Nucleophilic reactivities of deoxy breslow intermediates: How does aromaticity affect the catalytic activities of N-heterocyclic carbenes?

Article abstract of DOI:10.1002/anie.201202327

Aromatic or nonaromatic? Kinetic investigations show that structurally analogous saturated and unsaturated N-heterocyclic carbenes have almost identical nucleophilic reactivities, while the corresponding deoxy Breslow intermediates differ dramatically. Co

Full text of DOI:10.1002/anie.201202327

Angewandte
Chemie
DOI: 10.1002/anie.201202327
Organocatalysis
Nucleophilic Reactivities of Deoxy Breslow Intermediates: How Does
Aromaticity Affect the Catalytic Activities of N-Heterocyclic
Carbenes?**
Biplab Maji, Markus Horn, and Herbert Mayr*
Dedicated to Professor George A. Olah on the occasion of his 85th birthday
N-Heterocyclic carbenes[1] (NHCs, 1) are widely used as
umpolung reagents[2] in organocatalysis.[3] In benzoin con-
densations[4] and Stetter reactions[5] the initially formed
Breslow intermediate A,[6] a nucleophilic acyl anion equiv-
alent, reacts with an aldehyde or Michael acceptor to give 1,2-
or 1,4-functionalized products. Recently, Fu, Matsuoka, and
Glorius independently reported the umpolung of the b-
position of Michael acceptors, where 1,1-diaminoalkenes B
act as key intermediates.[7] Since the structure of B is closely
related to A, it has been named “deoxy Breslow intermedi-
ate” (Scheme 1).[7c,8]
As the different catalytic activities of unsaturated and
saturated carbenes thus cannot be assigned to the different
properties of the carbenes themselves, the question arose
whether it is due to the different reactivities of the corre-
sponding Breslow intermediates. While characterizations of
Breslow intermediates by spectroscopic and theoretical
methods have been reported,[10] we are not aware of any
kinetic investigations comparing the reactivities of 1,1-di-
aminoethenes derived from different classes of NHCs. There-
fore, we have now synthesized compounds 2[11] and deter-
mined the kinetics of their reactions with electrophiles.
The reactions of 1a and 1b with benzyl or 4-nitrobenzyl
bromide, and subsequent deprotonation of the resulting
amidinium ions with NaH in the presence of a catalytic
amount of KOtBu in THF afforded 2a–2b’ in yields of 30–
90% (Scheme 2). While 2a and 2a’ could also be generated
Scheme 1. Reactions of NHCs with aldehydes and Michael acceptors
to give intermediates A and B, respectively.
Most suitable for these reactions were 1,2,4-triazol-5-
ylidenes, 1,3-thiazol-2-ylidenes, and imidazol-2-ylidenes,
while imidazolidin-2-ylidenes are not effective as umpolung
reagents.[3,8] This observation is surprising, because in recent
work we have shown that the imidazol-2-ylidene 1a and
imidazolidin-2-ylidene 1b have almost the same nucleophi-
licities and Lewis basicities, while Endersꢀs carbene 1c
reacted 103 times more slowly and 55 kJmolꢀ1 less exothermic
with C-electrophiles.[9]
Scheme 2. Synthesis of deoxy Breslow intermediates 2.
[*] M. Sc. B. Maji, Dr. M. Horn, Prof. Dr. H. Mayr
Department Chemie, Ludwig-Maximilians-Universitꢀt Mꢁnchen
Butenandtstrasse 5–13 (Haus F), 81377 Mꢁnchen (Germany)
E-mail: herbert.mayr@cup.uni-muenchen.de
with stoichiometric amounts of KOtBu in the absence of
NaH,[8] this procedure did not allow the synthesis of 2b and
2b’. Attempts to synthesize 2c’ analogously resulted in
complex reaction mixtures. However, 2c’ was synthesized in
60% yield from 4-nitrobenzyl bromide and 2 equivalents of
1c in toluene, the second molecule of 1c acting as the base.
For details of the synthetic procedures see the Supporting
Information.
Homepage: http://www.cup.lmu.de/oc/mayr
[**] We thank the Deutsche Forschungsgemeinschaft (SFB 749) for
financial support, Dr. Peter Mayer for the determination of the X-ray
structures, and Dr. Sami Lakhdar, Dr. Guillaume Berionni, Dr. Armin
R. Ofial, Prof. Paul von Raguꢂ Schleyer, and Dr. Judy Wu for helpful
discussions.
In order to quantify the nucleophilic reactivities of 2 we
have studied the kinetics of their reactions with the benzhy-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201202327.
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Table 1: Benzhydrylium ions 3a–f and quinone methides 3g,h employed
as reference electrophiles in this work.
Table 2: Second-order rate constants k (mꢀ1 sꢀ1) for the reactions of the
deoxy Breslow intermediates 2 with the reference electrophiles 3 at 208C.
[a]
Electrophile
E[a]
Nucleophile
Solvent
THF
N, sN
Electrophile
k [mꢀ1 sꢀ1
]
R=NMe2
R=N(CH2)4
3a
3b
ꢀ7.02
ꢀ7.69
2a
17.12, 0.80
3e
3 f
1.33ꢃ106
4.50ꢃ105
n=2
n=1
3c
3d
ꢀ8.22
ꢀ8.76
DMSO
THF
17.41, 0.74
14.45, 0.71
13.91, 0.64
3e
3 f
3g
3h
8.80ꢃ105
2.30ꢃ105
6.10ꢃ103
1.05ꢃ103
n=2
n=1
3e
3 f
ꢀ9.45
ꢀ10.04
2a’
3c
3d
3e
3 f
2.96ꢃ104
7.89ꢃ103
5.16ꢃ103
1.16ꢃ103
R=OMe
R=NMe2
3g
3h
ꢀ12.18
ꢀ13.39
2b
THF
3b
3c
3d
3e
3 f
9.60ꢃ103
5.95ꢃ103
1.53ꢃ103
8.88ꢃ102
3.01ꢃ102
[a] Electrophilicity parameters E for 3a–f from Ref. [12a], for 3g,h from
Ref. [12b].
drylium ions 3a–f and the quinone methides 3g,h (Table 1)
which have been used as reference electrophiles for charac-
terizing the reactivities of manifold structurally variable
nucleophiles.[12]
2b’
2c’
THF
THF
11.42, 0.70
12.75, 0.71
3a
3b
3c
3d
1.10ꢃ103
4.35ꢃ102
1.74ꢃ102
6.83ꢃ101
log k ¼ sNðN þ EÞ
ð1Þ
3b
3d
3 f
4.00ꢃ103
5.91ꢃ102
8.68ꢃ101
Equation (1) has been demonstrated to reliably predict
second-order rate constants k for a wide range of electro-
phile–nucleophile combinations. In this approach, electro-
philes are assigned a solvent-independent electrophilicity
parameter E, whereas nucleophiles are characterized by
a pair of solvent-dependent parameters (N, sN).[13]
Representative product studies (Scheme 3) revealed that
the benzhydrylium ion 3a attacks the exocyclic olefinic
carbon atoms of the deoxy Breslow intermediates 2 to give
the azolium salts 4a–c which were isolated and fully
characterized (4c by X-ray crystallography; for details see
the Supporting Information).[14]
[a] N, sN as defined by Equation (1).
When values of logk were plotted against the correspond-
ing electrophilicity parameters E of 3, linear correlations were
obtained (Figure 1). Equation (1) can therefore be used to
evaluate the N and sN parameters of the deoxy Breslow
intermediates 2 (third column of Table 2).[12] Table 2 and
Figure 1 show that the reactions are only slightly slower in
DMSO than in THF (by a factor of 1.6).
The order of the nucleophilic reactivities of compounds 2
differs dramatically from the reactivity order of the corre-
sponding precursor carbenes 1 (Scheme 4): While the carbene
1a was found to be 2.5 times less reactive than 1b,[9] the
benzylidene imidazole 2a reacts 103 times faster than its
Scheme 3. Reactions of 2a, 2b’, and 2c’ with the reference electrophile
3a.
The kinetics of the reactions of 2 with 3 were followed
photometrically in THF or DMSO at 208C by monitoring the
disappearance of the absorbances of 3 using conventional or
stopped-flow spectrophotometers. Pseudo-first-order condi-
tions were established by using a high excess of 2. The first-
order rate constants kobs (sꢀ1) were obtained by least-squares
fitting of the decay of the absorbances of 3 to the function
At ¼ A0 expðꢀkobstÞ þ C. The slopes of the linear plots of kobs
against the concentrations of 2 (see Figure S4 and pp. S14–S24
in the Supporting Information) gave the second-order rate
constants k listed in Table 2.
Figure 1. Plot of logk for the reactions of 2 with the electrophiles 3
(THF, 208C) versus the corresponding electrophilicity parameters E.
Open circles: DMSO solvent.
2
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Scheme 4. Relative reactivities of the NHCs 1 towards benzhydrylium
ions (taken from Ref. [9]) and comparison with the corresponding
reactivities of deoxy Breslow intermediates 2 (THF, 208C). [a] In C6D6.
Figure 2. Crystal structures of 2a (top) and 2b (bottom). Only one
position of the disordered atoms C1 and C2 is shown for 2b. Selected
bond lengths [pm] and angles [8]: 2a: C3-C4 136.1, N1-C3-C4-C5 9.9,
C3-C4-C5-C10 32.1; 2b: C3-C4 135.4, N1-C3-C4-C5 11.6, C3-C4-C5-C10
26.7.
saturated analogue 2b. The attenuating effect of the nitro
group reduces the reactivity ratio k2a’/k2b’ to 102, and even the
triazole-derived olefin 2c’ is one order of magnitude more
reactive than the imidazolidine derivative 2b’.
The reactivity orders 2a @ 2b and 2a’ > 2c’ > 2b’ are in
line with the relative charge densities at the nucleophilic
carbon atoms which can be derived from the corresponding
13C NMR chemical shifts (Scheme 4) as well as from quantum
chemical calculations (Scheme S1 in the Supporting Informa-
tion).
How can one explain the high reactivity ratio k2a/k2b
=
1494 which contrasts the relative nucleophilicities of the
precursor carbenes k1a/k1b = 0.44? In the X-ray structures of
2a and 2b (Figure 2)[14] one can observe that the exocyclic
double bond in 2a is only slightly longer than that in 2b (D =
0.7 pm), indicating that the resonance structures with aro-
matic rings have only little significance for the ground state of
2a (Scheme 5).
Scheme 6. Comparison of the proton affinities (PA) of the diamino-
ethylenes 2 with the methyl cation affinities (MCA, from Ref. [9]) of the
corresponding carbenes 1 (in kJmolꢀ1, MP2/6-31+G(2d,p)//B98/6-
31G(d)) and the NICS(1) values of 1, 2, and 5 (B3LYP/6-311+G(d)).
Scheme 5. Resonance structures for 2-alkylidene imidazoles.
In order to compare the thermodynamics of these
reactions, gas-phase proton affinities of the 1,1-diaminoethy-
lenes 2a’’, 2b’’, and 2c’’ were calculated on the MP2/6-31 +
G(2d,p)//B98/6-31G(d) level of theory using the Gaussian 09
program package.[15] Scheme 6 shows that the proton affinity
of 2b’’, derived from the saturated Arduengo carbene 1b’, is
60 kJmolꢀ1 lower than that of 2a’’. Compound 2b’’ is an even
weaker Brønsted base than the triazole-derived olefin 2c’’
which includes an electronegative nitrogen atom (DPA =
21 kJmolꢀ1). The nucleophilicity order 2a’ > 2c’ > 2b’
(Scheme 4, bottom line) thus mirrors the proton affinity
order 2a’’ > 2c’’ > 2b’’ (Scheme 6, top). Analogously, the
completely different nucleophilicity order of the NHCs 1a ꢁ
1b @ 1c (Scheme 4, top row) is also reflected by the order of
methyl cation affinities 1a’ ꢁ 1b’ @ 1c’ (Scheme 6, bottom).[9]
As shown in Table S29 in the Supporting Information,
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difference. In this work we have shown that Breslow
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significantly more nucleophilic than those derived from
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Received: March 23, 2012
Published online: && &&, &&&&
Keywords: azolium ions · kinetics · Lewis basicity ·
.
linear free energy relationships · umpolung
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Angew. Chem. Int. Ed. 2012, 51, 1 – 6
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
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These are not the final page numbers!

.
Angewandte
Communications
Communications
Organocatalysis
B. Maji, M. Horn,
H. Mayr*
&&&& — &&&&
Nucleophilic Reactivities of Deoxy
Breslow Intermediates: How Does
Aromaticity Affect the Catalytic Activities
of N-Heterocyclic Carbenes?
Aromatic or nonaromatic? Kinetic inves-
tigations show that structurally analo-
gous saturated and unsaturated N-heter-
ocyclic carbenes have almost identical
nucleophilic reactivities, while the corre-
sponding deoxy Breslow intermediates
differ dramatically.
6
www.angewandte.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 1 – 6
These are not the final page numbers!