A stable N-heterocyclic carbene organocatalyst for hydrogen/deuterium exchange reactions between pseudoacids and deuterated chloroform

Article abstract of DOI:10.1021/jo502578x

It was observed that the stable and commercially available N-heterocyclic carbene (NHC) 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene, the so-called IDipp, catalyzes hydrogen/deuterium exchange reactions between pseudoacids and chloroform-d₁

Full text of DOI:10.1021/jo502578x

Article
pubs.acs.org/joc
A Stable N‑Heterocyclic Carbene Organocatalyst for Hydrogen/
Deuterium Exchange Reactions between Pseudoacids and
Deuterated Chloroform
Fabien Perez, Yajun Ren, Thomas Boddaert,† Jean Rodriguez,* and Yoann Coquerel*
́
Aix Marseille Universite, Centrale Marseille, CNRS, iSm2 UMR 7313, 13397 Marseille, France
S
* Supporting Information
ABSTRACT: It was observed that the stable and commercially
available N-heterocyclic carbene (NHC) 1,3-bis(2,6-diisopropyl-
phenyl)imidazol-2-ylidene, the so-called IDipp, catalyzes hydrogen/
deuterium exchange reactions between pseudoacids and chloroform-
d1, while the analogous saturated NHC 1,3-bis(2,4,6-trimethyl-
phenyl)imidazolin-2-ylidene, the so-called SIMes, is inefficient for
the same transformation. Experimental and computational DFT
studies allowed these differences of reactivity to be attributed to the
relative stability of the corresponding azolium−trichloromethyl anion ion pairs: in the former case, the complex evolves toward
dissociation of the ions to produce an aromatic azolium cation and a basic trichloromethyl anion, while in the latter case, it
evolves by ion recombination to give the product of formal carbene C−H insertion into the C−H bond of chloroform. These
results provide a rationale for some early intuitions and observations of Wanzlick, Arduengo, and others on the reactivity of
NHCs with chloroform as well as a simple organocatalytic method for the deuteration of pseudoacids (pKa,DMSO = 14−19) with
chloroform-d1.
Scheme 1. IDipp-Catalyzed H/D Exchange Reaction
between Dimethyl Malonate and CDCl3 (Dipp = 2,6-
Diisopropylphenyl)
INTRODUCTION
■
N-heterocyclic carbenes (NHCs) have explosively moved from
the status of understudied laboratory curiosities to routine
molecular objects in organometallic chemistry and catalysis
over the past two decades.1−3 On the one side, NHCs are
excellent σ-donating ancillary ligands in transition-metal
complexes with a multitude of applications,4−7 and on the
other side, free NHCs have also found a number of applications
as organocatalysts.8,9 Organocatalysis with NHCs can involve
either their ambiphilic properties to trigger catalytic “umpo-
lung” reactivity of aldehydes and enals,10,11 their Lewis base
properties for nucleophilic activation, or also their Brønsted
base properties for applications requiring a proton shuttle.12−14
Of course, the reactivity profiles of the various classes of NHCs
are very dependent on their intimate electronics and sterics.15,16
In the course of our studies on NHC-catalyzed (hetero-)
Michael additions using NHCs as catalytic proton shuttles,17−20
we fortuitously observed that the stable and commercially
available NHC 1,3-bis(2,6-diisopropylphenyl)imidazol-2-yli-
dene (IDipp, 1) efficiently catalyzes the hydrogen/deuterium
RESULTS AND DISCUSSION
■
The NHC-catalyzed H/D exchange reaction between pseu-
doacids and deuterated chloroform was examined with several
prototypical pseudoacids (Table 1 and Figure 1) ranging from
easily enolizable/deprotonable substrates such as 2-nitro-1-
phenylethanone (pKa,DMSO = 7.7; entry 1) to weakly acidic
compounds such as propionitrile (pKa,DMSO = 32.5; entry 12).
The reactions were periodically monitored by 1H NMR
spectroscopy until no significant change was observed
(equilibrium). Overall, and as shown in Figure 1, it was
observed that the NHC IDipp (1) could efficiently catalyze the
hydrogen/deuterium exchange reaction of deuterated chloro-
form only with moderately acidic substrates (pKa,DMSO = 14−
19) and that the reaction was shut down with the tested
substrates having pKa,DMSO values equal to or lower than 10
(entries 1 and 2) and higher than 29 (entries 11 and 12).
exchange reaction between dimethyl malonate (pKa,DMSO
=
15.921) and deuterated chloroform (Scheme 1). This intriguing
NHC-catalyzed H/D exchange reaction was further examined
both experimentally and computationally, which allowed us to
rationalize previous experimental observations and our own
ones as well as to gain further insight into the Brønsted base
properties of NHCs and their insertion reactions into the C−H
bonds of pseudoacids.
Received: November 11, 2014
© XXXX American Chemical Society
A
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The other well-known stable and commercially available
NHCs SIMes (2) and the so-called “Ender’s carbene” 3,31 as
well as the organic Brønsted base 1,8-diazabicyclo[5.4.0]undec-
7-ene (DBU), were tested as catalysts for the H/D exchange
reaction of chloroform-d1 with dimethyl malonate (Figure 2).
Table 1. IDipp-Catalyzed Hydrogen/Deuterium Exchange
Reaction between Various Pseudoacids and Deuterated
Chloroform
a
Figure 2. H/D exchange reactions with the NHC catalysts 1−3 and
DBU using dimethyl malonate in CDCl3 (0.1 M) with 2 mol %
catalyst.
In sharp contrast to the reaction with IDipp (1), the reactions
with SIMes (2) and NHC 3 were found to produce only very
small amounts of the H/D exchange product. However, the
reaction with DBU led to a significant H/D exchange (ca. 50%)
after 50 h.
From this set of data and the fact that chloroform is a weak
Brønsted acid (pKa,aq = 2432), it was logically concluded that
the above NHC-catalyzed H/D exchange reaction between
chloroform-d1 and pseudoacids with 1 proceeds by deprotona-
tion of chloroform-d1 with NHC 1 to form a catalytic amount
of the deuterated azolium cation33 and the basic trichlor-
omethyl anion (Scheme 2). The latter would deprotonate the
pseudoacid substrate to form chloroform, and a deuterium
atom would be transferred from the deuterated azolium cation
to the pseudoacid anion. Overall, NHC 1 (pKa,aq of the
corresponding azolium cation = 21.134) would operate as a
a
The reactions were performed in CDCl3 (0.05 M) at 21 °C with 1
(10 mol %) for 48 h (entries 1−5, 7, and 12), 1 h (entry 6), or 43 h
b
c
d
(entries 8−11). From ref 22. From ref 23. From refs 24 and 25.
e
f
g
h
i
Scheme 2. Postulated Mechanism of the NHC-Catalyzed H/
D Exchange Reaction
From ref 26. From ref 27. From ref 28. From ref 29. From ref 30.
Figure 1. Trend line of H/D exchange with CDCl3 using the NHC
catalyst IDipp (1) against pKa,DMSO values (data from Scheme 1 and
Table 1). The solid line accounts for all of the experiments, and the
dotted line accounts for all of the experiments except Table 1, entry
10.
B
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catalytic deuterium atom shuttle in this reaction, and the same
should hold true for the H/D exchange reaction catalyzed by
DBU (Figure 2). If this is indeed the case, one should question
why the moderately less basic NHC 3 (pKa,aq of the
corresponding azolium cation = 16.835) and, more strikingly,
the slightly more basic NHC 2 (pKa,aq of the corresponding
azolium cation = 21.334) are not efficient catalytic deuterium
atom shuttles in this reaction. While the lower Brønsted basicity
of NHC 3 compared with IDipp (1) could very significantly
slow the deprotonation of chloroform-d1 and thus the overall
H/D exchange process, the reaction with SIMes (2) should be
at least operative if not accelerated compared with the reaction
with IDipp (1) unless another competitive reaction occurs in
the case of SIMes (2). This is obviously the case.
the IEFPCM solvation model for chloroform. It was found that
the reaction of 2 with chloroform produces the C−H insertion
product 4 by a formally stepwise mechanism (Figure 3), and we
In 1999, Arduengo and co-workers reported the insertion
reaction of the NHC SIMes (2) into the C−H bond of
chloroform to afford the insertion product 4 in good yield after
3 days in hexane (Scheme 3).36 As to the mechanism of this
Figure 3. Detailed mechanism and energy profile of the reaction of
SIMes (2) with chloroform in chloroform (blue) and energies of the
stationary points A, B, and 4 in n-hexane (green). The energy profile
was obtained by DFT calculations at the B3LYP/6-311++G** level of
theory (free energies at 25 °C including ZPE corrections in kcal/mol
with the IEFPCM solvation model); see the Supporting Information
for details.
Scheme 3. C−H Insertion Reaction of SIMes (2) with
Chloroform (from ref 36)
were not able to identify a transition state that could account
for a truly concerted pathway. The system 2 + CHCl3 without
interaction (A) spontaneously evolves to the stabilized
Brønsted pair B (−5.8 kcal/mol). Then the proton exchange
step producing the zwitterionic Brønsted pair C can occur via
TSBC with a relatively low energy barrier (+3.0 kcal/mol from
A). From C, the C−H insertion product 4 is then formed with
a reasonable energy barrier (+9.1 kcal/mol from A) and a
stabilization of the system of −5.3 kcal/mol relative to A (−7.1
kcal/mol relative to C). These calculations indicate that the
Brønsted pair B and the C−H insertion product 4 are roughly
isoenergetic and are most probably in equilibrium at room
temperature with a small preference for B. However, under the
reaction conditions using chloroform as both the substrate and
the solvent, this equilibrium is virtually entirely shifted to the
C−H insertion product 4, thus fully justifying the rapid loss of
activity of NHC 2 in the studied H/D exchange reaction. The
isolation of 4 from 2 + CHCl3 as depicted in Scheme 3
questioned the validity of our computational data, indicating
that B is slightly more stable than 4 in chloroform. In order to
address this specific point, the geometries and energies of both
B and 4 were recalculated modeling n-hexane as the solvent,
and 4 was found to be slightly more stable than B (energy
values in green in Figure 3), which nicely fits with the
experimental results reported by Arduengo and co-workers
(where both a long reaction time and a large excess of CHCl3
were required). Overall, the present computational study sheds
some light on the actual mechanism of the reaction 2 + CHCl3
→ 4 (and the reverse reaction). Our conclusion on this matter
is that the mechanism of this reaction is best regarded as a
formally stepwise mechanism with indeed “some degree of
concertedness”, as proposed early-on by Arduengo and co-
workers, due to the existence of the weakly stabilized, fleeting
zwitterionic intermediate C.
reaction, the authors noted that it is consistent with a stepwise
pathway initiated by the deprotonation of chloroform with 2;
−
however, evidence for the formation of the free CCl3 anion
that would be formed by a fully stepwise process was not
observed, and it was concluded that “there may be some degree
of concertedness to these insertions”. In the case of the NHC-
catalyzed H/D exchange reaction between chloroform-d1 and
pseudoacids with catalyst 2, the quantitative and irreversible
formation of 4-d1 would explain why the catalytic activity of 2 is
rapidly shut down after the beginning of the reaction. But it
should nevertheless be noted that in our case a fraction of the
dimethyl malonate substrate was actually rapidly deuterated (ca.
3% after 1 h; see Figure 2), pointing out the possible generation
−
of the free CCl3 anion in the early stages of the reaction
(before equilibrium is reached). Beside this, in their pioneering
work directed at the isolation of stable carbenes, Wanzlick and
co-workers used the reverse reaction, namely, the 1,1-
elimination of chloroform from 1,3-diphenyl-2-(trichloro-
methyl)imidazolidine, which resulted in the production of the
corresponding carbene dimer, probably via the transitory NHC
analogue of 2, 1,3-diphenylimidazolin-2-ylidene.37−39 Also,
more recently, Waymouth, Hedrick, and co-workers used the
1,1-elimination of chloroform from 4 to produce the NHC 2 in
solution.40 They also questioned the mechanism of the reaction
and noted that it “is consistent with a concerted elimination of
HCCl3 ... rather than a stepwise ionic mechanism”.
Intrigued by these apparently contradictory results, we
embarked on a theoretical computational study with the
intention to rationalize the sharp difference in reactivity
between the two structurally very similar NHCs IDipp (1)
and SIMes (2) in the H/D exchange reaction and possibly to
elucidate the actual mechanism of the C−H insertion reaction
of SIMes (2) with chloroform. The reactions of the NHCs 1
and 2 with chloroform were investigated using DFT with the
B3LYP functional and the extended 6-311++G** basis set to
account for polarization and diffusion on all atoms, along with
A similar series of calculations was performed for the reaction
of the NHC IDipp (1) with chloroform (Figure 4). The energy
profiles of the proton exchange reactions of the NHCs 1 and 2
with chloroform reflect their very similar Brønsted basicities
(compare A → B → C with D → E → F) and also the slightly
C
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reaction between 1 and chloroform-d1 is not basic enough to
deprotonate the substrate and continue the H/D exchange
reaction at a significant rate. Similarly, the poor to nonexistent
catalytic activity of IDipp (1) with more acidic substrates (e.g.,
entries 1 and 2) is attributed to the largely favored protonation
of the NHC catalyst 1 by the acidic substrate at equilibrium.
Indeed, under the conditions of our study, the almost
quantitative (ca. 96−99%) formation of the azolium cation
1
[1−H]+ could be detected by H NMR spectroscopy in the
case of entries 1 and 2 (at 10.22 and 9.89 ppm, respectively, for
the H atom at C2), indicating that protonation by the substrate
occurred faster than the H/D exchange reaction with
chloroform-d1. Taking advantage of the pKa-dependent
efficiency of the NHC-catalyzed H/D exchange reaction with
IDipp (1) and chloroform-d1, we questioned whether the
selective deuteration of dimethyl malonate could be possible in
the presence of a more acidic substrate. A somewhat selective
deuteration was indeed observed for the N−H proton in the
secondary β-keto amide substrate of entry 5 in Table 1. In the
presence of a catalytic amount of IDipp (1), a 1:1 solution of
dimethyl malonate and 3-oxo-3-phenylpropanenitrile in chloro-
form-d1 did show the selective deuteration of dimethyl
malonate, but at a very low rate (Scheme 5). Actually, 94%
Figure 4. Detailed mechanism and energy profile of the reaction of
IDipp (1) with chloroform in chloroform. The energy profile was
obtained by DFT calculations at the B3LYP/6-311++G** level of
theory (free energies at 25 °C including ZPE corrections in kcal/mol
with the IEFPCM solvation model); see the Supporting Information
for details.
more basic character of 2 compared with 1 (ΔEBC = 7.6 kcal/
mol vs ΔEEF = 8.7 kcal/mol). With IDipp (1), the possible C−
H insertion product G was found to be significantly less stable
than the two Brønsted pairs E and F, which corresponds to a
negligible amount of G at equilibrium. Moreover, the
conversion of F into G requires a relatively high activation
energy (+16.1 kcal/mol from D), and if it occurs, the formation
of G should be slow and quickly reversible. The unfavored
formation of the C−H insertion product G reflects, at least in
part, the aromaticity of the azolium cation in F. Thus, in the
presence of a large excess of chloroform, the system 1 + CHCl3
(D) should exist predominantly as intermediate F at
Scheme 5. Selective Deuteration of Pseudoacids
−
equilibrium, liberating some amount of free CCl3 anion. The
−
α-elimination of a chlorine atom from the free CCl3 anion is
1
of the introduced amount of NHC catalyst 1 was found by H
known to produce the electrophilic dichlorocarbene. Thus, in
the absence of any other proton source, solutions of IDipp (1)
in CHCl3 should produce some amount of dichlorocarbene,
which would rapidly react with additional 1 to form the
heterodimeric product 5 (Scheme 4).41 In practice, a signal
NMR analysis to exist in its [1−H]+ azolium form, accounting
for the observed very low rate. Overall, despite the fact that the
range of substrates is somewhat limited, the organocatalytic H/
D exchange method discussed herein has some practical value,
especially considering that CDCl3 is a cheap and widely
available deuterium atom source. An obvious practical bottom
line to this study is that chloroform-d1 should, of course, be
avoided as a solvent for NMR experiments involving free
NHCs.
Scheme 4. Formation of the Heterodimeric Compound 5
CONCLUSION
■
In summary, efficient NHC-catalyzed H/D exchange reactions
between pseudoacids having pKa,DMSO values of 14−19 and
chloroform-d1 were observed when the stable NHC 1,3-bis(2,6-
diisopropylphenyl)imidazol-2-ylidene (IDipp, 1) was used as a
catalyst, thereby providing an original organocatalytic method
for the deuteration of pseudoacids. The excellent organo-
catalytic activity of 1 was attributed to its ideally suited
deuterium-shuttling properties for the studied system, involving
a stable azolium−trichloromethyl anion Brønsted pair. The
structurally similar NHC 1,3-bis(2,4,6-trimethylphenyl)-
imidazolin-2-ylidene (SIMes, 2), despite exhibiting almost
identical Brønsted basicity as 1, is an incompetent catalyst for
the same transformation. A theoretical study indicated that the
reaction of NHC 2 with chloroform actually produces a fleeting
azolinium−trichloromethyl anion Brønsted pair that rapidly
rearranges into the product of insertion of the NHC into the
C−H bond of chloroform, shutting down the deuterium-
shuttling activity of 2. These results provide a rationale for
attributed to the product 5 and its isotopes was detected by
mass spectrometry analysis of a chloroform solution of IDipp
(1) that was allowed to stand at room temperature, probing the
−
formation of the free CCl3 anion (see the Experimental
Section). Similarly, diluted solutions of IDipp (1) in chloro-
form-d1 at equilibrium should produce largely the correspond-
ing deuterated azolium cation33 [1−D]+ and the free CCl3
−
anion, both of which are responsible for the observed H/D
exchange reaction.42 Accordingly, the 13C NMR analysis of a
solution of 1 in chloroform-d1 showed no detectable amount of
1 (or 1-d242) after a few hours.43
As shown in Table 1 and Figure 1, the H/D exchange
reaction between chloroform and pseudoacids catalyzed by
IDipp (1) is efficient only with substrates having pKa,DMSO
values in the 14−19 range. With poorly acidic substrates (e.g.,
entries 11 and 12 in Table 1), the trichloromethyl anion
catalytically generated by the deuterium atom exchange
D
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some early intuitions and observations of Wanzlick, Arduengo,
and others on the reactivity of NHCs with chloroform.
ACKNOWLEDGMENTS
■
Financial support from the European CMST COST Action
CM0905 on organocatalysis, the Agence National de la
Recherche (ANR), the China Scholarship Council (CSC),
Aix-Marseille Universite, and the Centre National de la
́
Recherche Scientifique (CNRS) is gratefully acknowledged.
EXPERIMENTAL SECTION
■
General Methods. Reagents and catalysts were weighed in air at
room temperature, and all of the reactions were conducted under an
argon atmosphere in sealed reaction vessels. CHCl3 and CDCl3 used
in this study were stored over a bed of 4 Å molecular sieves and solid
K2CO3. Unless stated otherwise, all of the chemicals were obtained
from commercial sources and used as received. The substrates in
entries 4 and 5 in Table 1 were prepared by described methods.44 1H
NMR spectra were recorded in CDCl3 at 294 K at 300 or 400 MHz
using the residual nondeuterated solvent as an internal standard (δ =
7.26 ppm). 13C{1H} NMR spectra were recorded in CDCl3 at 294 K at
75 or 100 MHz using the deuterated solvent as an internal standard (δ
= 77.16 ppm).
REFERENCES
■
(1) N-Heterocyclic Carbenes: From Laboratory Curiosities to Efficient
Synthetic Tools, Díez-Gonzal
Cambridge, U.K., 2010.
́
ez, S., Ed.; Royal Society of Chemistry:
(2) Heterocyclic Carbenes in Transition Metal Catalysis and Organo-
catalysis; Cazin, C. S. J., Ed.; Springer: Dordrecht, The Netherlands,
2011.
(3) Hopkinson, M. N.; Richter, C.; Schedler, M.; Glorius, F. Nature
Data in Scheme 1, Table 1, and Figure 1. To a solution of the
pseudoacid substrate (0.10 mmol) in CDCl3 (2.0 mL) was added
IDipp (1) (4 mg, 0.01 mmol). The resulting solution was stirred at 21
°C and periodically monitored by 1H NMR spectroscopy (single-scan
experiments) until no significant change was observed. The percentage
of deuterium incorporation was determined by measuring the decrease
in the integration of the signal corresponding to the enolizable/
deprotonable position compared with an internal standard present on
the substrate (a nonexchangeable position).
Data in Figure 2. To a solution of dimethyl malonate (57 μL, 0.50
mmol) in CDCl3 (5.0 mL) was added the NHC catalyst 1−3 or DBU
(0.01 mmol). The resulting solution was stirred at 21 °C and
periodically monitored by 1H NMR spectroscopy over 50 h. The
percentage of deuterium incorporation was determined by measuring
the decrease in the integration of the signal corresponding to the
enolizable position (δ = 3.39 ppm) compared with an internal
standard present on the substrate (the methyl groups).
2014, 510, 485−496.
(4) Bellemin-Laponnaz, S.; Dagorne, S. Chem. Rev. 2014, 114, 8747−
8774.
(5) Visbal, R.; Gimeno, C. Chem. Soc. Rev. 2014, 43, 3551−3574.
(6) Liu, W.; Gust, R. Chem. Soc. Rev. 2013, 42, 755−773.
(7) Wang, F.; Liu, L.-j.; Wang, W.; Li, S.; Shi, M. Coord. Chem. Rev.
2012, 256, 804−853.
(8) Enders, D.; Niemeier, O.; Henseler, A. Chem. Rev. 2007, 107,
5606−5655.
(9) Grossmann, A.; Enders, D. Angew. Chem., Int. Ed. 2012, 51, 314−
325.
(10) Bugaut, X.; Glorius, F. Chem. Soc. Rev. 2012, 41, 3511−3522.
(11) For recent work from this laboratory, see: Nawaz, F.;
Zaghouani, M.; Bonne, D.; Chuzel, O.; Rodriguez, J.; Coquerel, Y.
Eur. J. Org. Chem. 2013, 8253−8264.
̀
(12) Fevre, M.; Pinaud, J.; Vignolle, J.; Gnanou, Y.; Taton, D. Chem.
Data in Scheme 4. A 0.01 M solution of IDipp (1) in CHCl3 was
allowed to stand overnight at 21 °C. The analysis of this solution
(highly diluted in MeOH) by mass spectrometry (ESI+) expectedly
showed a very largely major ion at m/z 389.3 corresponding to the
azolium cation [1−H]+ but also ions at m/z 471.2 (100%), 472.2,
473.2, 474.2, 475.2, and 476.2, an isotopic pattern corresponding to
the isotopic distribution of the cation [5−H]+ of formula
Soc. Rev. 2013, 42, 2142−2172.
(13) Ryan, S. J.; Candish, L.; Lupton, D. W. Chem. Soc. Rev. 2013, 42,
4906−4917.
(14) Chen, J.; Huang, Y. Nat. Commun. 2014, 5, No. 3437.
(15) Droge, T.; Glorius, F. Angew. Chem., Int. Ed. 2010, 49, 6940−
̈
6952.
(16) Nelson, D. J.; Nolan, S. P. Chem. Soc. Rev. 2013, 42, 6723−6753.
(17) Boddaert, T.; Coquerel, Y.; Rodriguez, J. Adv. Synth. Catal.
2009, 351, 1744−1748; Adv. Synth. Catal. 2009, 351, 2541
(corrigendum).
+
C28H37Cl2N2 (see the Supporting Information).
Data in Scheme 5. To a 1:1 solution of dimethyl malonate (11
μL, 0.10 mmol) and 3-oxo-3-phenylpropanenitrile (15 mg, 0.10
mmol) in CDCl3 (2 mL) was added IDipp (1) (4 mg, 0.01 mmol),
(18) Boddaert, T.; Coquerel, Y.; Rodriguez, J. Chem.Eur. J. 2011,
1
and the resulting solution was stirred at 21 °C for 4 days. H NMR
17, 2266−2271.
analysis of the reaction mixture revealed 15% deuterium incorporation
at the methylene position of dimethyl malonate and no deuterium
incorporation in 3-oxo-3-phenylpropanenitrile.
(19) Boddaert, T.; Coquerel, Y.; Rodriguez, J. Eur. J. Org. Chem.
2011, 5061−5070.
(20) Hans, M.; Delaude, L.; Rodriguez, J.; Coquerel, Y. J. Org. Chem.
2014, 79, 2758−2764.
ASSOCIATED CONTENT
* Supporting Information
(21) Arnett, E. M.; Maroldo, S. G.; Schilling, S. L.; Harrelson, J. A. J.
Am. Chem. Soc. 1984, 106, 6759−6767.
■
S
(22) Bordwell, F. G.; Van der Puy, M.; Vanier, N. R. J. Org. Chem.
1976, 41, 1883−1885.
Geometries of all stationary points of the theoretical computa-
tional study, selected computed structural parameters, details of
the H/D exchange reaction at the 4 and 5 positions in 1, and a
copy of the mass spectrum of 5. This material is available free of
charge via the Internet at http://pubs.acs.org.
(23) When unknown, pKa,DMSO values could be satisfactorily
estimated from the Bordwell pKa database: http://www.chem.wisc.
edu/areas/reich/pkatable/.
(24) Sanchez Duque, M. M.; Basle,
Genisson, Y.; Plaquevent, J.-C.; Rodriguez, J.; Constantieux, T. Org.
Lett. 2011, 13, 3296−3299.
(25) Quintard, A.; Cheshmedzhieva, D.; Sanchez Duque, M. M.;
Gaudel-Siri, A.; Naubron, J.-V.; Genisson, Y.; Plaquevent, J.-C.;
́
O.; Isambert, N.; Gaudel-Siri, A.;
́
AUTHOR INFORMATION
Corresponding Authors
*E-mail: jean.rodriguez@univ-amu.fr.
*E-mail: yoann.coquerel@univ-amu.fr.
■
́
Bugaut, X.; Rodriguez, J.; Constantieux, T. Chem.Eur. J. 2014,
DOI: 10.1002/chem.201404481.
Present Address
†T.B.: CP3A Organic Chemistry Group, ICMMO (UMR
(26) Matthews, W. S.; Bares, J. E.; Bartmess, J. E.; Bordwell, F. G.;
Cornforth, F. J.; Drucker, G. E.; Margolin, Z.; McCallum, R. J.;
McCollum, G. J.; Vanier, N. R. J. Am. Chem. Soc. 1975, 97, 7006−
7014.
(27) Bordwell, F. G.; Cornforth, F. J. J. Org. Chem. 1978, 43, 1763−
1768.
CNRS 8182), Universite
Clemenceau, 91405 Orsay Cedex, France.
Notes
The authors declare no competing financial interest.
́
Paris Sud, 15 rue Georges
́
E
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(28) Bordwell, F. G.; Drucker, G. E.; Andersen, N. H.; Denniston, A.
D. J. Am. Chem. Soc. 1986, 108, 7310−7313. In a singular manner,
significant deuteration was reproducibly observed with phenyl-
acetylene.
(29) Zhang, X. M.; Bordwell, F. G.; Van Der Puy, M.; Fried, H. E. J.
Org. Chem. 1993, 58, 3060−3066.
(30) Bordwell, F. G.; Van der Puy, M.; Vanier, N. R. J. Org. Chem.
1976, 41, 1885−1886.
(31) Enders, D.; Breuer, K.; Raabe, G.; Runsink, J.; Teles, J. H.;
Melder, J.-P.; Ebel, K.; Brode, S. Angew. Chem., Int. Ed. Engl. 1995, 34,
1021−1023.
(32) Margolin, Z.; Long, F. A. J. Am. Chem. Soc. 1973, 95, 2757−
2762.
(33) This may actually be an evolving mixture of the azolium-d1, -d2,
and -d3 cations as a result of H/D exchange reactions at the 4 and 5
positions of NHC 1 (see ref 42).
(34) Higgins, E. M.; Sherwood, J. A.; Lindsay, A. G.; Armstrong, J.;
Massey, R. S.; Alder, R. W.; O’Donoghue, A. C. Chem. Commun. 2011,
1559−1561.
(35) Massey, R. S.; Collett, C. J.; Lindsay, A. G.; Smith, A. D.;
O’Donoghue, A. C. J. Am. Chem. Soc. 2012, 134, 20421−20432.
(36) Arduengo, A. J., III; Calabrese, J. C.; Davidson, F.; Dias, H. V.
R.; Goerlich, J. R.; Krafczyk, R.; Marshall, W. J.; Tamm, M.;
Schmutzler, R. Helv. Chim. Acta 1999, 82, 2348−2364.
(37) Wanzlick, H.-W.; Schikora, E. Chem. Ber. 1961, 94, 2389−2393.
(38) Wanzlick, H.-W. Angew. Chem., Int. Ed. Engl. 1962, 1, 75−80.
(39) Wanzlick, H.-W.; Esser, F.; Kleiner, H.-J. Chem. Ber. 1963, 96,
1208−1212.
(40) Nyce, G. W.; Csihony, S.; Waymouth, R. M.; Hedrick, J. L.
Chem.Eur. J. 2004, 10, 4073−4079.
(41) Arduengo, A. J., III; Davidson, F.; Dias, H. V. R.; Goerlich, J. R.;
Khasnis, D.; Marshall, W. J.; Prakasha, T. K. J. Am. Chem. Soc. 1997,
119, 12742−12749.
(42) Interestingly, CDCl3 solutions of NHC 1 showed complete H/
D exchange at the 4 and 5 positions of the NHC itself to produce [1-
d2−D]+ (or 1-d2 after removal of the solvent under reduced pressure;
see the Supporting Information).
(43) The chemical shifts of the carbene carbon atoms of NHCs 1 and
1-d2 would be expected around 220 ppm, and no signal was detected
in this part of the 13C NMR spectrum. However, signals were detected
at 128−130 ppm, which were attributed to the azolium cations [1−
D]+, [1-d1−D]+, and [1-d2−D]+ (see ref 42 and the Supporting
Information).
(44) Presset, M.; Coquerel, Y.; Rodriguez, J. J. Org. Chem. 2009, 74,
415−418.
F
DOI: 10.1021/jo502578x
J. Org. Chem. XXXX, XXX, XXX−XXX