Nucleophilicity parameters of enamides and their implications for organocatalytic transformations

Article abstract of DOI:10.1002/chem.201103519

The kinetics of the reactions of eleven substituted enamides with benzhydrylium ions (diarylcarbenium ions) were determined in acetonitrile solution. The second-order rate constants follow the correlation log k ₂(20°C)=s_N(E+N), which allowed us to derive reactivity parameters N and s_N. With 4.6N parameters with the previously reported E parameters of typical Michael acceptors, α,β-unsaturated iminium ions, and the chlorinating agent hexachlorocyclohexa-2,4-dienone allowed us to reliably reproduce the experimental rate constants of the reactions with these electrophiles. The reactions of enamides with α,β-unsaturated iminium ions only proceeded in the presence of bases (e.g., 2,6-lutidine), which was explained by the low Lewis acidities of the iminium ions. The consequences of these results for the use of enamides in organocatalytic reactions are discussed. Nucleophile-specific parameters N and s_N of enamides allowed a prediction of the rates of their reactions with various electrophiles and enabled a resolution of the mechanism of iminium-activated reactions of α,β-unsaturated aldehydes with enamides (see scheme).

Full text of DOI:10.1002/chem.201103519

DOI: 10.1002/chem.201103519
Nucleophilicity Parameters of Enamides and Their Implications for
Organocatalytic Transformations
Biplab Maji, Sami Lakhdar, and Herbert Mayr*[a]
Dedicated to Professor Lutz F. Tietze on the occasion of his 70th birthday
Abstract: The kinetics of the reactions
of eleven substituted enamides with
benzhydrylium ions (diarylcarbenium
ions) were determined in acetonitrile
solution. The second-order rate con-
stants follow the correlation log k2-
pyrroles. The combination of the N and
sN parameters with the previously re-
ported E parameters of typical Michael
acceptors, a,b-unsaturated iminium
ions, and the chlorinating agent hexa-
us to reliably reproduce the experimen-
tal rate constants of the reactions with
these electrophiles. The reactions of
enamides with a,b-unsaturated imini-
um ions only proceeded in the pres-
ence of bases (e.g., 2,6-lutidine), which
was explained by the low Lewis acidi-
ties of the iminium ions. The conse-
quences of these results for the use of
enamides in organocatalytic reactions
are discussed.
chlorocyclohexa-2,4-dienone
allowed
ACHTUNGTRENNUNG(208C)=sNACHTUNGTRENNUNG(E+N), which allowed us to
derive reactivity parameters N and sN.
With 4.6<N<7.1, enamides had simi-
lar nucleophilicities to enol ethers and
non- or weakly activated indoles and
Keywords: counterion effect · imi-
nium ions · kinetics · linear free en-
ergy relationship · Michael addition
Introduction
gated independently by the groups of Hayashi and Wang,[6]
who reported the enantioselective formation of tetrahydro-
pyridines (9) from the reactions of 1 with a,b-unsaturated
aldehydes (2) catalyzed by diarylprolinol silyl ether (3a;
Scheme 1).[6] Whilst Hayashi et al. proposed a concerted ene
reaction of the intermediate iminium ion 4 with 1 to give 5
(Scheme 1, a,b,c), Wang suggested a stepwise mechanism
that proceeded via initial nucleophilic attack of enamide
1 onto the iminium ion (4) to yield Michael adduct 6
(Scheme 1, a), which then tautomerized to give 8. Both
mechanisms agreed that a series of proton-shifts and partial
hydrolysis gave 7, which may cyclize into 9. Hydrolysis of 5,
6, 7, or 8 may yield diketone 10, which was observed by
Hayashi as a side-product and obtained by Wang through
the hydrolysis of 9.[6]
Iminium ions (4) that were derived from chiral amines (3;
Scheme 2) have previously been isolated and characterized
by NMR spectroscopy and X-ray analysis.[7,8a] Because we
have studied their reactivity with different nucleophiles and
found that iminium ions that were derived from MacMil-
lanꢀs second generation catalyst (3c) were 102 more reactive
than those derived from catalyst 3a (Scheme 2),[8d] we were
puzzled by Wangꢀs report that, in contrast to catalyst 3a, 3c
was unable to catalyze the reactions of a,b-unsaturated alde-
hydes with enamides.[6b] Therefore, we employed kinetic
methods to elucidate the mechanism of iminium-activated
reactions of enamides.[8,9]
Enamides and enecarbamates (1),[1] which are endowed with
a fine balance of stability and reactivity, may be considered
as “tunable enamines”.[1b] Their facile synthetic accessibility
and stability in air makes them attractive reagents in organic
synthesis. They have frequently been used as nucleophiles in
a manifold of organic reactions, including metal-catalyzed
and organocatalyzed asymmetric transformations. Although
reactions of electrophiles with enamides and enecarbamates
have been known for three decades,[1d] their use in asymmet-
ric synthesis has only recently been pioneered by Kobayashi
and co-workers,[1a,2] who achieved enantioselective CuII-
ligand-catalyzed additions of 1 to imines, aldehydes, azodi-
carboxylates, and Michael acceptors.[1a,2] Enantioselective
ene reactions of N-acylimines and glyoxylates with 1 have
been developed by Terada et al. by using chiral phosphoric
acid derivatives as catalysts.[3] Recently, Zhong and co-work-
ers used chiral Brønsted acids to catalyze the a-aminoxyla-
tion reactions of enamides.[4]
The use of enamides as nucleophilic substrates in imini-
um-activated enantioselective reactions[5] has been investi-
[a] B. Maji, Dr. S. Lakhdar, Prof. Dr. H. Mayr
Department Chemie
Ludwig-Maximilians-Universiꢁt Mꢂnchen
Butenandtstraße 5–13 (Haus F), 81377 Mꢂnchen (Germany)
Fax : (+49)89-2180-77717
Qualitative studies have shown that enamides are general-
ly less nucleophilic than enamines and enolate anions.[1a] To
include enamides on our quantitative nucleophilicity scale[9]
we studied the kinetics of their reactions with benz-
E-mail: herbert.mayr@cup.uni-muenchen.de
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201103519.
AHCTUNGTREGhNNUN ydrylium ions, and we demonstrate the implications of
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Chem. Eur. J. 2012, 18, 5732 – 5740

FULL PAPER
bonate (Table 1, method I). Enamides 14 were obtained ex-
clusively when the addition products (12) were treated with
Table 1. Products of the reactions of enamides 1 with dimethylamino-
substituted benzhydrylium tetrafluoroborate, (dma)2CH+BF4ꢀ, in CH3CN
at 208C.[a]
Entry
Enamide
Method
Yield [%][d]
13
14
Scheme 1. Mechanisms for the formation of tetrahydropyridines (9) from
a,b-unsaturated aldehydes (2) and enamides (1) catalyzed by diarylproli-
nol ether 3a. DCE=1,2-dichloroethane.
1
2
I[b]
22
–
62
89
II[c]
3
4
I[b]
29
–
52
95
II[c]
5
6
I[b]
30
–
64
90
II[c]
7
8
II[c]
–
–
89
78
Scheme 2. Chiral amine catalysts (3) and the corresponding iminium ions
(4) that were formed from cinnamaldehyde. [a] Empirical electrophilicity
parameters (E) were taken from references [8a,d].
II[c]
these results for elucidating the mechanism of iminium-acti-
vated Michael additions of enamides.[6]
9
II[c]
–
–
93
93
Results and Discussion
10
II[c]
Reactions of enamides with benzhydrylium ions: The reac-
tions of 1 with the dimethylamino-substituted benzhydryli-
ꢀ
um tetrafluoroborate (dma)2CH+BF4 gave acyl-iminium
[a] For reaction conditions, see the Supporting Information. [b] Method I:
work-up with aqueous K2CO3. [c] Method II: work-up with 2,6-lutidine.
[d] Yield of isolated product after column chromatography on silica gel.
dma=p-Me2NC6H4.
salts (12), which were converted into mixtures of ketones
(13) and benzhydryl-substituted enamides (14; as a mixture
of E/Z isomers) by hydrolysis with aqueous potassium car-
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5733

H. Mayr et al.
2,6-lutidine (method II). However, the reaction of
ꢀ
(dma)2CH+BF4 with enamide 1h yielded an imine
(Table 1, entry 8), and the reactions of compounds 1i and 1j
ꢀ
with (dma)2CH+BF4 gave enamides in which the position
of the double bond had been shifted (Table 1, entries 9 and
10). For details of the isolation and characterization of the
products, see the Supporting Information.
The rates of the reactions of enamides 1 with the benzhy-
drylium ions (11; Table 2) were determined photometrically
in CH3CN at 208C by monitoring the decrease in the absor-
Table 2. Abbreviations and electrophilicity parameters (E) for the benz-
hydrylium ions (11) that were used as reference electrophiles.
Figure 1. Exponential decay of the absorbance (A) at 612 nm during the
ꢀ
reaction of 1j (c=5.76ꢄ10ꢀ4 m) with (mor)2CH+BF4 (c=2.05ꢄ10ꢀ5 m) in
CH3CN at 208C (kobs =1.27ꢄ10ꢀ2 sꢀ1). Inset: determination of the
second-order rate constant k2 from the dependence of kobs on the concen-
tration of compound 1j (k2 =2.15ꢄ101 mꢀ1 sꢀ1).
X
Abbreviations
(pfa)2CH+
(mfa)2CH+
(mor)2CH+
(mpa)2CH+
(dma)2CH+
E[a]
N(Ph)CH2CF3
N
N
G
ꢀ3.14
ꢀ3.85
ꢀ5.53
ꢀ5.89
ꢀ7.02
E
ACHTUNGTRENNUNG
R
ACHTUNGTRENNUNG
When the logarithms of the second-order rate constants
(Table 3) for the reactions of enamides 1 with benzhydryli-
um ions 11 were plotted against the electrophilicity parame-
ters (E) for the benzhydrylium ions (11; Table 2), linear cor-
relations were obtained that were in accordance with Equa-
tion (2) (Figure 2). The slopes of these correlation lines
yielded the nucleophile-specific sensitivity parameters (sN)
and the intercepts on the abscissa gave the nucleophilicity
parameters (N), which are given in Table 3.
N(Ph)CH3
(CH3)2
ACHTUNGTRENNUNG
N
A
ACHTUNGTRENNUNG
[a] Electrophilicity parameters (E) for the benzhydrylium ions were
taken from reference [9b].
bances of the benzhydrylium ions by using conventional or
stopped-flow UV/Vis spectrometry as described previously.[9]
An excess of the nucleophiles 1 over benzhydrylium ions 11
was used to achieve pseudo-first-order conditions, and the
pseudo-first-order rate constants kobs (sꢀ1) were obtained by
least-squares fits of the mono-exponential decays of the ab-
sorbances of ions 11 to the function A=A0eꢀk . The plots
obst
of kobs against the concentrations of nucleophiles 1 were
linear, with negligible intercepts (Figure 1), thus indicating
a second-order rate law [Eq. (1)].
ꢀd½11ꢁ=dt ¼ k2½1ꢁ½11ꢁ
ð1Þ
The slopes of these correlation lines yielded the second-
order rate constants (k2, in mꢀ1 sꢀ1; see Table 3).
Relationship between the structure and nucleophilicity of
the enamides: In previous reports, it has been shown that
the rates of the reactions of carbocations and Michael ac-
ceptors with n, p, and s-nucleophiles can be described by
the linear-free-energy relationship, [Eq. (2)], in which elec-
trophiles are characterized by the electrophilicity parameter
(E) and the nucleophiles are characterized by the nucleophi-
licity parameter (N) and by the nucleophile-specific sensitiv-
ity parameter (sN, previously termed s).[9] On the basis of
Equation (2), it was possible to develop the most compre-
hensive nucleophilicity scale presently available.[9]
Figure 2. Plots of log k2 for the reactions of enamides 1 with benz-
AHCTUNTGREGNhNNU ydrylium ions 11 in CH3CN at 208C versus the electrophilicity parame-
ters (E). For the sake of clarity, correlation lines are only shown for
a few nucleophiles (for the others, see the Supporting Information).
The similar magnitudes of the slopes of these correlation
lines (sN ꢃ1.0) implied that the relative nucleophilicities of
the enamides only depended slightly on the reactivities of
the electrophiles.
log k2ð20 ꢂCÞ ¼ sNðN þ EÞ
ð2Þ
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Nucleophilicity Parameters of Enamides
FULL PAPER
Table 3. Second-order rate constants for the reactions of benzhydrylium ions 11 with enamides 1 in MeCN at 208C.
[a]
[a]
Enamide
N, sN
(Ar)2CH+
k2 [mꢀ1 sꢀ1
]
Enamide
N, sN
(Ar)2CH+
k2 [mꢀ1 sꢀ1
]
A
4.73ꢄ102
4.20ꢄ101
1.82ꢄ100
5.73, 0.97
6.57, 0.91
G
(5.44, 1.0)[b]
6.28, 0.95
G
8.22ꢄ10ꢀ1
AHCTUNGTRENNUNG
E
1.29ꢄ103
6.01ꢄ100
6.35ꢄ100
1.50ꢄ103
1.05ꢄ102
6.23ꢄ100
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
N
3.61ꢄ10ꢀ1
A
2.40ꢄ103
4.37ꢄ102
2.12ꢄ101
1.08ꢄ100
E
4.64ꢄ101
5.24ꢄ100
3.28ꢄ10ꢀ1
AHCTUNGTRENNUNG
7.06, 0.85
5.60, 1.00
4.91, 0.87
5.64, 0.79
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
A
2.30ꢄ101
1.62ꢄ100
6.91ꢄ10ꢀ2
E
2.94ꢄ102
1.19ꢄ100
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
A
3.39ꢄ103
4.16ꢄ102
2.15ꢄ101
1.16ꢄ100
AHCTUNGTRENNUNG
(pfa)2CH+
(mor)2CH+
(mpa)2CH+
(dma)2CH+
4.53ꢄ102
2.78ꢄ100
3.47ꢄ100
1.59ꢄ10ꢀ1
7.06, 0.87
4.61, 0.98
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
6.21, 0.87
AHCTUNGTRENNUNG
A
G
3.6ꢄ101[c]
3.8ꢄ100[c]
1.4ꢄ10ꢀ1[c]
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
[a] Nucleophilicity parameters N (and sN) were derived by using Equation (2). [b] N values were calculated with the assumption that sN =1.0. [c] Kinetics
were of lower quality; mono-exponential behavior was only observed during the first half-reaction time.
Table 4 compares selected enamides with structurally re-
lated compounds and shows that an acetamido group (1a)
enhanced the nucleophilicity of styrene by approximately 5
proximately 4 orders of magnitude less-reactive than their
structurally analogous enamines.[9b,10]
As in the enamine series,[9f,10] the cyclopentanone-derived
enamide (1j) was significantly more-nucleophilic than the
cyclohexanone-derived enamide (1i; Figure 2), whilst the
Table 4. Comparison of the nucleophilicity parameters for enamides with
those of structurally related p-systems.
pinaACTHNUGRTENUNGcolone-derived enamide (1k) was the least-nucleophilic
compound in this series.
p-System
N
p-System
N
A plot of log k2 for the reactions of 4-X-substituted 1-aryl
enamides with the benzhydrylium ion (mor)2CH+ versus
0.78[a]
6.21[b]
+
Hammettꢀs sp constants[11] of the aryl-substituents (X) gave
the reaction constant 1=ꢀ1.40 (Figure 3). The small magni-
5.73[b]
5.44[b]
6.22[a]
9.96[a]
[a] In CH2Cl2, taken from references [9b] and [10]. [b] In MeCN, from
Table 3.
orders of magnitude. Whilst replacement of the acetamido
group by a benzamido group (1 f) slightly reduced the nucle-
ophilicity (by a factor of 2 towards (mor)2CH+), the benzyl-
carbamate group (1e) had a small accelerating effect, the
magnitude of which slightly depended on the electrophile
(by a factor of 1.7 toward (mor)2CH+). However, as the sen-
sitivity parameters did not deviate significantly from sN =1,
one can generalize that enamides have similar nucleophilici-
ties to their analogously substituted enol ethers, and are ap-
Figure 3. Plot of log k2 for the reactions of 4-X-substituted 1-aryl en-
ꢀ
+
+
AHCTUNGTRENNUNG
amides with (mor)2CH+BF4 versus sp (sp taken from reference [11];
log k2 =ꢀ1.40sp++0.27, r2 =0.9909).
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5735

H. Mayr et al.
Table 6. Yields and experimental (k2exptl) and calculated second-order
tude of 1 indicated that, in the transition state, most of the
developing charge was stabilized by the acetamido group
and only a small amount of the positive charge required sta-
bilization by the aryl ring.
rate constants [k2calcd; in mꢀ1 sꢀ1] for the reactions of nucleophiles 1 with
17.
Reactions with Michael acceptors and chlorinating agents:
To examine the applicability of the N and sN parameters
(Table 3) for the reactions of enamides with other electro-
philes, we investigated the rates of the reactions of enamides
with 5-benzylidene-2,2-dimethyl-1,3-dioxane-4,6-dione (15),
which yielded the Michael adducts (16) after hydrolysis
(Table 5).
exptl
calcd[b]
exptl
Nucleophile
Yield [%][a]
k2
k2
k2calcd/k2
1a
1b
1c
1i
56
44
3.20ꢄ10ꢀ2
3.39ꢄ10ꢀ2
1.59ꢄ10ꢀ1
1.63ꢄ10ꢀ1
7.94ꢄ10ꢀ1
1.02ꢄ10ꢀ1
6.86ꢄ10ꢀ1
1.83
3.2
20
12
0.82
2.3
52
1.33ꢄ10ꢀ1
1.86
1j
[a] Yield of isolated product after column chromatography on neutral
alumina (activity grade IV). [b] Calculated by using Equation (2), the
electrophilicity parameter E=ꢀ6.75 (from reference [13]), and N and sN
values of compound 1 from Table 3.
Table 5. Yields and experimental (k2exptl) and calculated second-order
rate constants [k2calcd; in mꢀ1 sꢀ1] for the reactions of enamides 1b and 1c
with Michael acceptor 15.
Iminium-activated reactions of enamides: When iminium
salts 4a-OTf, 4b-OTf, 4b-PF6, and 4c-PF6 (about 5ꢄ10ꢀ5 m),
which were synthesized according to literature procedures,[7]
were combined with about 25 equivalents of 1b or 1c in
CH2Cl2 or CH3CN, no consumption of the iminium ions was
observed. This observation was surprising for us because
second-order rate constants of 10ꢀ2–101 mꢀ1 sꢀ1 were calculat-
ed by using Equation (2), N and sN values of compounds 1b
and 1c (Table 3), and E values of iminium ions 4a–4c (Sche-
me 2),[8a,d] thereby suggesting that the reactions occurred
readily at room temperature. On the other hand, Wang and
co-workers reported that imidazolidinone 3c did not cata-
lyze the reactions of a,b-unsaturated aldehydes with en-
exptl
calcd[b]
calcd
Nucleophile
Yield [%][a]
k2
k2
k2exptl/k2
1b
1c
45
66
7.54ꢄ10ꢀ3
2.64ꢄ10ꢀ2
4.49ꢄ10ꢀ3
1.67ꢄ10ꢀ2
1.7
1.6
[a] Yield of isolated product after column chromatography on silica gel.
[b] Calculated by using Equation (2), the electrophilicity parameter E=
ꢀ9.15 (from reference [12]), and N and sN values of 1b and 1c from
Table 3.
The rates of the reactions of 1 with compound 15 were
measured by using the same method as described previously,
by following the decay of the absorbance of 15 at l=
317 nm. Table 5 shows that the experimental second-order
rate constants agreed, within a factor of 1.7, with those cal-
culated by using Equation (2) (with the N parameters given
in Table 3 and the previously reported electrophilicity pa-
rameter, E=ꢀ9.15,[12] for 15). This remarkable agreement
AHCTUNGTRENNUNG
amides,[6b] whilst Hayashi–Jørgensenꢀs catalyst (3a), which
was a precursor of the 102-times less electrophilic iminium
ion 4a, was an effective catalyst for this conversion.[6]
A solution for this discrepancy came from Table 1 of ref-
erence [6b], which showed that the two catalysts were em-
ployed with different co-catalysts. Whilst TsOH (p-toluene-
sulfonic acid) was used as a co-catalyst for the attempted re-
actions with MacMillanꢀs catalyst (3c), benzoic acid acted as
a co-catalyst for the efficient catalysis with pyrrolidine 3a.
Assuming that the failure of the iminium triflates and
hexafluorophosphates to react with enamides 1b and 1c was
due to unfavorable thermodynamics, we tried to investigate
the kinetics of the reactions of compounds 1b and 1c with
iminium salts 4a-OTf, 4b-OTf, 4b-PF6, and 4c-PF6 in the
presence of base, by using previously described methods
(photometric monitoring of the decay of the absorbances of
the electrophiles 4a–4c at l=367 nm).[8] Additives of tetra-
n-butylammonium benzoate and potassium trifluoroacetate
were inefficient because iminium ions 4a–4c underwent fast
ꢀ
supported a mechanism that contained a rate-limiting C C
bond formation,[2i] i.e., the type of electrophile–nucleophile
combination for which Equation (2) was parameterized.
Chlorination and bromination reactions of alkenes often
proceed via bridged intermediates, i.e., through the simulta-
neous formation of two new bonds in the rate-limiting step,
and therefore do not follow Equation (2). However, we
have reported that, in the reactions of 2,3,4,5,6,6-hexachlor-
ocyclohexa-2,4-dienone 17 with enamines, enol ethers, pyr-
roles, and indoles, non-bridged intermediates were involved,
with the consequence that these reactions followed Equa-
tion (2), which could therefore be used to derive the electro-
philicity parameter (E) for the chlorinating agent 17.[13]
exptl
calcd
ꢀ
Analogously, fair agreement between k2
and k2
has
combinations with PhCO2 and slowly decomposed in the
ꢀ [14]
also been reported for the reactions of enamides with chlori-
nating agent 17 (Table 6), which was quite remarkable be-
cause the N and sN parameters of enamides 1 (as with most
other nucleophiles) were derived from the kinetics of their
reactions with benzhydrylium ions.
presence of CF3CO2 .
The addition of 3-chloropyridine
did not promote the reaction, and the addition of pyridine
led to incomplete reactions with iminium salts 4a-OTf, 4b-
PF6, and 4c-PF6. However, full conversion (Figure 4) of imi-
nium salts 4b-PF6 and 4c-PF6 was observed when 2,6-luti-
dine or 2,4,6-collidine were added.[15]
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Chem. Eur. J. 2012, 18, 5732 – 5740

Nucleophilicity Parameters of Enamides
FULL PAPER
Rearrangement of Equation (3) gave Equation (4) which
implied a linear plot of [1]/kobs versus [B]ꢀ1 (Figure 4,
inset).[17] The reciprocals of the intercepts of these plots
gave the second-order rate constants (k2; Table 7).[18]
½1ꢁ
1
kꢀ2
kBk2½Bꢁ
ð4Þ
¼
þ
kobs k2
Table 7. Experimental and calculated rate constants k2 [in mꢀ1 sꢀ1] for the
reactions of iminium ions 4b and 4c with enamides 1b and 1c in the
presence of 2,6-lutidine in CH2Cl2 at 208C.
exptl
calcd[a]
calcd
k2exptl/k2
Enamide
Iminium ion
k2
k2
1b
1c
1b
1c
4b
4b
4c
4c
0.26
0.73
3.3
0.19
0.55
9.0
1.4
1.3
0.36
0.35
Figure 4. Exponential decay of the absorbance (A, at 367 nm) of 4b-PF6
(3.94ꢄ10ꢀ5 m) in the reaction with 1b (1.82ꢄ10ꢀ3 m) in the presence of
2,6-lutidine (3.53ꢄ10ꢀ3 m) in CH2Cl2 at 208C. Inset: determination of
second-order rate constant k2 =(1/3.8)=0.26 mꢀ1 sꢀ1 from the plot of
7.1
20
[a] Calculated by using Equation (2), N and sN values of 1 from Table 3,
and the E value of 4 from Scheme 2.
ꢀ1
[1b]kobs versus [lutidine]ꢀ1; [4b]=3.9ꢄ10ꢀ5 m, [1b]=1.75ꢄ10ꢀ3 m, 3.53ꢄ
10ꢀ3 m<[lutidine]<1.37ꢄ10ꢀ2 m.
The second-order rate constants for the reactions of en-
amides 1b and 1c with iminium ions 4b and 4c (Table 7)
agreed within a factor of 3 with those calculated by using
These observations were rationalized by assuming that
the reaction of iminium ions 4 with enamides 1 gives inter-
mediates 6 in small, non-observable, equilibrium concentra-
tions (Scheme 3). In the presence of lutidine, deprotonation
of intermediate 6 occurred, and the equilibrium was shifted
toward adduct 19. Therefore, the proposal by Wang and co-
workers[6b] of a stepwise process (Scheme 1, a) was support-
ed, because the formation of the iminium ion 5 from the re-
action between 4 and 1 by a concerted ene reaction
(Scheme 1, a,b,c) would not require base catalysis.
Equation (2) from the
E parameters of 4b and 4c
(Scheme 2) and the N and sN parameters for enamides 1b
and 1c (Table 3), which were derived from the rates of their
reactions with benzhydrylium ions (Table 2). This fair agree-
ment between the experimental and calculated rate con-
stants was a further argument for the stepwise mechanism
of the reactions of enamides 1 with iminium ions 4, wherein
ꢀ
C C bond formation became rate-determining in the pres-
ence of an appropriate base.
Therefore, it appeared likely that, in contrast to previous
reports,[6b] MacMillanꢀs imidazolidinones 3b and 3c should
be able to catalyze the reactions of enamides with a,b-unsa-
turated aldehydes, if deprotonation of intermediate 6 by
a base was warranted. In line with this conclusion, we found
that secondary amines 3b and 3c (Table 8) did catalyze the
reactions of cinnamaldehyde (2) with enamides 1a–1c in
Table 8. Reactions of enamides 1a–1c with cinnamaldehyde (2) in the
presence of catalysts 3b and 3c with CF3CO2H as a co-catalyst.[a]
Scheme 3. Proposed mechanism for the reactions of iminium ions (4)
with enamides (1).[16]
When intermediate 6 was formed reversibly in a low equi-
librium concentration, the observed rate constant (kobs) for
a pseudo-first-order reaction with [1]0 @[4]0 was given by
Equation (3), where the second term reflected the ratio of
the forward reaction (kB[B]) over the sum of the backward
(kꢀ2) and forward reactions.
Enamide
Catalyst
Yield [%][b]
ee [%][c]
1a
1b
1c
1a
1b
1c
3b
3b
3b
3c
3c
3c
73
75
64
63
58
51
19
13
9
52
50
55
[a] For the reaction conditions, see the Supporting Information. [b] Yield
of isolated product 10 after column chromatography on silica gel. [c] De-
termined by chiral HPLC analysis (for details, see Supporting Informa-
tion). TFA=trifluoroacetic acid. DCE=1,2-dichloroethane.
kB½Bꢁ
ð3Þ
kobs ¼ k2½1ꢁ
kꢀ2 þ kB½Bꢁ
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5737

H. Mayr et al.
1,2-dichloroethane at room temperature, when CF3CO2H
was used as a co-catalyst because then CF3CO2 may act as
energy of a reaction from a combination of the reaction free
ꢀ
¼
energy (DG0) and the intrinsic barriers (DG0 ) [Eq. (5)].
the base. According to Table 8, ketoaldehydes 10 were
formed in moderate yields and enantioselectivities under
these conditions.
¼
¼
2
¼
DG ¼ DG0 þ0:5 DG0þððDG0Þ =16 DG0
Þ
ð5Þ
As has recently been discussed in detail,[21] the intrinsic
barrier corresponds to the barrier of a reaction from which
the thermodynamic component has been eliminated. Be-
cause the quadratic term in [Eq. (5)] was generally negligi-
ble in group-transfer reactions and in electrophile–nucleo-
phile combinations, we concluded that reactions that pro-
ceeded more-slowly despite having a higher thermodynamic
driving force (i.e., a more-negative DG0 value) reacted
through higher intrinsic barriers (DG0 ). Thus, the lower nu-
cleophilicity of 4-dimethylaminopyridine (DMAP) com-
pared with the less-basic 1,4-diazabicycloACTHNURTGNEU[GN 2.2.2]octane
(DABCO) has been assigned to the higher intrinsic barriers
for the reactions with DMAP.[22] A revision of the rationali-
zation of ambident reactivity has recently been based on
this concept.[21]
According to Marcus, the intrinsic barrier (DG0 ) is relat-
ed to the reorganization energy (l) by l=4DG0 . Because
The clean second-order kinetics observed for the reactions
of benzhydrylium ions with compounds 1 (see above) were
surprising in view of the problems encountered in the kinet-
ics of the reactions of iminium ions 4 with enamides 1b and
1c. To elucidate whether adducts 12 (Table 1) were formed
from reversible or irreversible reactions, the kinetics of the
ꢀ
reaction of (dma)2CH+BF4 with the enamide 1b were also
studied in the presence of various concentrations of 2,6-luti-
dine. As the first-order rate constants (kobs) were not affect-
ed by the concentration of 2,6-lutidine (Figure 5) and were
the same as those observed in the absence of base, we con-
cluded that the first step of the sequence (Table 1) was irre-
versible.
¼
¼
¼
less reorganization is required for the addition of a nucleo-
phile onto the b-carbon of an unsaturated iminium ion than
onto the central carbon atoms of benzhydrylium ions, we re-
cently explained why the addition of azoles to iminium ions
are more reversible than the comparably fast addition of
azoles to benzhydrylium ions.[23] The different behavior of
benzhydrylium and iminium ions herein can be explained
analogously.
ꢀ
Figure 5. Plot of kobs versus [lutidine] for the reaction of (dma)2CH+BF4
Conclusion
(c=1.90ꢄ10ꢀ5 m) with the enamide 1b (c=7.41ꢄ10ꢀ4 m) at various con-
~
*
centrations of 2,6-lutidine in CH3CN at 208C. ( ). Data point was ex-
The reactions of enamides 1 with benzhydrylium ions were
found to follow a linear free energy relationship [Eq. (2)],
which allowed us to determine the nucleophilicity parame-
ters for enamides 1 (4.6<N<7.1) and to integrate them
into our comprehensive nucleophilicity scale (Figure 6).
By using the rule of thumb that electrophile–nucleophile
combinations may take place at room temperature when
E+N>ꢀ5,[9c] one can rationalize that enamides 1 do not
react with aldehydes, imines, or simple Michael acceptors
such as benzylidenemalonates in the absence of catalysts.[24]
However, their reactions with electrophiles in the presence
of either Lewis[2] or Brønsted acids[3] have been reported.
Because of their low Lewis acidity, iminium ions only
react with enamides when bases (e.g. 2,6-lutidine) are pres-
ent, which deprotonate the initially generated acyliminium
ions (6). As bases are not involved in the pericyclic process
(Scheme 1, a,b,c), one can conclude that the amine-cata-
lyzed reactions of enamides with a,b-unsaturated aldehydes
do not proceed through concerted ene reactions with the in-
termediate iminium ions to give 5 directly, but rather
through a stepwise mechanism via intermediate 6. By clari-
fying the role of general base catalysis for the deprotonation
of intermediate 6, one can furthermore rationalize why
trapolated from the Supporting Information, Table S2.
Now, the question arises why benzhydrylium ions 11 re-
acted with enamides 1 without a base, whilst iminium ions 4,
of similar electrophilicity (i.e., comparable k2 values) did
not? Obviously, the reverse reactions (kꢀ2) were much faster
for iminium ions than for their corresponding benzhydryli-
um ions, with the result that the equilibrium constants K=
k2/kꢀ2 were much smaller for iminium ions than for benzhy-
drylium ions of similar reactivity (k2). In other words, imini-
um ions 4 were weaker Lewis acids (i.e., smaller K values)
than benzhydrylium ions of equal electrophilicity (i.e., equal
k2 values).
Deviations from Brønsted correlations or, more generally,
from rate–equilibrium relationships (log k versus log K) has
been a topic of intensive research over recent decades. Ber-
nasconi used the term “nonperfect synchronization” to ac-
count for deviations from nucleophilicity/Lewis basicity or
from electrophilicity/Lewis acidity correlations,[19] whilst
other authors have preferred to discuss these phenomena in
terms of Marcus theory,[20] which derives the activation free
5738
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Chem. Eur. J. 2012, 18, 5732 – 5740

Nucleophilicity Parameters of Enamides
FULL PAPER
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Acknowledgements
We thank Dr. Mahiuddin Baidya, Dr. Markus Horn, and Dr. Armin R.
Ofial for their helpful discussions, Konstantin Troshin for help with the
HPLC analysis, and the Deutsche Forschungsgemeinschaft (SFB 749) for
their generous support.
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1
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10ꢀ3 m); i.e., the reverse reaction (kꢀ2) was much slower than the de-
protonation when a certain concentration of base was present, and
Equation (4) simplified to kobs =k2[1]. The second-order rate con-
stants (k2) that were obtained from the slopes of plots of kobs versus
[1] were in good agreement with those that were obtained from the
intercepts of the plots of [1]/kobs versus [B]ꢀ1. For a comparison of
the two methods of evaluation, see the Supporting Information,
page S47.
Received: November 8, 2011
Revised: January 4, 2012
Published online: March 27, 2012
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Chem. Eur. J. 2012, 18, 5732 – 5740