Nucleophilicities and Lewis basicities of imidazoles, benzimidazoles, and benzotriazoles

Article abstract of DOI:10.1039/c000965b

The kinetics of the reactions of some imidazoles, benzimidazoles and benzotriazoles with benzhydrylium ions (diarylcarbenium ions) have been studied photometrically in DMSO, acetonitrile, and aqueous solution at 20 °C. The resulting second-order rate constants have been used to determine the nucleophile-specific parameters N and s of these azoles according to the linear-free-energy relationship log k (20 °C) = s(N + E). With N = 11.47 (imidazole in acetonitrile), N = 10.50 (benzimidazole in DMSO), and N = 7.69 (benzotriazole in acetonitrile) these azoles are significantly less nucleophilic than previously characterized amines, such as DMAP (N = 14.95 in acetonitrile) and DABCO (N = 18.80 in acetonitrile). For some reactions of the 1-methyl substituted azoles with benzhydrylium ions equilibrium constants have been measured, which render a comparison of the Lewis basicities of these compounds. Substitution of the rate and equilibrium constants of these reactions into the Marcus equation yields the corresponding intrinsic barriers ΔG ₀^≠. From the ranking of ΔG₀ ^≠ (imidazoles > pyridines > 1-azabicyclooctanes) one can derive that the reorganization energies for the reactions of imidazoles with electrophiles are significantly higher than those for the other amines and that imidazoles are less nucleophilic than pyridines and 1-azabicyclooctanes of comparable basicity.

Full text of DOI:10.1039/c000965b

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Nucleophilicities and Lewis basicities of imidazoles, benzimidazoles, and
benzotriazoles†‡
Mahiuddin Baidya, Frank Brotzel and Herbert Mayr*
Received 18th January 2010, Accepted 16th February 2010
First published as an Advance Article on the web 5th March 2010
DOI: 10.1039/c000965b
The kinetics of the reactions of some imidazoles, benzimidazoles and benzotriazoles with
benzhydrylium ions (diarylcarbenium ions) have been studied photometrically in DMSO, acetonitrile,
and aqueous solution at 20 ◦C. The resulting second-order rate constants have been used to determine
the nucleophile-specific parameters N and s of these azoles according to the linear-free-energy
relationship log k (20 ◦C) = s(N + E). With N = 11.47 (imidazole in acetonitrile), N = 10.50
(benzimidazole in DMSO), and N = 7.69 (benzotriazole in acetonitrile) these azoles are significantly
less nucleophilic than previously characterized amines, such as DMAP (N = 14.95 in acetonitrile) and
DABCO (N = 18.80 in acetonitrile). For some reactions of the 1-methyl substituted azoles with
benzhydrylium ions equilibrium constants have been measured, which render a comparison of the
Lewis basicities of these compounds. Substitution of the rate and equilibrium constants of these
π
reactions into the Marcus equation yields the corresponding intrinsic barriers DG0 . From the ranking
π
of DG0 (imidazoles > pyridines > 1-azabicyclooctanes) one can derive that the reorganization energies
for the reactions of imidazoles with electrophiles are significantly higher than those for the other amines
and that imidazoles are less nucleophilic than pyridines and 1-azabicyclooctanes of comparable basicity.
Ishihara and co-workers developed artificial acylases derived from
L-histidine for the kinetic resolution of mono-protected cis-1,2-
Introduction
diols and N-acylated 1,2-amino alcohols.10j Imidazoles have also
been used to promote Baylis–Hillman and aza-Morita–Baylis–
Hillman reactions11 including reactions of nitroalkenes with
carbonyl compounds and azodicarboxylates.12 Six-membered car-
bocycles have been obtained by imidazole-catalyzed reactions of
nitroalkenes with two equivalents of benzylidenemalononitriles.13
Recently 1-methylimidazole was employed for transferring the
thiocyanate group from acylisothiocyanates to phenacyl or benzyl
bromides.14
Though all of these reactions have been rationalized by the
nucleophilic properties of azoles,15 quantitative studies of their
reactivities are rare.16 It was the goal of this investigation to
quantify the nucleophilicities and Lewis basicities of imidazoles
1a–g, benzimidazoles 2a–g, and benzotriazoles 3a,b (Scheme 1) in
comparison with previously characterized nucleophilic organocat-
alysts. For this purpose we have performed kinetic and equilibrium
studies with the title azoles by employing the benzhydrylium
methodology where benzhydrylium ions (diarylcarbenium ions,
Table 1) are used as reference electrophiles and reference Lewis
acids.17
Azoles, such as imidazoles, benzimidazoles, and benzotriazoles,
are important reagents in organic synthesis.1 They are common
structural motifs in natural products, and several N-substituted
azoles have become well established drugs,1d–g which can be synthe-
sized by metal catalyzed N-arylation2 and N-allylation3 of imida-
zoles and benzimidazoles. Iminium catalyzed enantioselective
1,4-conjugate additions of azoles to a,b-unsaturated aldehydes
have been reported by Jørgensen et al. and Vicario et al. and
reviewed by Buckley and Enders.4 A chiral [(salen)Al] complex
was used as catalyst for conjugate additions of azoles to a,b-
unsaturated ketones and imides by Jacobsen and Gandelman.5
Wang and co-workers reported cinchona alkaloid-catalyzed enan-
tioselective additions of benzotriazole to nitroolefins.6 The nucle-
ophilic displacement of acetoxy groups in Baylis–Hillman acetates
by imidazoles and benzimidazoles under DABCO-catalysis has
been demonstrated by Zhang et al.7
Since the discovery of the participation of the imidazole
moiety of histidine in the active center of several enzymes,8
imidazole and its derivatives have become a natural choice as
organocatalysts for a manifold of reactions9 in particular for
acylation reactions.10 Miller has designed imidazole containing
small peptides for kinetic resolutions of alcohols.10h Recently
Department Chemie, Ludwig-Maximilians-Universita¨t, Butenandtstraße
5-13 (Haus F), 81377 Mu¨nchen, Germany. E-mail: herbert.mayr@cup.uni-
muenchen.de; Fax: +49-89-2180-77717; Tel: +49-89-2180-77719
† Dedicated to Professor Christian Reichardt on the occasion of his 75th
birthday.
‡ Electronic supplementary information (ESI) available: Synthetic proce-
dures and product characterization, details of the determination of rate
and equilibrium constants. See DOI: 10.1039/c000965b
Scheme 1 Azoles investigated in this work (for precise structures see
Table 3).
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Table 1 Abbreviations and electrophilicity parameters E of the benz-
Table 2 Benzhydrylations of imidazoles and benzimidazoles
hydrylium ions Ar2CH+
Ar2CH+
(lil)2CH+
Ea
Entry NuH
1
Solvent Product
1a CH3CN
Yield/%a
87
-10.04
2
1e CH3CN
82b
(jul)2CH+
-9.45
3
4
2a DMSO
2d DMSO
76
(ind)2CH+
(thq)2CH+
-8.76
-8.22
74c
5
2f DMSO
84
(pyr)2CH+
(dma)2CH+
(mpa)2CH+
(mor)2CH+
(mfa)2CH+
(pfa)2CH+
X = N(CH2)4
-7.69
-7.02
-5.89
-5.53
-3.85
-3.14
X = N(CH3)2
a Isolated yield. b 1.0 : 0.4 mixture of regioisomers. c 1 : 1 mixture of
regioisomers.
X = N(Ph)CH3
X = N(CH2CH2)2O
X = N(CH3)CH2CF3
X = N(Ph)CH2CF3
a Empirical electrophilicity parameter from ref. 17a.
absorbances after combining the benzhydrylium tetrafluoro-
borates with the azoles 1–3 using stopped-flow techniques or
conventional UV-Vis spectrometers equipped with fiber optics as
described previously.17 As 1–3 are generally used in high excess over
the benzhydrylium ions to achieve pseudo-first-order conditions,
the absorbances of the benzhydrylium ions decrease mono-
exponentially (Fig. 1) and the pseudo-first-order rate constants
kobs (s-1) were obtained by fitting the decays of the absorbances to
the monoexponential function A = A0 exp(-kobst) + C.
Results and discussion
Product studies
When solutions of (dma)2CH+BF4 in acetonitrile were added
to solutions of imidazoles in acetonitrile at room temperature,
1-benzhydryl substituted imidazoles were formed and isolated
after deprotonation with K2CO3 (Table 2, entries 1, 2). 1-
Benzhydryl substituted benzimidazoles were obtained analogously
in DMSO solutions (Table 2, entries 3–5). Unsymmetrical imida-
zoles or benzimidazoles yield mixtures of regioisomers. While 5-
methylbenzimidazole renders equal amounts of both regioisomers
(entry 4), 4-methylimidazole yields a 1.0 : 0.4 mixture of 4-methyl
and 5-methyl-1-benzhydrylimidazole (entry 2), the constitution of
which was derived from two-dimensional 1H NMR spectroscopy.
This ratio may be rationalized by the repulsive steric interaction of
the ortho-substituents in the 5-methyl-isomer. Details of individual
experiments are given in the ESI.‡
-
Products of the reactions of benzotriazole with highly reactive
benzhydrylium ions (E > 0) have previously been reported.18 We
have now observed that the reactions with amino-substituted benz-
hydrylium ions (E < -7) are highly reversible. Only small amounts
of carbocations were consumed even when high concentrations
of benzotriazole were added, and products from the reactions of
highly stabilized benzhydrylium ions with benzotriazole could not
be isolated.
Fig. 1 Exponential decay of the absorbance A at 610 nm and linear
correlation of the pseudo-first-order rate constants kobs vs. [2b] for the
reaction of (dma)2CH+BF4 with 2b in acetonitrile at 20 ◦C.
-
Plots of kobs versus the concentrations of 1–3 were linear with
the second-order rate constants k (M-1 s-1) being the slopes of the
correlations lines (Fig. 1, Table 3). Because most benzimidazoles
2 have low solubility in CH3CN, and on the other side DMSO
reacts with benzhydrylium ions which are more reactive than
(dma)2CH+, it was not possible to perform all kinetic investigations
in one of these solvents. However, kinetic studies with the parent
compound 1a show that the rate constants of its reactions with
Kinetics
Rates of the reactions of the imidazoles 1, benzimidazoles 2,
and benzotriazoles 3 (Table 3) with benzhydrylium ions (Table 1)
were determined by monitoring the decay of the benzhydrylium
1930 | Org. Biomol. Chem., 2010, 8, 1929–1935
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Table 3 Second-order rate constants (k) for the reactions of azoles 1–3
Table 3 (Contd.)
with the benzhydrylium ions (Ar2CH+) in different solvents at 20 ◦C
Azoles
solvent N, s
Ar2CH+
k/M-1s-1
Azoles
solvent
N, s
Ar2CH+
k/M-1s-1
2d
DMSO 10.69, 0.79
(jul)2CH+
(ind)2CH+
(thq)2CH+
(pyr)2CH+
9.75
1a
CH3CN
11.47, 0.79
(ind)2CH+
(thq)2CH+
(pyr)2CH+
(dma)2CH+
(ind)2CH+
(thq)2CH+
(pyr)2CH+
(dma)2CH+
(lil)2CH+
1.24 ¥ 102
3.52 ¥ 102
1.14 ¥ 103
2.74 ¥ 103
1.37 ¥ 102
4.78 ¥ 102
1.61 ¥ 103
3.09 ¥ 103
6.10 ¥ 10-1
1.23
2.73 ¥ 101
9.13 ¥ 101
3.19 ¥ 102
(dma)2CH+ 6.37 ¥ 102
DMSO
H2O
11.58, 0.79
9.63, 0.57
11.90, 0.73
2e
2f
DMSO 10.21, 0.85
DMSO 11.08, 0.71
(jul)2CH+
(ind)2CH+
(thq)2CH+
(pyr)2CH+
4.53
1.45 ¥ 101
4.75 ¥ 101
2.00 ¥ 102
(dma)2CH+ 4.12 ¥ 102
(jul)2CH+
(pyr)2CH+
(dma)2CH+
(lil)2CH+
(lil)2CH+
(jul)2CH+
(ind)2CH+
(thq)2CH+
5.87
1.22 ¥ 101
3.22 ¥ 101
2.33 ¥ 101
1.88 ¥ 102
4.81 ¥ 102
1.44 ¥ 103
3.48 ¥ 103
9.44 ¥ 10-1
3.79
1.46 ¥ 101
3.65 ¥ 101
1.18 ¥ 102
1b
CH3CN
(ind)2CH+
(thq)2CH+
(pyr)2CH+
(dma)2CH+
(lil)2CH+
(dma)2CH+ 8.03 ¥ 102
2g
3a
DMSO 11.0, 0.71
CH3CN 7.69, 0.76
(lil)2CH+
(jul)2CH+
4.62
1.22 ¥ 101
(dma)2CH+ h.r.b
H2O
9.91, 0.55
(mor)2CH+ 4.50 ¥ 101
(mfa)2CH+ 8.64 ¥ 102
(ind)2CH+
(thq)2CH+
(pyr)2CH+
(dma)2CH+
(thq)2CH+
(pyr)2CH+
(dma)2CH+
(mpa)2CH+
(mor)2CH+
(mfa)2CH+
(lil)2CH+
8.01
3b
CH3CN 7.77, (0.76)a (pyr)2CH+
n.r.c
1.63 ¥ 101
4.51 ¥ 101
9.44 ¥ 101
2.64 ¥ 102
7.29 ¥ 102
6.75 ¥ 103
5.21 ¥ 103
8.14 ¥ 104
1.95 ¥ 101
5.27 ¥ 101
1.72 ¥ 102
4.73 ¥ 102
1.47 ¥ 103
3.29 ¥ 103
5.38 ¥ 10-1
1.92
(dma)2CH+ n.r.c
(mfa)2CH+ 9.46 ¥ 102
1c
1d
CH3CN
11.31, 0.67
a N was calculated from the single rate constant, see text. b h.r. = highly
reversible. c n.r. = no reaction.
CH3CN
11.74, 0.76
(jul)2CH+
(ind)2CH+
(thq)2CH+
(pyr)2CH+
(dma)2CH+
(lil)2CH+
various benzhydrylium ions differ by less than a factor of 1.4
in DMSO and CH3CN. For that reason one can neglect solvent
effects when comparing rate constants determined in any of these
two solvents.
H2O
9.45, 0.54
Some rate constants for the reactions of imidazoles with
benzhydrylium ions have also been determined in water. When
an amine is dissolved in water, the concentration of hydroxide ions
increases by protolysis. For that reason competing reactions of the
carbocations with hydroxide have to be considered.19 However, the
pKaH values of imidazoles 1 in H2O are close to 7;20 therefore, only
very small amounts of hydroxide ions will be generated which are
negligible when evaluating the kinetic experiments. This statement
is quantified in the ESI (pp. S49–S51),‡ where the second-order
rate constant for the reaction of 2-methylimidazole (1d) with
(ind)2CH+ was calculated with and without consideration of the
contribution of hydroxide ions. Both methods yielded identical
second-order rate constants and because the other azoles have
similar or even smaller pKaH values, we have generally neglected
the effect of OH-. As the reactions of benzhydrylium ions with
water21 are also very slow compared to the corresponding reactions
with imidazoles, the second-order rate constants for the reactions
of azoles 1 with benzhydrylium ions in water (Table 3) were
determined without considering the contribution from hydroxide
ions and water, following the procedure described for the reactions
in acetonitrile and DMSO.
(ind)2CH+
(thq)2CH+
(pyr)2CH+
(dma)2CH+
(lil)2CH+
4.66
8.72
2.21 ¥ 101
2.37 ¥ 101
6.41 ¥ 101
1.96 ¥ 102
5.23 ¥ 102
1.76 ¥ 103
4.59 ¥ 103
4.96 ¥ 101
2.44 ¥ 102
4.92 ¥ 102
2.06 ¥ 103
5.41 ¥ 103
3.69 ¥ 101
1.20 ¥ 102
1.03 ¥ 103
2.74 ¥ 103
2.34 ¥ 104
6.97
1e
CH3CN
11.79, 0.77
(jul)2CH+
(ind)2CH+
(thq)2CH+
(pyr)2CH+
(dma)2CH+
(jul)2CH+
(ind)2CH+
(thq)2CH+
(pyr)2CH+
(dma)2CH+
(jul)2CH+
(ind)2CH+
(pyr)2CH+
(dma)2CH+
(mpa)2CH+
(jul)2CH+
(ind)2CH+
(thq)2CH+
(pyr)2CH+
(dma)2CH+
(ind)2CH+
(thq)2CH+
(pyr)2CH+
(dma)2CH+
(mpa)2CH+
(jul)2CH+
(ind)2CH+
(thq)2CH+
(pyr)2CH+
(dma)2CH+
1f
CH3CN
CH3CN
DMSO
CH3CN
DMSO
11.51, 0.84
11.43, 0.79
10.50, 0.79
10.37, 0.82
10.02, 0.85
1g
2a
2b
2c
1.96 ¥ 101
6.55 ¥ 101
2.19 ¥ 102
4.65 ¥ 102
2.02 ¥ 101
5.97 ¥ 101
1.60 ¥ 102
4.47 ¥ 102
4.84 ¥ 103
2.89
Correlation analysis
In numerous publications we have shown that the rate constants
for the reactions of carbocations with nucleophiles can be de-
scribed by eqn (1) where electrophiles are characterized by the
electrophilicity parameter E and nucleophiles are characterized
1.08 ¥ 101
3.38 ¥ 101
1.39 ¥ 102
2.75 ¥ 102
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by the nucleophilicity parameter N and the nucleophile-specific
slope parameter s. On this basis it became possible to compare
the reactivities of numerous s-, n-, and p-nucleophiles in a single
scale.17
log k(20 ◦C) = s(N + E)
(1)
Fig. 2 correlates second-order rate constants k (Table 3) with the
previously published electrophilicity parameters E (Table 1). The
linear correlations for the different reaction series demonstrate
that the reactions of carbocations with the azoles 1–3 also follow
eqn (1). The slopes of these correlations yield the nucleophile-
specific parameters s, and the intercepts on the abscissa give the
nucleophilicity parameters N listed in Table 3.
Fig. 3 Plots of nucleophilicity parameters N (in CH3CN or DMSO) vs.
pKaH (H2O) for the azoles 1–3.
N
Fig. 4 Plot of rate constants log k vs. ET for the◦reactions of imidazole
-
1a with (pyr)2CH+ BF4 in different solvents at 20 C.24
Fig. 2 Plots of log k for the reactions of 1–3 with the benzhydrylium ions
versus the electrophilicity parameters E in acetonitrile at 20 ◦C (1b also
in H2O; for the sake of clarity only a few correlation lines are shown, for
other correlations see ESI‡).
In agreement with our earlier observations,17b Table 3 demon-
strates that structurally related nucleophiles have closely similar
s values in a particular solvent. Therefore, the nucleophilicity
parameter N of 3b was derived from the rate constant for its
reaction with (mfa)2CH+ in CH3CN assuming s = 0.76 as for 3a.
The almost parallel correlation lines in Fig. 2 imply that the
relative reactivities of the N-heterocyclic compounds 1–3 are
almost independent of the reactivities of electrophiles (Ar2CH+).
Table 3 and Fig. 2 show that in acetonitrile imidazoles 1 are
one and three orders of magnitude more nucleophilic than the
benzimidazoles 2 and the benzotriazoles 3, respectively.
Because of the paucity of pKaH values for 1–3 in organic solvents,
pKaH values in water have been used for the Brønsted correlations
shown in Fig. 3.20,22 Though the correlation is not very good, one
can see that in general the nucleophilicities increase with basicities.
Fig. 4 shows that the second-order rate constant for the reaction
-
of the parent imidazole 1a with (pyr)2CH+BF4 decreases with
Fig. 5 Comparison of the nucleophilicities of organocatalysts and of
nucleophilic substrates used in organocatalysis (solvent is CH3CN unless
otherwise mentioned, N from ref. 25, 26).
N
23
increasing solvent polarity ET
.
The reactions in water are
approximately two orders of magnitude slower than in CH3CN
and DMSO.
Fig. 5 compares the nucleophilicities of azoles with those of
other nucleophilic organocatalysts and some compounds which
have been used as nucleophilic substrates in iminium catalyzed
reactions.25,26 The N-values show that the imidazoles 1 are among
the weakest nucleophiles of the commonly used catalysts in Baylis–
Hillman reactions. They are more than six orders of magnitude less
nucleophilic than DABCO and 102 to 103 times less nucleophilic
than Ph3P, DBU, and DMAP. While the reactivities of the
imidazoles are comparable to those of cyclic ketene acetals, they
are considerably higher (DN ≥ 2.5) than those of Hantzsch ester,
1932 | Org. Biomol. Chem., 2010, 8, 1929–1935
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pyrroles, indoles, and silyl enol ethers. Ordinary enamines are also
more nucleophilic than imidazoles.
Lewis basicities and intrinsic barriers
In previous work we have shown that nucleophilicity is not the only
factor controlling the efficiency of nucleophilic organocatalysts.
Lewis basicity towards an electron deficient carbon center is an
equally important issue.25h,i Therefore, we have also determined
the equilibrium constants for the reactions of azoles with benz-
hydrylium ions (eqn (2)).
(2)
While most of the azoles 1–3 react quantitatively with the
benzhydrylium tetrafluoroborates, some of the reactions proceed
incompletely. As benzhydrylium ions are colored and the resulting
adducts are colorless, the equilibrium constants can be determined
by UV-Vis spectroscopy. Assuming proportionality between the
absorbances and the concentrations of the benzhydrylium ions
(Lambert–Beer law), the equilibrium constants K for reaction (2)
can be expressed by the absorbances of the benzhydrylium ions
before (A0) and after (A) addition of the amines (eqn (3)).
Fig. 6 Relationship between rate and equilibrium constant◦s of the
reaction of (ind)2CH+ with different Lewis bases in CH3CN at 20 C. Data
from Tables 3 and 4 and ref. 25h and 28; log k for 1c was calculated from
N, s, and E.
From the rate (Table 3) and equilibrium constants (Table 4)
one can calculate activation free energies DGπ (using the Eyring
equation) and reaction free energies DG0 (-RT lnK) for the
reactions of the azoles 1–3 with benzhydrylium ions (Ar2CH+).
Substitution of these values into the Marcus equation (eqn
(3)
π
(4)) yields the intrinsic barriers DG0 , which are defined as the
activation free energies of processes with DG0 = 0.27
Comparison of the equilibrium constants in Table 4 shows
that 1-methylimidazole 1b is a 30 times stronger Lewis base than
1-methylbenzimidazole 2b and a 50–60 times stronger Lewis base
than 1-phenylimidazole 1c. Though a direct comparison of the
Lewis basicity of the benzotriazole 3b with the Lewis basicities of
imidazole 1b and benzimidazole 2b is not possible, it is obvious that
1-methylbenzotriazole 3b is a much weaker Lewis base because it
only gives adducts with less stabilized carbocations (E > -7).
Fig. 6 shows that the nucleophilicities (k) and Lewis basicities
(K) of different organocatalysts towards a carbon center do not
correlate with each other. Despite the fact that 1-methylimidazole
1b has a higher Lewis basicity than DABCO and Ph3P, it is
less nucleophilic. DMAP is a 100 times stronger Lewis base
than 1-methylimidazole 1b. This absence of a rate-equilibrium-
relationship indicates the presence of different intrinsic barriers.27
DGπ = DG0 + 0.5 DG0 + ((DG0)2/16DG0 )
(4)
π
π
In line with previous studies,19a,25g,h,29 Table 5 shows that for
π
reactions with a certain azole, the intrinsic barriers DG0 decrease
slightly with increasing reactivity of the benzhydrylium ions,
though this decrease is not steady. Comparison of the intrinsic
barriers referring to reactions with the same carbocations shows
that those for the reactions of the imidazoles 1b,c are similar and
Table 5 Activation energies DGπ, reaction free energies DG0, intrinsic
π
barriers DG0 (in kJ mol-1) and rate constants of the reverse reactions k←
for the reactions of benzhydrylium ions with azoles 1–3 in CH3CN at 20 ◦C
π
Azoles
Ar2CH+
DGπ
DG0
DG0
k←/s-1
1b
(lil)2CH+
64.1
59.0
56.7
60.7
58.2
55.7
64.4
61.8
59.4
56.9
55.1
53.1
48.7
46.4
32.2
30.0
27.7
52.4
-13.4
-21.0
-22.1
-12.7
-15.0
-20.7
-12.7
-13.5
-16.8
-22.7
-13.0
-24.6
-32.2
(-33.7)
(-16.2)
-17.9
-20.7
-18.0
70.6
69.1
67.3
66.9
65.5
65.6
70.6
68.4
67.5
67.8
61.4
64.8
63.8
(62.1)
(39.9)
38.4
37.3
61.1
0.10
(ind)2CH+
(thq)2CH+
(thq)2CH+
(pyr)2CH+
(dma)2CH+
(ind)2CH+
(thq)2CH+
(pyr)2CH+
(dma)2CH+
(mfa)2CH+
(lil)2CH+
0.034
0.055
0.52
0.56
0.15
0.11
0.23
0.16
0.040
4.5
0.086
0.023
(3 ¥ 10-2)
(1 ¥ 104)
1.79 ¥ 104
1.42 ¥ 104
1.7
Table 4 Equilibrium constants (K) for the reactions of the azoles 1-3 with
benzhydrylium ions in CH3CN at 20 ◦
C
1c
2b
Azoles
Ar2CH+
K/M-1
1b
(lil)2CH+
2.44 ¥ 102
2.42 ¥ 102
5.56 ¥ 103
8.69 ¥ 103
9.08 ¥ 101
1.83 ¥ 102
4.72 ¥ 102
4.99 ¥ 103
1.86 ¥ 102
2.60 ¥ 102
9.99 ¥ 102
1.11 ¥ 104
2.11 ¥ 102
8.54 ¥ 103
(jul)2CH+
(ind)2CH+
(thq)2CH+
(ind)2CH+
(thq)2CH+
(pyr)2CH+
(dma)2CH+
(ind)2CH+
(thq)2CH+
(pyr)2CH+
(dma)2CH+
(mfa)2CH+
(pfa)2CH+
3b
1c
2b
3b
DMAPa,b
(ind)2CH+
(thq)2CH+
(ind)2CH+
(thq)2CH+
(pyr)2CH+
(ind)2CH+
DABCOa,b
Ph3P
a DGπ, DG0, and k← values for DMAP and DABCO from ref. 25h; DG0
π
has been recalculated. b Values in parentheses were estimated in ref. 25h.
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1–2 kJ mol-1 lower than those for benzimidazole 2b. The reactions
involving 1b have intrinsic barriers which are 5–6 kJ mol-1 higher
than those for the corresponding reactions with DMAP because
electrophilic attack at the unsubstituted nitrogen is associated
with a significant structural reorganization, i.e. lengthening of
CN-double bond and shortening of the vicinal CN-bond.25h This
finding is in line with the principle of least motion which was
used by Hine to rationalize why imidazoles abstract protons
more slowly than pyridines of comparable basicity.30 From the
comparison of the reaction free energies DG0, it is clear that
imidazole 1b is a significantly stronger Lewis base than DABCO
(DDG0 = 5 kJ mol-1). It is the large reorganization energy for
the electrophilic attack at the imidazoles, which gives rise to the
high intrinsic barriers of these reactions and eventually leads to
the much lower nucleophilicities of imidazoles compared with
DABCO. The higher nucleophilicity of Ph3P compared with the
stronger Lewis base imidazole 1b can analogously be assigned to
the 8 kJ mol-1 difference of the intrinsic barriers.
Notes and references
1 (a) A. F. Pozharskii, A. T. Soldatenkov and A. R. Katritzky, Hetero-
cycles in Life and Society, Wiley, New York, 1997; (b) A. R. Katritzky
and A. F. Pozharskii, Handbook of Heterocyclic Chemistry, 2nd ed,
Pergamon, Oxford, 2000; (c) A. R. Katritzky, X. Lan, J. Z. Yang
and O. V. Denisko, Chem. Rev., 1998, 98, 409–548; (d) I. L. Kruse,
in Comprehensive Medicinal Chemistry, C. Hansch, P. G. Sammes,
J. B. Taylor, Eds, Pergamon Press: Oxford, England, 1990, vol. 2, pp
123–145; (e) F. Corelli, V. Summa, A. Brogi, E. Monteagudo and M.
Botta, J. Org. Chem., 1995, 60, 2008–2015; (f) M. C. Venuti, R. A.
Stephenson, R. Alvarez, J. J. Bruno and A. M. Strosberg, J. Med.
Chem., 1988, 31, 2136–2145; (g) M. Botta, F. Corelli, F. Gasparrini, F.
Messina and C. Mugnaini, J. Org. Chem., 2000, 65, 4736–4739.
2 For arylation reactions see: (a) I. P. Beletskaya and A. V. Cheprakov,
Coord. Chem. Rev., 2004, 248, 2337–2364; (b) S. V. Ley and A. W.
Thomas, Angew. Chem., Int. Ed., 2003, 42, 5400–5449; (c) R. A. Altman
and S. L. Buchwald, Org. Lett., 2006, 8, 2779–2782; (d) R. Jitchati, A. S.
Batsanov and M. R. Bryce, Tetrahedron, 2009, 65, 855–861.
3 For allylation reactions see: L. M. Stanley and J. F. Hartwig, J. Am.
Chem. Soc., 2009, 131, 8971–8983.
4 (a) P. Dine´r, M. Nielsen, M. Marigo and K. A. Jørgensen, Angew.
Chem., Int. Ed., 2007, 46, 1983–1987; (b) U. Uria, J. L. Vicario, D.
Badia and L. Carrillo, Chem. Commun., 2007, 2509–2511; (c) B. R.
Buckley, Annu. Rep. Prog. Chem., Sect. B, 2008, 104, 88–105; (d) D.
Enders, C. Wang and J. X. Liebich, Chem.–Eur. J., 2009, 15, 11058–
11076.
5 M. Gandelman and E. N. Jacobsen, Angew. Chem., Int. Ed., 2005, 44,
2393–2397.
6 J. Wang, H. Li, L. Zu and W. Wang, Org. Lett., 2006, 8, 1391–1394.
7 J. Li, X. Wang and Y. Zhang, Tetrahedron Lett., 2005, 46, 5233–5237.
8 F. Schneider, Angew. Chem., Int. Ed. Engl., 1978, 17, 583–592 and the
references therein.
Combination of the rate constants in Table 3 with the equi-
librium constants in Table 4 yields the rate constants for the
reverse reactions (k←) which reflect the leaving group abilities of
these amines (last column, Table 5).31 While the leaving group
ability of 1-methylimidazole 1b is 3–4 times smaller than that of
1-methylbenzimidazole 2b, it is comparable to that of DMAP and
3 ¥ 105 times smaller than that of DABCO.
9 Books: (a) P. I. Dalko, Enantioselective organocatalysis, Wiley-VCH,
Weinheim, 2007; (b) A. Berkessel, H. Gro¨ger, Asymmetric Organocatal-
ysis, Wiley-VCH, Weinheim, 2005.
Conclusion
10 (a) M. L. Bender and B. W. Turnquest, J. Am. Chem. Soc., 1957, 79,
1652–1655; (b) W. P. Jencks and J. Carriuolo, J. Biol. Chem., 1959,
234, 1272–1279; (c) W. P. Jencks and J. Carriuolo, J. Biol. Chem., 1959,
234, 1280–1285; (d) R. Wolfenden and W. P. Jencks, J. Am. Chem.
Soc., 1961, 83, 4390–4393; (e) J. F. Kirsch and W. P. Jencks, J. Am.
Chem. Soc., 1964, 86, 833–837; (f) K. A. Connors and N. K. Pandit,
Anal. Chem., 1978, 50, 1542–1545; (g) R. L. Kogan and T. H. Fife,
Biochemistry, 1984, 23, 2983–2989; (h) S. J. Miller, Acc. Chem. Res.,
2004, 37, 601–610; (i) B.-K. Liu, Q. Wu, J.-M. Xu and X.-F. Lin, Chem.
Commun., 2007, 295–297; (j) K. Ishihara, Y. Kosugi and M. Akakura,
J. Am. Chem. Soc., 2004, 126, 12212–12213; (k) K. Martinek, A. P.
Osipov, A. K. Yatsimirski and I. V. Berezin, Tetrahedron, 1975, 31, 709–
718.
11 (a) D. Basavaiah, A. J. Rao and T. Satyanarayana, Chem. Rev., 2003,
103, 811–892; (b) S. Luo, B. Zhang, J. He, A. Janczuk, P. G. Wang
and J.-P. Cheng, Tetrahedron Lett., 2002, 43, 7369–7371; (c) R. Gatri
and M. M. E. Gaied, Tetrahedron Lett., 2002, 43, 7835–7836; (d) J. E.
Imbriglio, M. M. Vasbinder and S. J. Miller, Org. Lett., 2003, 5, 3741–
3743; (e) S. Luo, X. Mi, P. G. Wang and J.-P. Cheng, Tetrahedron Lett.,
2004, 45, 5171–5174; (f) S. Luo, P. G. Wang and J.-P. Cheng, J. Org.
Chem., 2004, 69, 555–558; (g) C. E. Aroyan, M. M. Vasbinder and S. J.
Miller, Org. Lett., 2005, 7, 3849–3851; (h) S.-H. Chen, B.-C. Hong,
C.-F. Su and S. Sarshar, Tetrahedron Lett., 2005, 46, 8899–8903; (i) N.
Utsumi, H. Zhang, F. Tanaka and C. F. Barbas III, Angew. Chem., Int.
Ed., 2007, 46, 1878–1880.
The rate constants of the reactions of imidazoles and benzim-
idazoles with benzhydrylium ions follow the linear free energy
relationship (eqn (1)). It is, therefore, possible to determine the
nucleophilicity parameters N for these azoles and compare them
with those of other amines and phosphines. The poor correlation
between N and pKaH shows that Brønsted basicities cannot be used
for predicting relative nucleophilicities. Because pKaH values refer
to relative basicities towards the proton, while the nucleophilicity
parameters N refer to the rates of reactions with an electrophilic
carbon center, the origin of the poor Brønsted correlation has
previously been not clear.
By using benzhydrylium ions of variable reactivity as reaction
partners, it was possible to find systems for which rate and
equilibrium constants could be determined. Substitution of these
data into the Marcus equation rendered the corresponding
π
intrinsic barriers DG0 which decreased in the order imidazoles >
pyridines ꢀ 1-azabicyclooctane. As a result, imidazoles are weaker
nucleophiles than pyridines, and much weaker nucleophiles than
1-azabicyclooctanes of comparable Lewis and Brønsted basicity.
Because rate and equilibrium constants refer to reactions with the
same substrate, the low nucleophilicities of imidazoles can now
unambiguously be assigned to the high reorganization energies
required for their reactions with electrophiles.
12 (a) I. Deb, M. Dadwal, S. M. Mobin and I. N. N. Namboothiri, Org.
Lett., 2006, 8, 1201–1204; (b) M. Dadwal, S. M. Mobin and I. N. N.
Namboothiri, Org. Biomol. Chem., 2006, 4, 2525–2528.
13 (a) X.-G. Liu and M. Shi, Eur. J. Org. Chem., 2008, 6168–6174; See
also (b) M. Adib, B. Mohammadi, M. Mahdavi, A. Abbasi and M. R.
Kesheh, Synlett, 2007, 2497–2500.
14 C. C. Palsuledesai, S. Murru, S. K. Sahoo and B. K. Patel, Org. Lett.,
2009, 11, 3382–3385.
Acknowledgements
15 For more examples of nucleophilic behaviour of N-heterocycles see:
(a) R. K. Howe, J. Org. Chem., 1969, 34, 2983–2985; (b) M. J. Alves,
A. G. Fortes and L. F. Goncalves, Tetrahedron Lett., 2003, 44, 6277–
6279; (c) D. Lin, J. Zhang and L. M. Sayre, J. Org. Chem., 2007, 72,
9471–9480; (d) W. Zhang, L. Zhu and J. Hu, Tetrahedron, 2007, 63,
10569–10575; (e) M. D. S. Maria, R. M. Claramunt, M. A. Garcia and
We thank the Deutsche Forschungsgemeinschaft (Ma673/21-3)
and the Fonds der Chemischen Industrie for support of this work.
Valuable suggestions by Dr Armin R. Ofial and Martin Breugst
are gratefully acknowledged.
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J. Elguero, Tetrahedron, 2007, 63, 3737–3744; (f) W. Zhang, F. Wang
and J. Hu, Org. Lett., 2009, 11, 2109–2112; (g) K. F. Ansari and C. Lal,
Eur. J. Med. Chem., 2009, 44, 4028–4033.
23 C. Reichardt, Solvents and Solvent Effects in Organic Chemistry, 3rd
ed., Wiley-VCH, Weinheim, 2003.
24 Rate constant for the reaction of 1a with (pyr)2CH+ in MeOH was
calculated using eqn (1) with the published N = 10.41 and s = 0.69 of
imidazole in MeOH containing 9 vol% CH3CN, see: T. B. Phan, M.
Breugst and H. Mayr, Angew. Chem., Int. Ed., 2006, 45, 3869–3874.
25 (a) For silyl enol ethers and ketene acetals see: ref. 17a; (b) For indoles
see: S. Lakhdar, M. Westermaier, F. Terrier, R. Goumont, T. Boubaker,
A. R. Ofial and H. Mayr, J. Org. Chem., 2006, 71, 9088–9095; (c) For
pyridines see: ref. 19a; (d) For pyrroles see: T. A. Nigst, M. Westermaier,
A. R. Ofial and H. Mayr, Eur. J. Org. Chem., 2008, 2369–2374; (e) For
carbanions see: R. Lucius, R. Loos and H. Mayr, Angew. Chem., Int.
Ed., 2002, 41, 91–95; (f) For enamines see: B. Kempf, N. Hampel, A. R.
Ofial and H. Mayr, Chem.–Eur. J., 2003, 9, 2209–2218; (g) For Ph3P
see: B. Kempf and H. Mayr, Chem.–Eur. J., 2005, 11, 917–927; (h) For
DABCO see: M. Baidya, S. Kobayashi, F. Brotzel, U. Schmidhammer,
E. Riedle and H. Mayr, Angew. Chem., Int. Ed., 2007, 46, 6176–6179;
(i) For DBU see: M. Baidya and H. Mayr, Chem. Commun., 2008,
1792–1794.
16 (a) C. K. M. Heo and J. W. Bunting, J. Chem. Soc., Perkin Trans. 2,
1994, 2279–2290; (b) A. A. Matveev, A. N. Vdovichenko, A. F. Popov,
L. M. Kapkan, A. Y. Chervinskii and V. N. Matvienko, Russ. J. Org.
Chem., 1995, 31, 1646–1649.
17 (a) H. Mayr, T. Bug, M. F. Gotta, N. Hering, B. Irrgang, B. Janker, B.
Kempf, R. Loos, A. R. Ofial, G. Remennikov and H. Schimmel, J. Am.
Chem. Soc., 2001, 123, 9500–9512; (b) H. Mayr, B. Kempf and A. R.
Ofial, Acc. Chem. Res., 2003, 36, 66–77; (c) H. Mayr and A. R. Ofial,
J. Phys. Org. Chem., 2008, 21, 584–595; (d) H. Mayr and A. R. Ofial,
Pure Appl. Chem., 2005, 77, 1807–1821.
18 (a) A. R. Katritzky and B. Yang, J. Heterocycl. Chem., 1996, 33, 607–
610; (b) Also see ref. 1c.
19 For the contribution of OH- in reactions of amines in aqueous solution
see: (a) F. Brotzel, B. Kempf, T. Singer, H. Zipse and H. Mayr, Chem.–
Eur. J., 2007, 13, 336–345; (b) F. Brotzel, Y. C. Chu and H. Mayr, J. Org.
Chem., 2007, 72, 3679–3688.
20 pKaH values (a) For 1a see: V. P. Vasil’ev, N. K. Grechina and G. A.
Zaitseva, Zh. Obshch. Khim., 1983, 53, 199–203; (b) For 1b see: M. L.
Bender and B. W. Turnquest, J. Am. Chem. Soc., 1957, 79, 1656–1662;
(c) For 1d see: K. I. Skorey, V. Somayaji and R. S. Brown, J. Am. Chem.
Soc., 1989, 111, 1445–1452; (d) For 1e see: J. P. Street, K. I. Skorey,
R. S. Brown and R. G. Ball, J. Am. Chem. Soc., 1985, 107, 7669–7679;
(e) For 1f see: Y. Nozaki, F. R. N. Gurd, R. F. Chen and J. T. Edsall,
J. Am. Chem. Soc., 1957, 79, 2123–2129.
26 For comprehensive database of reactivity parameters E, N, and s:
www.cup.lmu.de/oc/mayr/DBintro.html.
27 (a) R. A. Marcus, J. Phys. Chem., 1968, 72, 891–899; (b) W. J. Albery,
Annu. Rev. Phys. Chem., 1980, 31, 227–263.
28 k = 2.79 ¥ 103 s-1 and K = 1.60 ¥ 103 M-1s-1 for the reaction of Ph3P with
(ind)2CH+ in CH3CN at 20 ◦C; M. Baidya and H. Mayr, unpublished.
29 H. F. Schaller, A. A. Tishkov, X. Feng and H. Mayr, J. Am. Chem. Soc.,
2008, 130, 3012–3022.
21 S. Minegishi, S. Kobayashi and H. Mayr, J. Am. Chem. Soc., 2004, 126,
30 J. Hine, J. Org. Chem., 1966, 31, 1236–1244.
5174–5181.
31 Benzotriazole as a leaving group see: (a) J. P. Richard, R. W. Nagorski,
S. Rudich, T. L. Amyes, A. R. Katritzky and A. P. Wells, J. Org. Chem.,
1995, 60, 5989–5991; (b) A. R. Katritzky and D. Toader, J. Org. Chem.,
1997, 62, 4137–4141; (c) A. R. Katritzky, L. Khelashvili, K. N. B. Le,
P. P. Mohapatra and P. J. Steel, J. Org. Chem., 2007, 72, 5805–5808;
(d) Also see ref. 1c.
22 pKaH values (a) For 2a see: H. F. W. Taylor, J. Chem. Soc., 1948, 765–
766; (b) For 2b-g see: T. M. Davies, P. Mamalis, V. Petrow and B.
Sturgeon, J. Pharm. Pharmacol., 1951, 3, 420–430; (c) For 3a see: H.
Wang, C. Burda, G. Persy and J. Wirz, J. Am. Chem. Soc., 2000, 122,
5849–5855.
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The Royal Society of Chemistry 2010
Org. Biomol. Chem., 2010, 8, 1929–1935 | 1935
©