Which Factors Control the Nucleophilic Reactivities of Enamines?

Article abstract of DOI:10.1002/chem.201705962

Changes in rate constants, equivalent to changes in Gibbs energies of activation ΔG^≠, are commonly referred to as kinetic effects and differentiated from thermodynamic effects (Δ_rG°). Often, little attention is paid to the fact that structural effects on ΔG^≠ are composed of a thermodynamic (Δ_rG°) and a truly kinetic (intrinsic) component (ΔG₀^≠), as expressed by the Marcus equation. Rate and equilibrium constants have been determined for a number of reactions of enamines with benzhydrylium ions (Aryl₂CH⁺), which has allowed the determination of Marcus intrinsic barriers and a differentiated analysis of structure–reactivity relationships. To our knowledge, this is the first report in which the Lewis basicity of a π_CC bond towards carbon-centered Lewis acids (for example, carbenium ions) has quantitatively been determined. The synthesis, structures, and properties of deoxybenzoin-derived enamines ArCH=C(Ph)NR₂, which have been designed as reference nucleophiles for the future quantification of electrophilic reactivities, are explicitly described.

Full text of DOI:10.1002/chem.201705962

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Accepted Article
Title: Which Factors Control the Nucleophilic Reactivities of Enamines?
Authors: Daria S. Timofeeva, Robert Mayer, Peter Mayer, Armin Ofial,
and Herbert Mayr
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Which Factors Control the Nucleophilic Reactivities of
Enamines?
Daria S. Timofeeva, Robert J. Mayer, Peter Mayer, Armin R. Ofial, and Herbert Mayr*
Dedicated to Professor Klaus Hafner on the occasion of his 90th birthday
Abstract: Changes in rate constants, equivalent to changes in
integration constant C also has the meaning of an intrinsic
barrier.
‡
Gibbs energies of activation (G ), are commonly called kinetic
0
effects and differentiated from thermodynamic effects (
r
G ). Often,
‡
‡
G0
little attention is paid to the fact that structural effects on G are
G =  
r
(2)
(3)
0
composed from a thermodynamic (
r
G ) and a truly kinetic (intrinsic)
‡
0
component, as expressed by the Marcus equation. For a variety of
G =  
r
G + C
+
reactions of enamines with benzhydrylium ions (Aryl
2
CH ), rate and
equilibrium constants could be determined, which allowed the
determination of Marcus intrinsic barriers and differentiated
The Bell-Evans-Polanyi relationship[3] correlates the Arrhenius
0
a
activation energy with the reaction enthalpy 
r
H
and thus
analysis of structure-reactivity relationships. To our knowledge, this
is the first report, where the Lewis basicity of a πCC bond towards C-
acids has quantitatively been determined. Syntheses, structures and
closely resembles equation (3).
Numerous investigations on the relationships between rate
and equilibrium constants have been reported,[8] and Bernasconi
introduced the ‘Principle of Nonperfect Synchronization’ to
2
properties of deoxybenzoin derived enamines ArCH=C(Ph)NR ,
‡
which are designed as reference nucleophiles for the future
quantification of electrophilic reactivities, are explicitly described.
explain deviations from linear correlations between G and
0

r
G by transition-state imbalances, i.e., nonconcerted changes
of reactant-stabilizing and product-stabilizing factors.[
9]
By using p- and m-substituted benzhydrylium ions as
reference electrophiles and as reference Lewis acids with
variable reactivities but constant steric surroundings of the
reaction center we have investigated correlations between rate
and equilibrium constants ranging from very slow reactions
Introduction
How reaction thermodynamics affects the rates of chemical
reactions is a question that has intrigued chemists for almost a
(
hours) to the diffusion limit (nanoseconds). We have found that
[
1]
century. In historical order, Brønsted correlations, Hammett
the reactions of these benzhydrylium ions with several hundreds
of n-, σ- and π-nucleophiles followed the linear free energy
relationship (equation 4), where s and N are solvent-dependent
N
nucleophile-specific parameters and E is an solvent-independent
electrophile-specific parameter.[10]
equation,[
2]
Bell-Evans-Polanyi
relationships,
[3]
Leffler’s
equation,[ and Hammond’s postulate are the best known
empirical correlations between rates and equilibria of chemical
reactions. After developing a theory for the rates of electron
transfer reactions[6a] Marcus reported that atom transfer
reactions can be treated by the same formalism[6b] and
introduced the concept of the ‘intrinsic barrier’, which
corresponds to the activation barrier of a reaction, from which
the thermodynamic component has been extracted.
4]
[5]
lg k
2
(20 °C) = s
N
(N + E)
(4)
Furthermore, we have recently demonstrated that the
equilibrium constants for reactions of benzhydrylium ions with
phosphines, pyridines, and other Lewis bases can be calculated
as the sum of a Lewis acidity parameter LA and a Lewis basicity
parameter LB, as expressed by equation (5).[11] We now report
ꢃ
(∆ꢀꢁꢂ
)
‡
‡
‡
0
1
0
∆
퐺 = ∆퐺 + ∆ 퐺 +
(1)
푟
2
16∆ꢁ
ꢂ
the first determination of the Lewis basicity of a πCC bond
towards C-acids.
According to the Marcus equation (eq. 1), the intrinsic barrier
‡
∆
G
0
equals the Gibbs activation energy of a reaction with a
0
[6]
r
Gibbs energy of reaction Δ G = 0. Zhu recently modified the
lg K (20 °C) = LA + LB
(5)
Marcus approach and derived an equation which reproduces
electron and group transfer reactions with high precision.[7]
Leffler’s empirical relationship,[4] which is commonly written as
equation (2), can be integrated to give equation (3), where the
For a variety of reactions of benzhydrylium ions with pyridines,
tert. amines, and phosphines rate and equilibrium constants
have been determined and their Marcus intrinsic barriers were
calculated.[12] Though CC-nucleophiles are the largest group of
compounds in our comprehensive nucleophilicity scale based on
equation (4),[13] we had so far not measured equilibrium
constants for their reactions with benzhydrylium ions to derive
their Lewis basicities [as defined in equation (5)] in this way. As
a consequence, a comparison of the corresponding intrinsic
[
a]
D. S. Timofeeva, R. J. Mayer, Dr. P. Mayer, Dr. A. R. Ofial,
Prof. Dr. H. Mayr
Department Chemie, Ludwig-Maximilians-Universität München
Butenandtstraße 5-13, 81377 München (Germany)
E-mail: herbert.mayr@cup.lmu.de
barriers or reorganization energies of reactions with n- and πCC
nucleophiles was not possible to date.
-
Supporting information for this article is given via a link at the end of
the document.
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We now report on the measurement of the rates and
equilibrium constants for the reactions of enamines[14] with the
benzhydrylium ions E listed in Table 1 in order to derive the
nucleophilic reactivities and Lewis basicities of the enamines 1–
8
(Scheme 1) as well as the intrinsic barriers for these reactions.
Results and Discussion
As the deoxybenzoin derived enamines 1–3 are colored
compounds (λmax = 315–476 nm), which will be used as
references for the characterization of the electrophilicities and
Lewis acidities of colorless electron-deficient species in future
work, their synthesis and properties will be explicitly described in
the following.
Synthesis of Deoxybenzoin Derived Enamines
Enamines 1–3 were obtained by refluxing of deoxybenzoins and
the corresponding secondary amines in the presence of either
10 mol% of boron trifluoride etherate or 1 mol% of p-toluene-
sulfonic acid in dry toluene under N
2
, using a Dean-Stark
apparatus to remove the generated water (Scheme 2).[ After
evaporation of the solvent, enamines 1-H and 2 were purified by
distillation and all others by recrystallization from acetonitrile.
15]
Scheme 1. Enamines 1–8 studied in this work.
Scheme 2. Synthesis of deoxybenzoin-derived enamines 1–3 (yields of
isolated enamines).
Table 1. Structures, absorption maxima, electrophilicities E, and Lewis
acidities LA of the reference benzhydrylium ions E in acetonitrile solution
−
(
counterion: BF
4
).
Single crystals suitable for X-ray diffraction were grown by
Electrophile
[a]
E[a]
LA[b]
λ
max (nm)
2
crystallization of 1-OMe, 1-CN, 1-NO , and 3 from acetonitrile
solutions at −25 °C.[16] As shown in Figure 1 and Table 2,
enamines synthesized by this method have (E)-configured
E1
E2
E3
E4
E5
586
611
605
611
616
−3.85
−6.33
 
double bonds. The shortened C -N and C -CAr bonds and the
elongated C

-C

double bonds of the acceptor substituted
enamines 1-NO
2
and 1-CN show the increasing contribution of
−5.53
−7.02
−7.69
−8.76
−7.52
the zwitterionic resonance structure. Whereas the -aryl ring is
almost coplanar with the olefinic double bond (dihedral angles ≈
1
1
70°), the -phenyl group is highly twisted (dihedral angles ≈
15–130°). According to Table 2, the structural features of the
−9.82
morpholino-derived enamine 3 resemble those of the p-methoxy
substituted pyrrolidine derivative 1-OMe most closely.
−10.83
−11.46
E6
E7
635
631
−9.45
−12.61
−12.76
−10.04
Figure 1. Crystal structures of the enamines 1-CN (left) and 3 (right). Thermal
[
a] From ref [10b]. [b] From ref [11].
ellipsoids are drawn at a 50% probability level.[
16]
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Combination of the enamines 1-H and 3 with the benzhydrylium
tetrafluoroborates E3-BF
evaporation of the solvent resulted in quantitative formation of
iminium salts 9a-BF and 9b-BF , respectively. The iminium salt
b-BF was hydrolyzed by dilute hydrochloric acid to give the
4 4
and E2-BF in acetonitrile at 20 °C and
Table 2. Selected interatomic distances and dihedral angles.
4
4
9
4
ketone 10 in a yield of 30% (from 3, Scheme 3).
Monitoring the reactions of the enamines 1-OMe and 1-CN
1
13
(
1.05 equiv.) with E3-BF
4
and E2-BF
4
in CD
3
CN by H and
C
Enamine
C -C
α β
α
C −N
C
β
−CAr
Ar−C−C−N
Ar−C−C−Ph
 
N-C -C-C
(
Å)
(Å)
(Å)
(°)
(°)
(°)
NMR spectroscopy showed the quantitative formation of the
iminium ions 9c-BF4 and 9d-BF4 (Scheme 3). However, the
iminium salts 9 decomposed during attempts to recrystallize
them from a mixture of dichloromethane and n-pentane or
acetone.
1
1
1
3
3
-OMe
1.348
1.371
1.361
1.345
1.348
1.392
1.361
1.361
1.413
1.412
1.471
1.446
1.460
1.475
1.473
−167.8
168.3
−171.4
167.1
168.5
9.2
−12.6
9.2
−10.5
−9.3
−117.2
116.6
−115.5
134.2
133.9
-NO
-CN
2
[
[
a]
a]
-cA
-cB
[
a] Two independent molecules in the asymmetric unit.
Kinetic Investigations
Second-order rate constants (k ) of the reactions of the
2
The NOESY spectra of the enamines reveal the proximity
between C -H and the N-CH protons and thus confirm that the
E)-configurations observed in the crystals also dominate in
β
2
enamines 1–8 with benzhydrylium ions E were determined
photometrically in acetonitrile solution at 20 °C under pseudo-
first-order conditions using a high excess (≥ 10 equiv.) of the
enamines. The disappearance of the colored benzhydrylium ions
was monitored by time-resolved UV-Vis spectroscopy at their
maximum wavelengths max (Table 1). The resulting mono-
exponential decays of the absorbances of E1–7 are illustrated
for the reaction of enamine 1-H with benzhydrylium ion E3 in
Figure 2.
(
CD
3
CN solution. While the 1H and 13C NMR spectroscopic
properties of the enamines 1-X show little correlation with the
electronic effect of X (Hammett σ), the UV-Vis maxima of these
enamines experience a strong bathochromic shift when the
electron-acceptor strength of X increases (Table 3).
Table 3. Spectral data for the enamines 1–3 (in CD
3
CN)
Enamine
max (nm)
(H
β
) (ppm)
(C
α
) (ppm)
(C
β
) (ppm)
1
1
1
1
2
3
-OMe
-H
-CN
298
317
375
465
316
306
5.32
5.34
5.30
156.8
149.5
152.8
152.7
153.0
152.3
99.8
99.8
97.5
97.3
105.7
106.3
5.31[
5.62
5.67
a]
[a]
[a]
-NO
2
[
3
a] In CDCl .
Products of the Reactions of the Enamines with
Benzhydrylium Ions
In analogy to the behavior of previously investigated
enamines,[
10b,17]
the reactions of deoxybenzoin-derived
enamines 1–3 with benzhydrylium ions led to the formation of
iminium ions, which were either isolated or hydrolyzed to the
corresponding ketones.
Figure 2. Exponential decay of the absorbance of E3 (c
0
= 7.24 × 10−6 M) at
= 2.65 × 10−4 M, kobs = 1.48 s ).
–1
605 nm during its reaction with enamine 1-H (c
0
Inset: Correlation of the rate constants kobs with [1-H] in MeCN at 20 °C. The
tagged data point refers to the depicted absorption-time trace.
The first-order rate constants kobs were derived by least-squares
fitting of the exponential function A = A exp(–kobst) + C to the
t
0
time-dependent absorbances of the benzhydrylium ions E1–7.
Plots of kobs against the concentrations of nucleophiles were
linear as exemplified in Figure 2 (inset). The intercepts of these
plots for the reactions which proceeded quantitatively were
negligible, while positive intercepts were found for the reactions
which led to an equilibrium, and – in ideal cases – correspond to
the rate constants of the backward reactions. The slopes of
Scheme 3. Reactions of enamines with benzhydrylium-tetrafluoroborates E
with enamines 1-X and 3.
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these plots gave the second-order rate constants k
which are summarized in Table 4.
2
(M−1 s−1),
electrophilic reaction partner. The nucleophilicity parameters N
of 6 and 7 have previously been reported to be 1–2 units higher
in CH Cl
2 2
than in acetonitrile used in this work.[17]
2
Table 4. Second-order rate constants k for the reactions of enamines 1–8
with benzhydrylium ions E1–E7 in MeCN at 20 °C.
N
(s )
N
CH+
2
k )
(M−1 s−1
Enamine
Ar
2
5
3
3
2
1
5
4
3
2
1
5
4
3
2
1
5
4
2
2
5
3
2
1
1
4
2
1
1
1
1
-H
11.66
0.82)
E2
E3
E4
E5
E6
E2
E3
E4
E5
E7
E1
E2
E3
E4
E5
E1
E2
E3
E4
E1
E2
E3
E4
E5
E1
E2
E3
E4
E3
E4
E5
E6
E3
E4
E5
E6
E2
E3
E4
E6
E6
1.10 × 10
5.96 × 10
1.79 × 10
2.13 × 10
7.11 × 10
3.46 × 10
1.20 × 10
3.32 × 10
4.87 × 10
5.36 × 10
4.68 × 10
2.20 × 10
1.03 × 10
2.59 × 10
3.97 × 10
2.39 × 10
1.23 × 10
5.69 × 10
1.80 × 10
1.54 × 10
6.50 × 10
4.03 × 10
6.42 × 10
1.08 × 10
1.41 × 10
3.76 × 10
3.51 × 10
7.73
(
-OMe
-CN
11.99
0.84)
(
10.63
0.84)
(
1-NO
2
10.42
(0.82)
2
9.94
(0.86)
2
Figure 3. Plots of the rate constants (log k ) for the reactions of representative
enamines with benzhydrylium ions E v ersus their electrophilicities E (MeCN,
20 °C).
3
8.78
(0.83)
4[a]
13.87
0.76)
1.68 × 10
4.31 × 10
6.08 × 10
2.55 × 10
9.32 × 10
3.02 × 10
3.86 × 10
1.80 × 10
1.26 × 10
7.39 × 10
2.00 × 10
4.70
5
4
3
3
4
4
3
3
5
3
3
(
Equilibrium constants
As the reactions of enamines with weakly Lewis-acidic
benzhydrylium ions proceed incompletely, the corresponding
equilibrium constants could be studied through UV-Vis
spectrophotometric titration in acetonitrile solution at 20 °C. For
that purpose the enamines were added portion by portion to the
solutions of the benzhydrylium tetrafluoroborates, and the
absorbances of the benzhydrylium ions E were measured after
each step as illustrated in Figure 4.
5
13.84
0.73)
(
6
11.66
(0.83)
[
[
b]
7
8
≈10.3
≈11.6
b]
1
5.68 × 10
[
2
a] Rate constants in ref [18] for the reactions of 4 with E3 and E4 were
0% smaller, and the rate constant for 4 + E5 was 50 % smaller. The
reason of these discrepancies is not known. [b] For an estimated s = 0.80.
Because of the proportionality between the absorbances and
the concentrations of the benzhydrylium ions in dilute solutions
N
(
Beer-Lambert law), the equilibrium constants K for the reactions
in equation (6) can be derived from the initial absorbances (A
of the benzhydrylium ions and their absorbances at equilibrium
eq) according to equation (7).
0
)
(
A
2
Plots of the rate constants (lg k ) for the reactions of the
enamines with the reference benzhydrylium ions E versus their
electrophilicities E (from Table 1) are linear (Figure 3), as
required by equation (4). The slopes of these correlations equal
the nucleophile-specific parameters
intercepts on the abscissa (lg k
nucleophilicity parameters N, which are listed in Table 4.
The almost identical values of the slopes (0.82 ≤ s
s
N
,
and the negative
2
= 0) correspond to the
N
≤ 0.86)
for the deoxybenzoin-derived enamines 1–3 listed in Table 4,
reflected by the parallel correlation lines in Figure 3, imply that
the relative reactivities of these enamines depend only little on
the nature of the electrophiles. As the -aminostyrenes 4 and 5
have somewhat smaller slopes, the relative reactivities 4/1-H
and 5/2 decrease slightly with increasing reactivity of the
0
The plots of (A – Aeq)/(Aeq) versus the concentrations of the
enamines at equilibrium [equation (8)] are linear (Figure 4, Inset)
and their slopes give the equilibrium constants K, which are
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summarized in Table 5. Lewis basicities (LB) of the enamines
were calculated from the equilibrium constants for their reactions
with benzhydrylium ions in acetonitrile using equation (5). As the
LBs of the enamines derived from equilibrium constants with
different benzhydrylium ions differed only insignificantly (Table
Quantum Chemical Calculations
Previous investigations have shown that experimental Lewis
basicitites (LB) for various classes of nucleophiles correlate well
with their corresponding quantum chemically calculated gas
phase methyl cation affinities (MCAs).[19] Therefore, in a slightly
adapted procedure, MCAs of the enamines 1–8 were calculated
5), we can conclude that equation (5) is applicable.
as Gibbs energies of methyl cation detachment reactions, G298
,
as depicted in Table 6, by applying the B3LYP/6-
3
11++G(3df,2pd)//B3LYP/6-31G(d,p) level of theory in gas
phase with the Gaussian software package.[
20–22]
As shown in Figure S4 in a plot of gas phase MCAs against
the Lewis basicities LB, deoxybenzoin-derived enamines 1–3
and -aminostyrenes 4–6 followed separate linear correlations.
However, when solvent effects were considered by adding
single-point calculations with the SMD solvation model for
acetonitrile[ to the gas phase optimized structures (Table 6), all
enamines 1–8 followed the same correlation (Figure S5).
23]
Table 6. Calculated Methyl Cation Affinities (MCA) and Benzhydryl
Cation Affinities (BCA) of enamines 1–8 in gas-phase and in solution
(
3
SMD
=
acetonitrile) at the B3LYP/6-311++G(3df,2pd)//B3LYP/6-
1G(d,p) level (in kJ mol–1).
Figure 4. Determination of the equilibrium constant for the reaction of enamine
= 1.96 × 10− M) at 611 nm (MeCN,
5
1-CN with the benzhydrylium ion E4 (c
0
20°C).
Enamine
MCA
gas
phase)
MCA
(SMD =
MeCN)
BHCA
(gas
phase)
BHCA
(SMD =
MeCN)
Table 5. Equilibrium constants K for the reactions of benzhydrylium ions E
with enamines and the resulting Lewis basicity parameters LB in MeCN at
(
20 °C.
1-H
528.5
518.8
501.5
501.2
505.7
485.9
515.2
541.4
360.5
351.7
342.5
350.6
354.7
344.8
370.2
386.1
72.6
63.8
49.1
63.9
68.9
50.3
85.5
101.9
42.9
36.7
29.0
51.9
56.8
46.3
75.5
85.4
Enamine
Ar
2
CH+
K (M−1
)
LB
퐿퐵
2
3
4
5
6
7
8
5
3
3
5
4
4
3
3
4
3
4
3
3
2
5
3
3
5
3
3
4
3
1
-H
E5
E6
E7
E5
E6
E7
E4
E5
E3
E4
E4
E5
E3
E4
E5
E6
E7
E5
E6
E7
E3
E4
E6
E6
1.11 × 10
6.45 × 10
6.55 × 10
3.45 × 10
1.36 × 10
1.31 × 10
4.82 × 10
1.12 × 10
1.93 × 10
1.62 × 10
2.76 × 10
9.64 × 10
6.00 × 10
3.59 × 10
1.15 × 10
5.09 × 10
4.81 × 10
1.47 × 10
8.16 × 10
8.03 × 10
7.77 × 10
5.78 × 10
16.50
16.42
16.58
17.00
16.74
16.88
14.51
14.51
14.10
14.04
15.26
15.44
13.60
13.39
16.52
16.32
16.44
16.63
16.52
16.66
14.71
14.59
≈18.1
≈18.7
16.50
1
-OMe
-CN
16.87
1
1
2
3
4
14.51
14.07
15.36
13.49
16.43
-NO
2
Analogously, benzhydryl cation affinities (BHCAs) were
calculated as Gibbs energies of the dissociation reactions of the
benzhydrylium ion adducts (Table 6). Figure 5 illustrates that the
calculated BHCA of enamines 1–8 in acetonitrile solution
correlate linearly with their experimental Lewis basicities LB
(from Table 5).
5
6
16.60
14.65
5
[a]
[a]
7
8
3.1 × 10
1.1 × 10
6
[
a] Approximate values, because the determination of such high
equilibrium constants is less reliable. Weaker Lewis acids, such as E7,
cannot be used either, because they react so slowly.
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The Hammett plots for the rate and equilibrium constants for the
−[26]
reactions of enamines 1-X with E4 versus σ
p
give the
reaction constants of  = −0.83 and  = −1.89, respectively,
indicating that the equilibrium constants are more affected by
variation of the substituents than the rate constants (Figure 6).
The corresponding Hammett plots versus 
give slightly greater reaction constants of  = −1.22 (for lg k
and  = −2.76 (for lg K), but the correlation of the equilibrium
constants versus  is of somewhat lower quality. Because of
the paucity of data, a Yukawa-Tsuno analysis was not attempted.
p
(see Figure S2)
2
)
p
Figure 5. Correlation of the benzhydryl cation affinitites (BHCA, in kJ mol–1) of
enamines 1–8 calculated at the B3LYP/6-311++G(3df,2pd)//B3LYP/6-31G(d,p)
level of theory in solution (SMD = acetonitrile) with their Lewis basicities (LB)
2
in acetonitrile (R = 0.8456).
Discussion
Let us first turn to the question whether the rate constants
determined by our kinetic experiments reflect the direct attack of
the benzhydrylium ions at the -carbon atom or whether we are
measuring the rate of attack at the enamine nitrogen to give
vinylammonium ions, which rearrange to the NMR-
spectroscopically observed iminium ions in a subsequent step.
In previous work[24] we have shown that neither N-methyl-
piperidine nor N-methylpyrrolidine give adducts with E4 and less
Lewis-basic benzhydrylium ions. Since replacement of the N-
methyl group in these two tertiary amines by a vinyl group to
give an enamine would reduce the Lewis basicity of the nitrogen,
one can conclude that the vinylammonium ions generated by
attack of weakly Lewis-basic benzhydrylium ions (LA < −9) can
certainly not accumulate during these reactions.
Figure 6. Correlation of the rate (lg k
2
) and equilibrium constants (lg K) of the
−
reactions of 1-X with the benzhydrylium ion E4 with Hammett σ
p
values for
the substituents X (MeCN, 20 °C).[
26]
The Leffler-Hammond coefficient  = lg k )/(lg K) = 0.44 for
2
the reactions of 1-X with E4 (Figure 7), which equals the ratio of
the two Hammett plots in Figure 6, shows that 44% of the effects,
which the substituents exert on the equilibrium constants, are
reflected by the differences of the activation energies.
This conclusion can be confirmed by another argument. In
the preceding section we have shown that most of the
investigated reactions of benzhydrylium ions with enamines 1–8,
which give iminium ions, are only weakly exergonic. As C-
methylation of vinyl amine was calculated to be 61 kJ mol−1
more exergonic than N-methylation,[25] all reactions yielding vinyl
ammonium ions from E1–E7 and the enamines 1–8 must be
highly endergonic. Both arguments do not exclude that N-attack
is also occurring during the kinetically investigated reactions.
The concentrations of the reversibly formed vinyl ammonium
ions would be so low, however, that their formation would not
affect the kinetics, and there is no doubt that the measured rate
constants refer to electrophilic attack at the carbon center of the
enamines.
Figure 7. Correlation of the rate constants (lg k , from Table 4) for the
2
reactions of 1-X with E4 with the corresponding equilibrium constants (lg K,
from Table 5).
Tables 4 and 5 show that nucleophilicities and Lewis
basicities of the pyrrolidino-substituted enamines 1-X increase
with increasing electron-donating abilities of the p-substituents X.
Replacement of H by the electron-donating methoxy group
As illustrated by Figure 8a the -piperidino- and -morpholino-
styrenes 5 and 6 are more Lewis basic than the corresponding
deoxybenzoin derived enamines 2 and 3, respectively, in line
with the calculated benzhydryl cation affinities (BHCA, Figure
increases
the
nucleophilic
reactivity
toward
various
benzhydrylium ions by a factor of 2–3, whereas the electron-
accepting nitro group reduces the reactivity by a factor of 10 (±1).
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8
b). Obviously, the steric strain introduced by the extra -phenyl
Removal of the -phenyl group from 2 and 3 to give the
corresponding -aminostyrenes 8 and 7, respectively, leads to
an increase of the Lewis basicity by 3 to 5 orders of magnitude,
due to reduction of steric strain in the products, which is also
reflected by the computationally determined BHCAs (Figure 8).
However, the LB values of 7 and 8 are only approximations,
because benzhydrylium ions which react with reasonable rates
give the products almost quantitatively, whereas benzhydrylium
ions which give equilibrium mixtures with comparable
concentrations of reactants and products react so slowly that
measurements of the equilibrium constants are problematic.
The availability of rate and equilibrium constants for several
reactions of enamines with benzhydrylium ions now allows one
group in the products obtained from 2 and 3 cannot be
compensated by the electron releasing effect of the -phenyl
group, which is almost perpendicular to the -system of the
resulting iminium ion according to our calculations. The fact that
the Lewis basicities as well as the BHCA of the morpholino
derivatives 3 and 6 are 8 to 11 kJ mol−1 smaller than those of the
corresponding piperidino derivatives 2 and 5, respectively, can
be explained by the inductive electron-withdrawing effect of
oxygen in the morpholino compounds.
to calculate the Marcus intrinsic barriers (G ‡
) by equation (1)
0
and compare them with those of reactions with other types of
nucleophiles (Table 7).
‡
Table 7. Calculation of the intrinsic barriers G
0
for the reactions of the
enamines 1–8 with benzhydrylium ions in MeCN at 20 °C (all Gibbs
energies in kJ mol–1
)
K (M−1
)
k
2
(M−1 s−1
)
Δ
G0
ΔG‡
‡
ΔG
0
Nu
E
r
1-H
E5
E6
1.11 × 105
6.45 × 103
2.13 × 102
7.11 × 101
–28.3
–21.4
58.7
61.4
72.2
71.7
1
-OMe
-CN
E5
3.45 × 105
1.31 × 104
4.82 × 103
4.87 × 102
5.36 × 101
2.59 × 102
–31.1
56.7
71.4
E7
E4
E5
E3
E4
E4
E5
E3
E4
–23.1
–20.7
–17.1
–24.1
–18.0
–24.9
–22.4
–21.2
–14.3
–28.4
–20.8
–29.0
–22.0
–27.4
–21.1
–31
62.1
58.2
62.8
56.3
59.1
61.6
66.0
63.1
66.8
50.5
52.6
51.6
53.5
50.0
53.2
68.0
61.9
73.2
68.2
71.1
67.8
67.8
73.5
76.7
73.3
73.8
63.9
62.6
65.3
64.0
63.0
63.3
≈ 83
≈ 78
1
1
2
3
3
1
1.12 × 10
3.97 × 10
-NO
2
1.93 × 104
5.69 × 102
3
2
1.62 × 10
1.80 × 10
Figure 8. Comparison of the a) Lewis basicities and b) calculated BHCAs
2.76 × 104
9.64 × 103
6.00 × 103
3.59 × 102
1.15 × 105
6.42 × 101
1.08 × 101
3.51 × 101
7.73
(SMD = acetonitrile) of deoxybenzoin-derived enamines 1–3 with those of
aminostyrenes 4–8.
4
5
6
E5
E6
E5
E6
E3
E4
E6
E6
6.08 × 103
3
3
5.09 × 10
2.55 × 10
Piperidino and pyrrolidino groups have different effects in the
deoxybenzoin and in the -aminostyrene series, however:
1.47 × 105
.16 × 103
3.86 × 103
3
8
1.80 × 10
7.77 × 104
5.78 × 103
3.1 × 105
1.1 × 106
7.39 × 103
2.00 × 103
4.70
Whereas piperidinostyrene
5 has almost the same Lewis
basicity (LB) and even a slightly higher calculated BHCA than
the corresponding pyrrolidinostyrene 4, experiments and
calculations agree that this ordering is reversed in the
deoxybenzoin series, where the pyrrolidino enamine 1-H is a
stronger Lewis base than the piperidino enamine 2 (LB = 1.2 ≙
7
8
5.68 × 101
–34
−
1
Whenever the intrinsic barrier (G ‡
enamine with different benzhydrylium ions was measured, one
generally observes a slight increase of G ‡
in the order E3 ≈ E4
E6 ≈ E5 < E7. Since the same ordering was previously
0
) for the reaction of a certain
6
.8 kJ mol ) close to the difference in the calculated BHCA (6.2
−
1
[27]
kJ mol ). The same trends are seen in an NBO analysis
Figures S15 and S16): From the charge density at the iminium
0
(
<
carbon one can derive that the piperidino ring is a better electron
donor than the pyrrolidino moiety in the iminium ions obtained
from 4 and 5, while the relative electron-donating abilities of the
two heterocycles is opposite in the iminium ions formed from 1-H
and 2, i.e., in this pair pyrrolidine is a better electron donor than
piperidine. The reduced electron donating ability of the
piperidino group in the iminium ion derived from 2 may be due to
observed for the reactions of these benzhydrylium ions with
pyridines, imidazoles, and tert. amines, these differences reflect
differences in the reorganization energies ( = 4G
0
‡) of the
different benzhydrylium ions.[ As a consequence, only intrinsic
barriers for reactions with the same electrophile can be
compared for examining the relationship between enamine
structure and intrinsic barrier.
12]
2
steric effects: While the dihedral angle H C-N=C–CAr is smaller
Figure
9 illustrates that the intrinsic barriers for the
than 2° in both iminium ions derived from 4 and 5 as well as in
pyrrolidino species from 1-H, it is 6° in the iminium ion derived
from 2.
deoxybenzoin derived enamines 1–3 as well as for the -
aminostyrenes 4–6 generally increase in the order pyrrolidine <
piperidine ≈ morpholine. One can furthermore see that the
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‡
intrinsic barriers G
0
for the -aminostyrenes 4–6 are 8 to 12 kJ
higher nucleophilicity of the latter (Figure 10) is an entirely
intrinsic effect (Figure 9). The dependence of the relative
activation of the enamine double bond by pyrrolidino and
piperidino groups on the substitution of the double bond has
−
1
mol smaller (Figure 9), while those for the -aminostyrenes 7
and 8 are 5–10 kJ mol larger (Table 7) than those for the
corresponding deoxybenzoin derived enamines 1–3.
−
1
previously
cyclohexanone-derived enamines.
been
observed
for
cyclopentanone-
As shown in the Figure 11,
and
[
17a]
pyrrolidinocyclohexene is 33 times more nucleophilic towards E6
than the corresponding piperidino compound whereas this
difference is reduced to a factor of 7 in the sterically less
demanding cyclopentene series.
Removal of the -phenyl group from the deoxybenzoin
derived enamines 2 and 3 to give 8 and 7, respectively,
increases the nucleophilic reactivity by less than two logarithmic
units (Figure 10). Thus, the high increase of Lewis basicity from
2
and 3 to 8 and 7 (Figure 8a), respectively, is largely
counterbalanced by the much larger intrinsic barrier for the
reactions of 7 and 8 with benzhydrylium ions.
‡
Figure 9. Comparison of the intrinsic barriers G
0
for the reactions of
enamines 1–6 towards benzhydrylium ion E5. [a] Rate and equilibrium
constants, k and K, were calculated according to equations (4) and (5) based
on the N (s ) and LB values from Tables 4 and 5 and then applied in equation
1) to derive G ‡
2
N
(
0
.
On this basis, a profound analysis of the nucleophilic reactivities
of the enamines 1–8 becomes possible. The nucleophilicity
ordering morpholino < piperidino < pyrrolidino in the series 3 < 2
<
1-H and 6 < 4 ≈ 5 (Figure 10) is predominantly controlled by
thermodynamics (Figure 8) though slightly enhanced by
intrinsics (Figure 9).
Figure 11. Comparison of the rate constants (in M–1 s–1, at 20 °C) for the
reactions of different pyrrolidine- and piperidine-derived enamines (k values
2
for the cyclopentanone- and cyclohexanone-derived enamines were taken
from ref [17a]).
Conclusions
While changes in G0 can unambiguously be assigned to the
difference in the thermodynamic stabilities of reactants and
‡
products, changes in G , i.e., kinetic effects can have a dual
origin. As expressed by the Marcus equation, changes in
activation Gibbs energies can either be due to changes in the
0
thermodynamic driving force G or to a truly kinetic, so-called
‡
intrinsic effect, i. e., a change in G
0
. We now reported one of
the very few reaction series, where this analysis is possible
because rate and equilibrium constants could be measured.
For the reactions of a series of enamines with benzhydrylium
ions we have now shown that the unambiguous interpretation of
the origin of structural effects on reaction rates requires a
separation of the thermodynamic and intrinsic contributions. This
is even more important when the reactivity of structurally diverse
nucleophiles is compared.
Figure 12a shows, for example, that the depicted enamines
are weaker nucleophiles than the tert. amines, pyridines, and
imidazoles shown in this graph, though the Lewis basicities of
these enamines are comparable to those of the strongest
Figure 10. Comparison of the nucleophilicities N of deoxybenzoin-derived
enamines 1–3 with those of aminostyrenes 4–8.
Removal of the -phenyl group (2→5, 3→6) leads to a
significant increase of nucleophilicity (by 3 lg k units, Figure 10),
much more than the increase in Lewis basicity (by 1.2 lg K units,
Figure 8a), because the thermodynamic effect is enhanced by
the simultaneous decrease of the intrinsic barrier (Figure 9).
Since 1-H and 4 have equal Lewis basicities (Figure 8a), the
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Figure 12. Comparison of the a) nucleophilicities, b) Lewis basicities, and c) and intrinsic barriers for the reactions with E5 with the corresponding descriptors for
[
11,12a,28]
[11,12a,19g]
[11,12b]
tert. amines,
pyridines,
and imidazoles.
[a] Intrinsic barriers were extrapolated according to footnote [a] of Figure 9.
nitrogen bases depicted (Figure 12b). Figure 12c shows the
reason for this change. The enamines react over high intrinsic
barriers which reduces their nucleophilicity. Since the intrinsic
barriers are related to Marcus’ reorganization energies  by the
kinetics studies and Nathalie Hampel for the preparation of the
electrophiles E1–E7. The authors are grateful to Prof. Dr.
Hendrik Zipse and Harish Jangra for helpful discussions
concerning quantum chemical calculations.
‡
[6]
relationship G
0
= /4, their ordering can be rationalized. The
tertiary amines react with the lowest intrinsic barriers because
their alkylation requires no reorganization of -electrons.
Pyridine has a higher intrinsic barrier, which is further increased
by the 4-dimethylamino group in DMAP, a strong mesomeric
electron donor, which enhances the geometrical changes during
alkylation of the pyridine nitrogen. Electrophilic attack at the
enamines as well as at N-methylimidazole is accompanied by
changes of bond orders and associated reorganization of
solvent molecules resulting in high intrinsic barriers.
In view of these data, one can expect that electrophilic attack
at the enamine nitrogen should also have a low intrinsic barrier.
Though the Lewis basicity of the enamine nitrogen is much
lower than that of the enamine CC-bond one cannot exclude that
the enamines are initially attacked at nitrogen to give vinyl
ammonium ions. From the monoexponential decays observed in
the kinetic investigations one can derive, however, that N-attack
Keywords: enamines • linear free-energy relationship •
structure-reactivity relationships • kinetics • nucleophilicity
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FULL PAPER
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10.1002/chem.201705962
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Strong Lewis bases but weak
nucleophiles – Nucleophilicities (N)
and Lewis basicities of deoxybenzoin-
Daria S. Timofeeva, Robert J. Mayer,
Peter Mayer, Armin R. Ofial, Herbert
Mayr*
derived
enamines
have
been
determined in order to employ them
for the characterization of colorless
electrophiles. High intrinsic barriers
are responsible for the observation
that they, like other enamines are
much weaker nucleophiles than
pyridines and tert. amines despite
their comparable Lewis basicity.
Page No. – Page No.
Which Factors Control the
Nucleophilic Reactivities of
Enamines?
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