by Mꢀller
et al., with one 2-substituted benzaldehyde a prerequisite for
good chemoselectivity.[6] Glorius and co-workers subse-
quently utilized this phenomenon in arylaldehyde cross-
benzoin reactions using thiazolium NHC precatalyst 7
(Scheme 1b).[5e,7] Gravel et al. have reported a triazolium
NHC-catalyzed cross-benzoin process between benzalde-
hydes and alkyl aldehydes, with preliminary kinetic studies
showing the reaction is at least first-order with respect to both
[*] Dr. C. J. Collett, Dr. J. E. Taylor, Prof. A. D. Smith
EaStCHEM, School of Chemistry, University of St Andrews
North Haugh, St Andrews, Fife, KY16 9ST (UK)
E-mail: ads10@st-andrews.ac.uk
Homepage: http://ch-www.st-andrews.ac.uk/staff/ads/group/
Dr. R. S. Massey, O. R. Maguire, Dr. A. C. O’Donoghue
Department of Chemistry, Durham University
South Road, Durham, DH1 3LE (UK)
aldehydes and that the chemoselectivity was determined at or
E-mail: annmarie.odonoghue@durham.ac.uk
[5h]
À
after the C C bond forming step.
[**] We thank the Royal Society for a University Research Fellowship
(A.D.S.), the EPSRC (C.J.C. and R.S.M.) grant number EP/G013268/
1 and the European Research Council under the European Union’s
Seventh Framework Programme (FP7/2007–2013) ERC grant
agreement no. 279850 (J.E.T.). We also thank the EPSRC UK
National Mass Spectrometry Facility at Swansea University.
Current explanations of the observed chemoselectivity in
cross-benzoin reactions of arylaldehydes are usually simplis-
tically based upon steric arguments. Previous to this inves-
tigation, it was commonly assumed that the presence of a 2-
substituent decreases the rate of NHC addition into an
arylaldehyde (Scheme 2).[8,9] The NHC I therefore preferably
adds into aldehyde II to form least-hindered 3-(hydroxyben-
zyl)azolium adduct IV, which undergoes deprotonation to
form Breslow intermediate V.[7,10] However, to account for the
observed selectivity, intermediate V must now add into the
more “hindered” 2-substituted benzaldehyde VI.[5c,d,6] This
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201501840.
ꢀ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co.
KGaA. This is an open access article under the terms of the Creative
Commons Attribution License, which permits use, distribution and
reproduction in any medium, provided the original work is properly
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Table 1: Equilibrium constants K for 3-(hydroxybenzyl)azolium adduct
formation.[a]
Entry
NHC
Ar1
Kexp
Adduct
Yield
[%][b]
[mÀ1
]
1
2
3
4
5
6
7
8
9
9
Ph
5
2
5
2
5
3
56
31
143
39
601
16
140
332
15
150
785
303
–
20
21
22
23
24
25
26
27
28
29
30
31
32
33
3
24
9
28
–
69
70
74
63
54
37
71
–
2-MeOC6H4
Ph
2-MeOC6H4
Ph
2-MeOC6H4
2-MeC6H4
2-ROC6H4
2-BrC6H4
4-BrC6H4
2-FC6H4
2,6-F2C6H3
2-pyridyl
10
10
11
11
10
10
10
10
10
10
10
10
2
12
13
14
15
16
17
18
19
[c]
9
10
11
12
13
14
Scheme 2. General mechanism for a cross-benzoin reaction.
6-Br-2-pyridyl
58
steric argument is therefore inherently contradictory. There
are currently no detailed mechanistic studies that offer insight
into the rate of NHC additions into 2-substituted benzalde-
hydes, the effect of the N-aryl NHC substituent upon the rates
of these processes, or the role of the 2-substituent in
chemoselective cross-benzoin reactions of arylaldehydes.
Building upon our previous mechanistic studies of NHC-
catalyzed processes,[11] herein the remarkable effect of 2-
arylaldehyde substitution upon equilibrium constants for 3-
(hydroxybenzyl)azolium adduct formation is demonstrated.
For the first time, individual rate constants for adduct
formation have been determined under stoichiometric con-
ditions and the effects of both aldehyde and N-aryl NHC
substitution have been probed, with the results offering
potential insight into the chemoselectivity of cross-benzoin
processes.
[a] Starting concentrations: aldehyde (0.01m), NHC precatalyst
(0.002m), Et3N (0.002m) in CD2Cl2 at 258C. [b] Yield of isolated product
from reaction between NHC precatalyst (1 equiv), aldehyde (1 equiv),
=
and Et3N (2 equiv) in CH2Cl2. [c] R=E-CH2CH CHCOOEt.
hyde 14 gave Kexp = 332 mÀ1 whereas reaction with 4-bromo-
benzaldehyde 15 gave Kexp = 15 mÀ1 (Table 1, entries 9 and
10). The introduction of an additional heteroatom substituent
in the 6-position further shifted the equilibrium in favor of
adduct formation. For example, reaction of 10 with 2,6-
difluorobenzaldehyde 17 gave Kexp = 785 mÀ1 whereas with 2-
fluorobenzaldehyde 16 Kexp = 150 mÀ1 (Table 1, entries 11 and
12). The use of 2-pyridinecarboxaldehyde 18 also gave an
equilibrium strongly in favor of the corresponding adduct,
while reaction with 6-bromo-2-pyridinecarboxyaldehyde 19
exclusively gave 3-(hydroxybenzyl)azolium adduct 33 such
that Kexp could not be measured (Table 1, entries 13 and 14).
In most cases, the 3-(hydroxybenzyl)azolium salts could also
be isolated from a stoichiometric reaction between the NHC
precatalyst and the corresponding aldehyde in the presence of
excess Et3N.
To gain further insight into the dramatic effect of 2-
heteroatom substitution, rate constants for 3-(hydroxy-
benzyl)azolium adduct formation were measured. First, the
effect of the N-aryl NHC substituent was assessed, as no
kinetic measurements have previously been made for triazo-
lium-catalyzed benzoin or Stetter processes.[13,14] Reactions of
aldehyde 13, which is often employed as a model substrate for
intramolecular Stetter reactions, were performed under pre-
steady-state conditions using stoichiometric concentrations of
NHC precatalysts in CD3OD with a Et3N:Et3N·HCl (2:1)
buffer at 158C,[15] analogous to the conditions used by Leeper
and White in their study of the thiazolium-catalyzed benzoin
reaction.[13a] Kinetic analysis of the reaction profiles obtained
before significant product formation (< 5%) allowed pseudo
First, the catalytic reactions between a range of substi-
tuted benzaldehydes (0.01m) and NHC precatalyst 9-11
(0.002m, 20 mol%) using Et3N (0.002m, 20 mol%) in
1
CD2Cl2 were monitored through in situ H NMR spectrosco-
py. Analysis of the resulting reaction profiles allowed
equilibrium constants for adduct formation (Kexp) to be
determined (Table 1).[12] The results demonstrate the remark-
able effect of having a heteroatom substituent in the 2-
position of the benzaldehyde on Kexp. For example, the
reaction between NHC precatalyst 9 and 2-methoxybenzal-
dehyde 2 gave Kexp = 56 mÀ1 compared with Kexp = 3 mÀ1 for
reaction with benzaldehyde 5 (Table 1, entries 1 and 2). As
observed previously,[11] the 2,6-substituted NHC precatalysts
10 and 11 gave significantly higher Kexp values, although 2-
methoxy aldehyde substitution again led to further prominent
increases (Table 1, entries 3–6). The importance of the 2-
heteroatom for this effect is demonstrated by reaction of
NHC precatalyst 10 with 2-tolualdehyde 12, which gives
Kexp = 16 mÀ1 (Table 1, entry 7). The effect is not limited to 2-
alkoxy substituents, as the reaction with 2-bromobenzalde-
2
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Table 2: Measurement of rate and equilibrium constants for 3-(hydroxybenzyl)azolium adduct
rate constants measured from both
formation.[a]
the forward and reverse reactions at
the same temperature are in good
agreement with each other, showing
that these methods can be used to
give reliable measurements.
Comparing the N-aryl NHC
precatalysts, the rate of adduct for-
mation (k1 or ka) increases with
more electron-withdrawing N-aryl
substituents (4-F > 4-H > 4-MeO).
This reflects the trend in pKa for
the NHC precatalysts (pKa 4-F < 4-
H < 4-MeO),[19] suggesting that the
rate of 3-(hydroxybenzyl)azolium
adduct formation is more influ-
enced by the equilibrium for preca-
talyst deprotonation. However, N-
Mes precatalyst 10 is an exception
Entry
Ar
k1
kÀ1
Kexp
Kfit
]
[mÀ1 sÀ1
]
[sÀ1
]
[mÀ1
]
[mÀ1 [b]
1
2
3
4
5
Ph
1.52ꢁ10À2
4.89ꢁ10À2
1.28ꢁ10À2
1.07ꢁ10À2
3.85ꢁ10À2
4.76ꢁ10À5
9.45ꢁ10À5
3.09ꢁ10À5
ꢀ1.01ꢁ10À7
1.25ꢁ10À5
319
383
414
394
433
555
7034
3414
4-FC6H4
4-MeOC6H4
2,6-(MeO)2C6H3
Mes
>1ꢁ105
3082
[a] Starting concentrations: aldehyde 13 (0.04m), NHC precatalyst (0.04m) in CD3OD and 0.18m
Et3N:Et3N·HCl (2:1) buffer at 158C. [b] Calculated through fitting of reaction profiles.
second-order rate constants for 3-(hydroxybenzyl)azolium
adduct formation (k1, mÀ1 sÀ1) and equilibrium constants (Kexp
as its pKa is similar to N-Ph precatalyst 9 (pKa 17.7 and 17.8,
respectively) but it reacts 2.5 times faster. This is postulated to
be due to the orthogonal orientation of the mesityl substituent
to the triazolium ring providing a more favorable approach of
the aldehyde.[20] In all cases 3-(hydroxybenzyl)azolium adduct
formation shows a degree of reversibility, however the kinetic
data shows the rate of dissociation for the adduct derived
from 13 and 10 is particularly slow, meaning that adduct
formation is effectively irreversible in this case.[21]
Having established reliable methods for measuring equi-
librium and rate constants for adduct formation this analysis
was extended to look at substituted benzaldehydes
(Table 4).[22] The reactions were performed using NHC
precatalyst 9, with comparable data obtained from both
kinetic analysis and reaction profile fitting in all cases. The
presence of a heteroatom in the aldehyde 2-position again has
a marked effect, leading to significantly higher equilibrium
constants for adduct formation.[23] The kinetic data gives an
insight into the origin of this trend. For example, the rate of
NHC addition into 2-methoxybenzaldehyde 2 is over 2.5
times faster than addition into benzaldehyde 5, and over ten
,
mÀ1) to be measured (Table 2).[16] Formation of the 3-
(hydroxybenzyl)azolium adduct involves two distinct steps:
the initial deprotonation of precatalyst by base and the
subsequent reaction of the NHC with aldehyde. After the
formation of adduct oxyanion, the base can be regenerated
upon protonation at oxygen resulting in an overall pseudo
second-order process under these experimental conditions.
This is confirmed by the excellent fitting of reaction data
to a kinetic expression describing a second-order reaction
proceeding to a position of equilibrium.[12] The pseudo first-
order rate constants for adduct dissociation (kÀ1, sÀ1) could
also be calculated as Kexp = k1/kÀ1. Additional estimates for k1
and kÀ1 were obtained from reaction profile fitting, with the
values used to calculate the corresponding equilibrium
constants (Kfit). Pleasingly, the fitted values obtained are in
good agreement with those obtained from kinetic analysis,
with the largest discrepancy occurring for the reaction using
NHC precatalyst 36 where adduct dissociation is negligible
(Table 2, entry 4).[17]
Next, the reverse decay towards
equilibrium was studied. Analysis
Table 3: Measurement of rate and equilibrium constants for 3-(hydroxybenzyl)azolium adduct
of the 1H NMR reaction profiles for
dissociation of the adducts of alde-
hyde 13 allowed rate and equilibri-
um constants of dissociation to be
measured (kd, sÀ1 and Kdiss, mÀ1) and
rate constants for association (ka,
dissociation.[a]
mÀ1 sÀ1)
to
be
calculated
(Table 3).[18] Although ka = k1 and
kd = kÀ1 a distinction has been made
to differentiate between the two
methods of measurement. The dis-
sociation analysis was not possible
for the N-2,6-(MeO)2C6H3 adduct
as the equilibrium lies so far
towards the adduct that insufficient
data could be obtained. Notably,
Entry
Ar
kd
ka
Kdiss
1/Kdiss
[mÀ1
[sÀ1
]
[mÀ1 sÀ1
]
[mÀ1
]
]
1
2
3
4
5
Ph
3.33ꢁ10À4
3.94ꢁ10À4
1.22ꢁ10À4
ND
5.14ꢁ10À2
8.76ꢁ10À2
2.76ꢁ10À2
ND
6.47ꢁ10À3
4.50ꢁ10À3
4.42ꢁ10À3
–
155
222
226
–
4-FC6H4
4-MeOC6H4
2,6-(MeO)2C6H3
Mes
5.34ꢁ10À5
9.90ꢁ10À2
5.40ꢁ10À4
1852
[a] Starting concentrations: 3-(hydroxybenzyl)azolium adduct (0.04m) in CD3OD and 0.18m
the values for the equilibrium and Et3N:Et3N·HCl (2:1) buffer at 258C.
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Table 4: Measurement of rate and equilibrium constants using substi-
tuted benzaldehydes.[a]
Entry Ar
k1
kÀ1
Kexp
k2
[mÀ1 sÀ1
]
[sÀ1
]
[mÀ1
]
[sÀ1
]
1
2
3
4
Ph
1.33ꢁ10À2 1.17ꢁ10À3
3.44ꢁ10À2 2.92ꢁ10À4
2.86ꢁ10À3 1.49ꢁ10À3
4.79ꢁ10À2 2.98ꢁ10À4
3.58ꢁ10À3 1.00ꢁ10À3
8.87ꢁ10À3 1.31ꢁ10À3
1.15ꢁ10À2 7.82ꢁ10À4
6.71ꢁ10À3 1.11ꢁ10À3
11.4 9.45ꢁ10À6
118 5.67ꢁ10À6
1.92 1.50ꢁ10À6
161 9.87ꢁ10À6
2-MeOC6H4
4-MeOC6H4
2-ROC6H4
[c]
5[b]
6[b]
7
4-ROC6H4
3.58
6.76
–
–
[c]
[c]
2-RCH2C6H4
2-MeC6H4
4-MeC6H4
14.7 3.59ꢁ10À6
6.02 4.57ꢁ10À6
8
[a] Starting concentrations: aldehyde (0.04m), NHC precatalyst 9
(0.04m) in CD3OD and 0.18m Et3N:Et3N·HCl (2:1) buffer at 258C.
=
[b] Reaction monitored at 158C. [c] R=E-CH2CH CHCOOEt.
Scheme 3. a) Cross-benzoin reaction; b) competition experiment;
c) possible chemoselectivity determining steps in the cross-benzoin
reaction.
times as fast as addition into 4-methoxybenzaldehyde
(Table 4, entries 1–3). A similar trend is seen comparing
intramolecular Stetter substrate 13 with its 4-substituted
analogue, demonstrating that the 2-substituent effect is not
purely electronic in nature (Table 4, entries 4 and 5). In both
cases the rate of the reverse process is also up to five times
slower for 2-substituted benzaldehydes, reflecting the
increased stability of these adducts. The importance of the
heteroatom substituent is highlighted by the use of an
analogue of 13 without the oxygen atom linker and 2- and
4-tolualdehyde, which all give equilibrium and rate constants
comparable with benzaldehyde 5 (Table 4, entries 6–8).
However, even in this case the rate of NHC addition into 2-
tolualdehyde is nearly twice as fast as addition into 4-
tolualdehyde (although the effect is smaller compared with
heteroatom substituents).
Further kinetic analysis of the reaction profiles following
the decreasing concentrations of the 3-(hydroxybenzyl)azo-
lium adducts over time allow estimation of the pseudo first-
order rate constants for deprotonation (k2, sÀ1) into the
transiently formed Breslow intermediates (Table 4). The rate
constants for deprotonation are of the same order of
magnitude for all the aldehydes, including those containing
a 2-substituent. Unlike the observed substituent effect on the
first step (k1 and K), the observed order of reactivity on k2
reflects normal through-bond electronic effects on carbon
acidity where electron-donating groups on the aldehyde
decrease the rate of deprotonation. This is in agreement
with our previous observations of normal electronic effects of
the NHC N-aryl substituent on this deprotonation step.[11]
Rate constants for deuterium exchange at the benzylic
position of O-methylated 3-(hydroxybenzyl)azolium adducts
were observed to decrease in the presence of electron-
donating substituents (for example, 2-MeO) on the N-aryl
ring.
chemoselectivity of cross-benzoin reactions. A representative
cross-benzoin reaction between benzaldehyde 5 and 2-
methoxybenzaldehyde 2 was performed using NHC precata-
lyst 3 (20 mol%) in CH2Cl2 at 458C (Scheme 3a). The
observed chemoselectivity is consistent with that previously
reported,[5e] with cross-product 37 favored and smaller
amounts of homo-benzoin 38 and benzoin 39 also formed
(Scheme 3a). Similar product ratios were observed using
NHC precatalyst 11, although the conversion was lower (ca.
15%). Monitoring the cross-reaction at 258C using NHC
precatalyst 11 revealed a 10:1 mixture of 3-(hydroxybenzy-
l)azolium adducts 25:24 at equilibrium, again demonstrating
a prominent 2-substituent effect in this system (Scheme 3b).
However, despite formation of adduct 25 being favored,
cross-product 37 is derived from reaction of minor adduct 24,
indicating the chemoselectivity must be determined later in
the reaction pathway.[24] This leads to three main possibilities
for the origin of the observed chemoselectivity: 1) formation
of the Breslow intermediate; 2) onwards reaction of the
Breslow intermediate; 3) dissociation of the resulting tetra-
hedral adducts (Scheme 3c).
The measured rate constants for Breslow intermediate
formation show that 2-MeO substitution decreases k2 by
a factor of about two relative to benzaldehyde 5 (Table 4,
entries 1 and 2), however this does not outweigh the tenfold
increase in equilibrium constant for adduct formation with
a 2-MeO substituent and cannot account for the observed
chemoselectivity. A difference in rate of the onwards reaction
of the two Breslow intermediates 40 and 41 would account for
the cross-benzoin selectivity. In both cases reaction with 2-
methoxybenzaldehyde 2 will be comparatively fast over
reaction with benzaldehyde 5 owing to the previously
described 2-substituent effect. However, the increased steric
hindrance around the nucleophilic carbon of 41 compared
The kinetic and equilibrium data of NHC addition into
the benzaldehydes potentially offers insight into the observed
4
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with 40 may decrease its relative rate of addition sufficiently
to explain the formation of cross-benzoin 37.[25]
Alternatively, NHC dissociation from tetrahedral inter-
mediate 43 may be slow compared with 42, again resulting in
preferential formation of cross-product 37. This would be
consistent with the measured rate constants for dissociation
(kÀ1) of the related 3-(hydroxybenzyl)azolium adducts in
which a 4-fold difference was observed (Table 4, entries 1 and
2). However, accumulation of intermediates such as 42 and 43
have not been observed in any of our NMR experiments to
date, or in earlier NMR studies by Leeper and White of the
thiazolium-catalyzed benzoin reaction,[13a] suggesting a faster
rate of breakdown relative to the rate of formation from the
relevant Breslow intermediate and aldehyde. Furthermore,
monitoring reactions of NHC precatalyst 11 with either 37 or
38 gave about 10% retro-benzoin products but no observable
products consistent with formation of the corresponding
tetrahedral adducts.[26] Additionally, a control experiment
reacting NHC precatalyst 11 with acetophenone gave no
observable products, suggesting that any NHC–ketone
adducts formed rapidly dissociate. Therefore, it seems more
likely that the chemoselectivity in cross-benzoin reactions is
determined by the onwards reaction of the Breslow inter-
mediate.
Although the increased rate of nucleophilic addition into
benzaldehydes bearing a 2-heteroatom substituent is clearly
evident, the origin of this phenomenon is unclear.[27] One
possibility is that the presence of a lone pair on an atom in the
2-position changes the conformation of the aldehyde carbonyl
such that it twists out of conjugation with the aryl ring. This
ground state destabilization of aldehyde could result in
increased reactivity towards nucleophiles. Alternatively
increased product stability due to hydrogen bond formation
between the 2-heteroatom substituent and the OH group of
the 3-(hydroxybenzyl)azolium adducts could also contribute
to the observed increase in both rate and equilibrium
constants. These ground and product state effects could be
realized in any nucleophilic addition to 2-substituted alde-
hydes of this type, including in the onward reaction of
Breslow intermediates in cross-benzoin reactions.
In conclusion, measurements of equilibrium and rate
constants for the reaction of triazolium NHC precatalysts
with substituted benzaldehydes to give 3-(hydroxybenzyl)-
azolium adducts under both catalytic and stoichiometric
conditions have been made. The results obtained from kinetic
analysis and fitting data for both the forward and backwards
processes show that nucleophilic addition into benzaldehydes
bearing a 2-heteroatom substituent is particularly fast. By
contrast, smaller substituent effects are observed on the rate
of deprotonation of 3-(hydroxybenzyl)azolium adducts, which
fall within the same order of magnitude regardless of
aldehyde substitution. The results offer insight into the
apparent inconsistency over the second aldehyde addition in
cross-benzoin reactions, overturning the assumption that 2-
substituted benzaldehydes are less reactive based upon steric
arguments.
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[12] See the Supporting Information for full details and all reaction
profiles.
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Z. Kelemen, L. Nyulꢃszi, J. Org. Chem. 2012, 77, 6014 – 6022;
c) while this work was under review, Gravel et al. published
Keywords: 2-substituent effect · kinetics · mechanistic studies ·
N-heterocyclic carbenes · organocatalysis
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ꢀ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
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.
Angewandte
Communications
a DFTand experimental study concerning NHC-catalyzed cross-
Benzoin processes: S. M. Langdon, C. Y. Legault, M. Gravel, J.
Org. Chem. 2015, 80, 3597 – 3610.
[21] This is consistent with the work of Bode et al. on the effect of the
N-Mes substituent in NHC reactions with enals; see: J.
Mahatthananchai, J. W. Bode, Chem. Sci. 2012, 3, 192 – 197.
[22] The reactions of benzaldehyde
5 with a range of NHC
[14] For mechanistic studies on the Stetter reaction, see: a) K. J.
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Houk, J. Am. Chem. Soc. 2011, 133, 11249 – 11254; d) J. L.
Moore, A. P. Silvestri, J. R. deAlaniz, D. A. DiRocco, T. Rovis,
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K. N. Houk, T. Rovis, Angew. Chem. Int. Ed. 2012, 51, 2391 –
2394; Angew. Chem. 2012, 124, 2441 – 2444.
[15] NHC precatalysts 3 and 11 gave full conversion into the product
in less than 5 min and therefore could not be examined further.
[16] A correction factor to account for hemiacetal formation was
required to accurately determine aldehyde concentrations. The
formation of 3-deutero 3-(hydroxybenzyl)azolium adducts were
also observed, presumably through deuteration of the transiently
formed Breslow intermediate. See the Supporting Information
for details.
[17] The same trends were observed at 258C, indicating that kinetic
analysis up to adduct equilibrium remains valid in cases where
Stetter product formation is more significant. See the Supporting
Information.
[18] Rate and equilibrium constants for dissociation were also
obtained from fitting analysis. See the Supporting Information.
[19] a) R. S. Massey, C. J. Collett, A. G. Lindsay, A. D. Smith, A. C.
O’Donoghue, J. Am. Chem. Soc. 2012, 134, 20421 – 20432;
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Jasiewicz, C. R. Bramley, A. D. Smith, A. C. OꢄDonoghue, J.
Phys. Org. Chem. 2015, 28, 108 – 115.
precatalysts show the same trends as previously, suggesting
that the effect of the N-aryl NHC substituent is independent of
aldehyde substitution. See the Supporting Information.
[23] Whilst the trends in Kexp are same between the reactions
performed in CD3OD and CD2Cl2, quantitative comparisons
cannot be made owing to the different concentrations and
temperatures.
[24] An alternative mechanism in which Breslow intermediate 41
reacts with benzaldehyde 5 to form an adduct (analogous to 42/
43) that undergoes a 1,2-hydride shift to eliminate the NHC
would also lead to major product 37. This mechanism has been
ruled out based upon a deuteration experiment. See the
Supporting Information for details.
[25] Scheidt et al. have recently proposed a similar argument to
explain the poor reactivity of 2-substituted benzaldehydes in
thiazolium-catalyzed acyl anion additions into aza-ortho-qui-
none methides; see: M. T. Hovey, C. T. Check, A. F. Sipher,
K. A. Scheidt, Angew. Chem. Int. Ed. 2014, 53, 9603 – 9607;
Angew. Chem. 2014, 126, 9757 – 9761.
[26] This is also in agreement with data from White and Leeper,
which show that the second-order rate constant for the
thiazolium-catalyzed retro-benzoin is 28-fold slower than the
analogous rate constant for the forward reaction of benzalde-
hyde. See Ref. [13a].
[27] Wolfenden and Jencks have shown that 2-substituted benzalde-
hydes have unexpectedly high rate and equilibrium constants for
benzaldehyde semicarbazide formation; see: R. Wolfenden,
W. P. Jencks, J. Am. Chem. Soc. 1961, 83, 2763 – 2768.
[20] a) B. Maji, M. Breugst, H. Mayr, Angew. Chem. Int. Ed. 2011, 50,
6915 – 6919; Angew. Chem. 2011, 123, 7047 – 7052; b) F. Ragone,
A. Poater, L. Cavallo, J. Am. Chem. Soc. 2010, 132, 4249 – 4258.
Received: February 26, 2015
Published online: && &&, &&&&
6
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Angew. Chem. Int. Ed. 2015, 54, 1 – 7
These are not the final page numbers!

Angewandte
Chemie
Communications
Reaction Mechanisms
C. J. Collett, R. S. Massey, J. E. Taylor,
O. R. Maguire, A. C. O’Donoghue,*
A. D. Smith*
&&&& — &&&&
Rate and Equilibrium Constants for the
Addition of N-Heterocyclic Carbenes into
Benzaldehydes: A Remarkable 2-
Substituent Effect
It takes 2-: Measurement of rate and
equilibrium constants for the reaction
between N-aryl triazolium NHC precata-
lysts and substituted benzaldehydes
under catalytic and stoichiometric condi-
tions demonstrate the remarkable kinetic
and thermodynamic effect of the benzal-
dehyde 2-substituent in these reactions,
potentially providing insight into the
chemoselectivity of cross-benzoin reac-
tions.
Angew. Chem. Int. Ed. 2015, 54, 1 – 7
ꢀ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
7
These are not the final page numbers!