Steric effects in the hydrolysis reactions of N-acylimidazoles. Effect of aryl substitution in the leaving group

Article abstract of DOI:10.1021/jo960508d

The kinetic and mechanistic effects of aryl substitution in the leaving group have been determined in the hydrolysis reactions of N-acylimidazoles. N-acyl derivatives of 2,4,5-triphenylimidazole hydrolyze rapidly in OH^- and water reactions. The latter reactions are pH independent from pH 4 to 9. The N-acetyl derivative hydrolyzes with rate constants similar to those of N-acetylimidazole in the OH^- reaction but 40-fold larger in the pH-independent reaction. N-(trimethylacetyl)-2,4,5-triphenylimidazole hydrolyzes at 15°C with k(OH), the second-order rate we constant for the OH^-reaction, 26-fold larger than the rate constant for alkaline hydrolysis of the corresponding N-acetyl derivative, even though steric hindrance to approach of a nucleophile is extreme in the former reaction. The pH-independent reaction of the N-trimethylacetyl compound is 4-fold faster than that of the N-acetyl derivative and is characterized by a D₂O solvent isotope effect (κ(H₂O)/κ(D₂O)) of 2.0. A phenyl substituent in the 2-position of the imidazole ring exerts a small rate-retarding effect in the hydrolysis reactions. N-(trimethylacetyl)-4,5-diphenylimidazole hydrolyzes 10- and 55-fold faster in the OH^- and water reactions, respectively, at 15°C, than N-(trimethylacetyl)benzimidazole at 30°C, although the pK(a) of the leaving group is identical in the two cases. The additive nature of the steric rate-accelerating effects in the acyl group and the leaving group indicates an effect on the ease of C-N bond breaking; the hydrolysis reactions very likely proceed in a concerted manner without the formation of a stable tetrahedral intermediate.

Full text of DOI:10.1021/jo960508d

2872
J . Org. Chem. 1997, 62, 2872-2876
Ster ic Effects in th e Hyd r olysis Rea ction s of N-Acylim id a zoles.
Effect of Ar yl Su bstitu tion in th e Lea vin g Gr ou p
J . P. Lee, Ramesh Bembi, and Thomas H. Fife*
Department of Biochemistry, University of Southern California, Los Angeles, California 90033
Received March 15, 1996X
The kinetic and mechanistic effects of aryl substitution in the leaving group have been determined
in the hydrolysis reactions of N-acylimidazoles. N-Acyl derivatives of 2,4,5-triphenylimidazole
hydrolyze rapidly in OH- and water reactions. The latter reactions are pH independent from pH
4 to 9. The N-acetyl derivative hydrolyzes with rate constants similar to those of N-acetylimidazole
in the OH- reaction but 40-fold larger in the pH-independent reaction. N-(trimethylacetyl)-2,4,5-
triphenylimidazole hydrolyzes at 15 °C with kOH, the second-order rate constant for the OH- reaction,
26-fold larger than the rate constant for alkaline hydrolysis of the corresponding N-acetyl derivative,
even though steric hindrance to approach of a nucleophile is extreme in the former reaction. The
pH-independent reaction of the N-trimethylacetyl compound is 4-fold faster than that of the N-acetyl
derivative and is characterized by a D2O solvent isotope effect (kH O/kD O) of 2.0. A phenyl substituent
2
2
in the 2-position of the imidazole ring exerts a small rate-retarding effect in the hydrolysis reactions.
N-(Trimethylacetyl)-4,5-diphenylimidazole hydrolyzes 10- and 55-fold faster in the OH- and water
reactions, respectively, at 15 °C, than N-(trimethylacetyl)benzimidazole at 30 °C, although the pKa
of the leaving group is identical in the two cases. The additive nature of the steric rate-accelerating
effects in the acyl group and the leaving group indicates an effect on the ease of C-N bond breaking;
the hydrolysis reactions very likely proceed in a concerted manner without the formation of a stable
tetrahedral intermediate.
The hydrolysis reactions of N-acylimidazoles and N-
The bimolecular reactions of N-acylimidazoles provide
highly unusual examples of steric acceleration due to the
increased size of the acyl group. Staab3 found that
N-(trimethylacetyl)imidazole hydrolyzes faster than N-
acetylimidazole in conductivity water. The abnormal
steric effect also extends to the OH-, conjugate acid, and
imidazole-catalyzed reactions.6-8 In those reactions the
rate constants are approximately 2-8-fold larger for
hydrolysis of the trimethylacetyl derivative than the
acetyl. In contrast, a normal steric effect in a bimolecular
reaction produced by a trimethylacetyl acyl group should
give a rate retardation of 50-100-fold, as exemplified by
the imidazole and OH- nucleophilic reactions of p-
nitrophenyl esters.6 The Taft steric effects constant Es
for trimethylacetyl is -1.54, whereas that for acetyl is
zero.18
Electronic effects of substituents in the imidazole
leaving group have been determined in the OH- and
water reactions,9 but steric effects in the leaving group
have not previously been investigated. We have there-
fore in the present work studied the hydrolysis reactions
of the N-acyl derivatives of 2,4,5-triphenylimidazole, I
and II, with which steric crowding of the carbonyl by the
leaving group is extreme. For comparison purposes
N-acylimidazoles of 4,5-diphenylimidazole III and IV,
4(5)-phenylimidazole V, and 2-phenylimidazole VI were
also studied.
acylbenzimidazoles have been actively studied.1-12 These
compounds are amides but possess structural features
that give rise to exceptional hydrolytic reactivity. The
second-order rate constant kOH for alkaline hydrolysis of
N-acetylimidazole is 316 M-1 s-1 at 25 °C,4 even though
the pKa of the imidazole leaving group is 14.5.13 N-
Acylimidazoles can be considered model amides that
illustrate the effect of restricted resonance with the
carbonyl group in hydrolytic reactions.5 N-Acylimida-
zoles have been observed as intermediates in bimolecular
and intramolecular nucleophilic reactions of imidazole
with esters14-17 and are possible intermediates in enzy-
matic acyl transfer reactions.2 Mechanistic understand-
ing of the reactions of N-acylimidazoles is, therefore, of
both chemical and biochemical significance.
X Abstract published in Advance ACS Abstracts, December 1, 1996.
(1) Gerngross, O. Chem. Ber. 1913, 46, 1908.
(2) (a) J encks, W. P. Catalysis in Chemistry and Enzymology;
McGraw-Hill; New York, 1969. (b) Bruice, T. C.; Benkovic, S. Bioor-
ganic Mechanisms; W. A. Benjamin: New York, 1966.
(3) Staab, H. A. Chem. Ber. 1956, 89, 1927, 2088; 1957, 90, 1320.
(4) J encks, W. P.; Carriuolo, J . J . Biol. Chem. 1959, 234, 1272, 1280.
(5) Fife, T. H. Acc. Chem. Res. 1993, 26, 325.
(6) Fife, T. H. J . Am. Chem. Soc. 1965, 87, 4597.
(7) Fee, J . A.; Fife, T. H. J . Org. Chem. 1966, 31, 2343.
(8) Fee, J . A.; Fife, T. H. J . Phys. Chem. 1966, 70, 3268.
(9) Fife, T. H.; Natarajan, R.; Werner, M. H. J . Org. Chem. 1987,
52, 740.
(10) Hogg, J . L.; Phillips, M. K.; J ergens, D. E. J . Org. Chem. 1977,
42, 2459.
(11) Kogan, R. L.; Fife, T. H. Biochemistry 1984, 23, 2983.
(12) Fife, T. H.; Przystas, T. J . J . Am. Chem. Soc. 1986, 108, 4631.
(13) Walba, H.; Isensee, R. W. J . Org. Chem. 1961, 26, 2789.
(14) Bender, M. L.; Turnquest, B. W. J . Am. Chem. Soc. 1957, 79,
1656,. Bruice, T. C.; Schmir, G. L. J . Am. Chem. Soc. 1957, 79, 1663.
(15) Bruice, T. C.; Sturtevant, J . M. J . Am. Chem. Soc. 1959, 81,
2860.
(16) Bruice, T. C. J . Am. Chem. Soc. 1959, 81, 5444.
(17) (a) Fife, T. H.; Bambery, R. J .; DeMark, B. R. J . Am. Chem.
Soc. 1978, 100, 5500. (b) Fife, T. H.; DeMark, B. R. J . Am. Chem.
Soc. 1979, 101, 7379.
a
O
C
N
N
R
b
c
I: R = CH3; a = phenyl; b = phenyl; c = phenyl
II: R = C(CH3)3; a = phenyl; b = phenyl; c = phenyl
III: R = CH3; a = H; b = phenyl; c = phenyl
IV: R = C(CH3)3; a = H; b = phenyl; c = phenyl
V: R = CH3; a = H; b = phenyl; c = H
(18) Taft, R. W., J r. In Steric Effects in Organic Chemistry; Newman,
M. S., Ed.; Wiley: New York, 1956; Chapter 13, p 556.
VI: R = CH2CH2phenyl; a = phenyl; b = H; c = H
S0022-3263(96)00508-7 CCC: $14.00 © 1997 American Chemical Society

Steric Effects in the Hydrolysis Reactions of N-Acylimidazoles
J . Org. Chem., Vol. 62, No. 9, 1997 2873
Exp er im en ta l Section
Ma ter ia ls. N-Acetyl-2,4,5-triphenylimidazole (I) was pre-
pared by mixing 2,4,5-triphenylimidazole (1.48 g, 0.005 mol)
and acetic anhydride (0.51 g, 0.005 mol) in 100 mL of ethyl
acetate and adding sodium methoxide (0.27 g). The mixture
was stirred at room temperature for 24 h. The solvent was
then removed by rotary evaporation. The residue was taken
up in 150 mL of dry ether, stirred for 30 min, and then filtered.
The ether was removed from the filtrate by rotary evaporation.
After recrystallization from an ether-hexane mixture, the
compound melted at 275 °C. Anal. Calcd for C23H18N2O; C,
81.62; H, 5.36; N, 8.28. Found: C, 81.49; H, 5.48; N, 8.18.
The N-acylimidazole derivatives II, III, and IV were pre-
pared by the same general method as that for I. After
recrystallization from an ether-hexane mixture, II melted at
272 °C. Anal. Calcd for C26H24N2O: C, 82.06; H, 6.36; N, 7.37.
Found: C, 82.19; H, 6.45; N, 7.21. After recrystallization from
an ether-hexane mixture, III melted at 182 °C. Anal. Calcd
for C17H14N2O: C, 77.86; H, 5.34; N, 10.69. Found: C, 77.99;
H, 5.18; N, 10.73. After recrystallization from ether-hexane,
IV melted at 150 °C. Anal. Calcd for C20H20N2O: C, 78.90;
H, 6.63; N, 9.21. Found: C, 78.76; H, 6.70; N, 9.09.
F igu r e 1. Plot of log kobsd vs pH at 25 °C and µ ) 0.5 M (with
KCl) for hydrolysis of N-acetyl-2,4,5-triphenylimidazole.
In the preparation of N-acetyl-4(5)-phenylimidazole (V),
4(5)-phenylimidazole (2.88 g, 0.02 mol) was suspended in 100
mL of ethyl acetate containing pyridine (1.58 g). The mixture
was stirred for 30 min, and 1.6 g of acetyl chloride was added.
The mixture was stirred overnight and then filtered. The
filtrate was transferred to a 200 mL round bottomed flask,
and the solvent was removed by rotary evaporation. The
residue was recrystallized from an ethyl acetate, cyclohexane
mixture and then melted at 107 °C. Anal. Calcd for
C11H10N2O: C, 70.95; H, 5.41; N, 15.05. Found: C, 71.21; H,
5.56; N, 14.86. Compound III was also prepared by this
general method.
F igu r e 2. Plots of log kobsd vs pH at 15 °C and µ ) 0.5 M
(with KCl) for hydrolysis of N-acetyl-2,4,5-triphenylimidazole
(k), N-(trimethylacetyl)-2,4,5-triphenylimidazole (b), and N-(tri-
methylacetyl)-4,5-diphenylimidazole (.).
Compound VI was prepared by adding â-phenylpropionyl
chloride in tetrahydrofuran (THF) dropwise to a solution of
2-equiv of 2-phenylimidazole in THF. The mixture was
refluxed for 48 h. The mixture was then filtered, and the
solvent was removed by rotary evaporation. The residual oil
was vacuum distilled and boiled at 190-192 °C (0.01 mm),
n22D ) 1.6121. Anal. Calcd for C18H16N2O: C, 78.24; H, 5.84;
N, 10.14. Found: C, 78.15; H, 6.00; N, 10.08.
Acetonitrile was Eastman-Kodak Spectro-Grade. All other
chemicals were reagent grade. The water employed was
deionized and distilled. Imidazole was obtained from Aldrich
and was sublimed prior to use.
Kin etic Meth od s. The rates of hydrolysis of compounds
I-VI in H2O were measured with a Pye-Unicam SP8-100 or
Beckman-25 recording spectrophotometer, by following the
spectral changes at 290-300 nm. Buffer solutions were
maintained at a constant ionic strength of 0.5 M with KCl. A
typical kinetic run was initiated by injecting 20-30 µL of a 2
× 10-2 M stock solution of the substrate in acetonitrile into 3
mL of buffer maintained at the appropriate temperature. The
buffers employed were formate, acetate, cacodylate, imidazole,
Tris, N-ethylmorpholine, and carbonate. The hydrolysis reac-
tions are catalyzed by buffer. Therefore, rate constants were
obtained by extrapolation to zero buffer concentration.
Ta ble 1. Ra te Con sta n ts for th e Hyd r olysis of
N-Acylim id a zoles w ith µ ) 0.5 M w ith KCl
kOH
compound
(M-1 s-1
)
k0 (s-1
)
T (°C)
I
180
250
316
4720
533
1580
204
6400
612
850
1.1 × 10-3
3.5 × 10-3
8.3 × 10-5
4.0 × 10-3
1.1 × 10-3
1.5 × 10-3
3.0 × 10-5
9.3 × 10-3
1.7 × 10-4
5.6 × 10-4
15
25
25
15
30
15
30
15
30
30
30
N-acetylimidazolea
II
N-(trimethylacetyl)imidazoleb
III
N-acetylbenzimidazolec
IV
N-(trimethylacetyl)benzimidazolec
V
VI
290
a
b
Reference 4. Reference 6. c Reference 9.
3.1 program; MM2 and MM3 failed. The energy minimized
structures were determined in the absence of solvent.
Reaction mixture pH values were measured with a Radi-
ometer type PHM 22r or a Beckman 3500 digital pH meter.
The values of pD were calculated by employing the glass
electrode correction equation of Fife and Bruice.19 In calculat-
ing second-order rate constants for the reaction with OH-, the
ion product of water (Kw) was taken to be 4.47 × 10-15 at 15
°C, 1.0 × 10-14 at 25 °C, and 1.47 × 10-14 at 30 °C.
Resu lts
Figure 1 is a plot of log kobsd at zero buffer vs pH for
hydrolysis of N-acetyl-2,4,5-triphenylimidazole in H2O at
25 °C, µ ) 0.5 M with KCl. A hydroxide ion promoted
reaction is observed at pH > 9; kOH, the second-order rate
constant, is 250 M-1 s-1. At pH < 9 the reaction is pH
independent (k0 ) 3.5 × 10-3 s-1). The rate constants
for the pH-independent reaction were also obtained at
15 and 30 °C.
Molecular modeling of the N-acylimidazoles was carried out
with a Silicon Graphics Indigo 2 workstation. The software
programs that were employed were Spartan 3.1 from Wave-
function, Inc., and Quanta 4.0 - Charmm from Molecular
Simulations. With the Quanta-Charmm program, energy
minimization was by the method of steepest descent and by
the method of Newton-Raphson until a constant value was
obtained. A Sybyl minimizer was employed with the Spartan
In Figure 2 the plot is shown of log kobsd vs pH for
hydrolysis of I, II, and IV at 15 °C (µ ) 0.5 M with KCl).
Rate constants for these reactions are given in Table 1.
The D2O solvent isotope effect (kH O/kD O) for the pH-
2
2
(19) Fife, T. H.; Bruice, T. C. J . Phys. Chem. 1961, 65, 1079.
independent reaction is 2.0 (kD O ) 5.4 × 10-4 s-1) with
2

2874 J . Org. Chem., Vol. 62, No. 9, 1997
Lee et al.
O–
C
O
C
R
N
N
R
N
N
(2)
branching in the hydrolysis of N-acylimidazoles.5-7 Pro-
tonation of N-3 would greatly diminish such a resonance
effect (eq 3),but the order of reactivity for a large series
O–
C
O
C
R
HN
N
R
HN
N
(3)
of N-acylimidazole conjugate acids is the same as in the
OH- reaction. The differences in the magnitudes of the
rate constants for the compounds in the series are also
nearly the same in the two reactions.7 N-Acetyl-N′-
methylimidazole is a good model for reactions of the
protonated N-acetylimidazole,20 which indicates that in
the conjugate acid the proton is on N-3.
An early transition state in which there is little bond
making with a nucleophile would be consistent with the
absence of large rate-retarding steric effects in the acyl
group of N-acylimidazoles.5-7 An early transition state
could not explain a rate-enhancing effect of increased acyl
group branching. However, the ease of C-N bond
breaking could be increased greatly by the relief of steric
strain. The observed steric effects are, therefore, in
accord with a transition state that involves C-N bond
breaking.6
Triphenyl substitution in the imidazole leaving group
has a large accelerating effect on the pH-independent
water reaction. N-Acetyl-2,4,5-triphenylimidazole (I) at
25 °C has a kOH that is similar to that for hydrolysis of
N-acetylimidazole. The water reaction, on the other
hand, is enhanced 40-fold by the triphenyl substitution,
which results in pH independence of the hydrolysis
reaction from at least pH 4 to 9. N-(Trimethylacetyl)-
2,4,5-triphenylimidazole (II) hydrolyzes 26-fold faster
than the corresponding acetyl derivative (I) in the
hydroxide ion reaction and 4-fold faster in the water
reaction, even though steric hindrance to approach of a
nucleophile at the carbonyl is extreme. Likewise, II
hydrolyzes 9-fold and 4-fold faster, respectively, in the
two reactions at 15 °C than N-(trimethylacetyl)imidazole
does at 30 °C. The pKa of the triphenylimidazole leaving
group is less than that of imidazole,21 but the steric bulk
due to the phenyl group substitution is large.
A phenyl group in the 2-position of the imidazole ring
exerts only a small rate-retarding steric effect in the
hydrolysis reactions; VI has a kOH that is 3-fold less than
that of the corresponding imidazole derivative. Accord-
ingly, N-(trimethylacetyl)-4,5-diphenylimidazole (IV) hy-
drolyzes 2-fold faster than the 2,4,5-triphenyl derivative
(II) in the water reaction and 4-6-fold faster than III in
the OH- and water reactions. Thus, IV is the most
reactive N-acylimidazole that has been investigated
kinetically.
F igu r e 3. Plot of kobsd for hydrolysis of N-(trimethylacetyl)-
2,4,5-triphenylimidazole at 15 °C (µ ) 0.5 M) vs the total
concentration of imidazole (B + BH+).
Ta ble 2. Secon d -Or d er Ra te Con sta n ts for th e
Ba se-Ca ta lyzed Rea ction s of
N-Acetyl-2,4,5-tr ip h en ylim id a zole in H2O a t 25 °C, µ ) 0.5
M w ith KCl
basea
imidazole
pKa
kB (M-1 s-1
)
7.05
8.10
7.80
0.031
0.04
0.05
Tris
N-ethylmorpholine
a
Total buffer concentration was varied from 0.02 to 0.4 M at
constant pH.
I, 2.0 (kD O ) 2.0 × 10-3 s-1) with II, and 2.1 (kD O ) 4.5
2
2
× 10-3 s-1) with IV.
N-Acetyl-4(5)-phenylimidazole (V) hydrolyzes at 30 °C
with kOH ) 850 M-1 s-1 and k0 ) 5.6 × 10-4 s-1. These
constants are less than those for III, even though the
pKa values for the substituted imidazole leaving groups
are similar,13 and there is less steric hindrance to
approach of a nucleophile with V.
The hydrolysis of VI at 30 °C proceeds with kOH ) 2.9
× 102 M-1 s-1, which is 3.0-fold less than the kOH for
hydrolysis of N-(â-phenylpropionyl)imidazole at 30 °C (8.6
× 102 M-1 s-1).9
The hydrolysis reactions of I-VI are markedly cata-
lyzed by the base species of the buffer. Figure 3 is a plot
of kobsd for hydrolysis of II at 15 °C vs the concentration
of total imidazole buffer (Im + ImH+). The second-order
rate constant kIm is 0.10 M-1 s-1. There is no evidence
for a general acid catalyzed reaction. Second-order rate
constants for the base-catalyzed reactions of I are given
in Table 2.
Discu ssion
The observed rate constants for hydrolysis of N-
acylimidazoles in H2O follow eq 1, where Ka is the
dissociation constant of the conjugate acid (the pKa of
N-acetylimidazolium ion is 3.6).4 Thus, there is a reaction
kobsd
)
aH
Ka
Molecular modeling reveals that in the energy-mini-
mized structures of the 2,4,5- and 4,5-phenyl-substituted
N-acylimidazoles the phenyl substituents cannot be
coplanar with the imidazole ring; in a coplanar system
there is direct steric interaction of the ortho hydrogens
of the 4- and 5-phenyl groups. Therefore, the phenyl
groups are each twisted out of the plane of the imidazole
k1
+ [k0 + kOH(Kw/aH)]
(1)
[
]
[
]
(Ka + aH)
(Ka + aH)
of the conjugate acid and also pH-independent and OH-
reactions of the neutral species.
Resonance involving N-1 and the carbonyl group (eq
2) will deactivate the carbonyl towards attack of a
nucleophile by reducing the partial positive charge on
carbon. Steric inhibition of this resonance is clearly not
responsible for the rate-enhancing effect of acyl group
(20) Wolfenden, R.; J encks, W. P. J . Am. Chem. Soc. 1961, 83, 4390.
(21) The pKa values for 2,4-diphenylimidazole and 4,5-diphenylimi-
dazole are 12.53 and 12.80, respectively.13

Steric Effects in the Hydrolysis Reactions of N-Acylimidazoles
J . Org. Chem., Vol. 62, No. 9, 1997 2875
ring so that the alignment is propeller like, with nearly
an edge to face alignment of the rings in the 4- and
5-positions. The steric interactions with the acyl group
are thereby increased and become pronounced with bulky
acyl groups (trimethylacetyl). The carbonyl group of the
acyl derivatives abuts the face of the phenyl group in the
2- or 5-position (VII). Steric distortion of an amide has
of eq 4 will place partial negative charge on N-3,25 which
O
C
O
C
(4)
N
N
R
–N
N
R
will promote hydrogen bonding of a water molecule (IX).26
O
δ+
δ–
N
N
C
R
H
H
O
C
O
IX
N
R
N
The structuring of solvent could be further enhanced by
a large hydrocarbon residue in the acyl group.8 Steric
effects are normal in the aminolysis reactions of N-
acylimidazoles in tetrahydrofuran,3 which suggests that
the solvent is important in determining the order of
reactivity.
The pH-independent reaction of I can be considered
analogous to that of N-acetylbenzimidazole9 and N-
acetylimidazole20,27 in which proton transfer from water
to N-3 is concerted with nucleophilic attack at the
carbonyl carbon and C-N bond breaking (X). A similar
VII
been found to give rise to enhanced rates of hydroly-
sis,22,23 and that is a possible explanation for the rapid
hydrolysis of the 4,5-diphenylimidazole derivatives III
and IV.24
With benzimidazole derivatives the increased reactivity
of the trimethylacetyl acyl group compared to acetyl is
maintained,9 but the rate constants for both the OH- and
water-promoted reactions of N-acylbenzimidazoles are
much less than those for the corresponding 4,5-diphenyl-
substituted compounds III and IV. N-(Trimethylacetyl)-
benzimidazole hydrolyzes with a k0 that is 55-fold less
at 30 °C than k0 for the pH-independent hydrolysis of
N-(trimethylacetyl)-4,5-diphenylimidazole (IV) at 15 °C.
Likewise, kOH for the benzimidazole derivative is 10-fold
less at 30 °C than kOH for IV at 15 °C. Benzimidazole
has a pKa of 12.8 (25 °C),13 which is identical with that
of 4,5-diphenylimidazole. Therefore, the relative reac-
tivities do not reflect electronic differences but must be
steric in origin. The benzimidazole leaving group of
N-acylbenzimidazoles is a planar system (VIII),in con-
δ–
O
N
N
C
CH3
O
H
O
H
H
H
O
H
H
X
mechanism was suggested in the hydrolysis of N-acetyl-
1,2,4-triazole and N-acetylbenzotriazole.28 Concerted
nucleophilic attack and C-N bond breaking in the
reactions of N-acylimidazoles would be in accord with the
additive steric rate-accelerating effects in the acyl group
and the leaving group; the transition state would then
be achieved with stretching of the C-N bond and
incomplete formation of a bond with the nucleophile.
Con cer ted Rea ction s. Breakdown of a tetrahedral
intermediate is not likely rate determining in the OH-
and conjugate acid reactions of N-acylimidazoles, in view
of the lack of significant 18O incorporation into the
carbonyl group when the hydrolysis reactions are carried
out in water enriched with 18O.29,30 The â1g value of -0.28
in the OH- reaction for substitution in the imidazole
leaving group9 (slope of a plot of log kOH vs the pKa of the
O
C
N
R
N
VIII
trast to the 4,5-phenyl-substituted imidazole VII. Steric
accelerating effects in the acyl group and the leaving
group are additive, which indicates an effect on the ease
of C-N bond breaking.
Wa ter Rea ction s. The large plateaus in the pH-rate
constant profiles for hydrolysis of I-IV provide an
opportunity for characterizing the water reactions since
observed rate constants can be measured that are not
influenced by the OH- and conjugate acid reactions. The
pH-independent reactions of the 2,4,5-triphenylimidazole
and 4,5-diphenylimidazole N-acyl derivatives proceed
more slowly in D2O than in H2O (kH O/kD O ) 2.0), which
(24) The computed C-N bond length of the amide function deter-
mined in the modeling studies was dependent on the program
employed.
(25) Pullman, B.; Pullman, A. Quantum Biochemistry; Wiley Inter-
science: New York, 1963; p 381. Molecular orbital calculations on
N-acetylimidazole indicate that N-3 has a net negative charge of 0.23-.
(26) A water molecule forms a hydrogen bond to imidazole with
considerable stability (5.6 kcal/mol). Del Bene, J . E.; Cohen, I. J . Am.
Chem. Soc. 1978, 100, 5285.
(27) Hogg, J . L.; Phillips, M. K. Tetrahedron Lett. 1977, 3011.
(28) Patterson, J . F.; Huskey, W. P.; Hogg, J . L. J . Org. Chem. 1980,
45, 4675. Gopalakrishnan, G.; Hogg, J . L. J . Org. Chem. 1981, 46,
4959. Reboud-Ravaux, M. J . Am. Chem. Soc. 1980, 102, 1039.
(29) Bunton, C. A. J . Chem. Soc. 1963, 6045.
2
2
indicates proton transfer in the transition state.
A
similar D2O solvent isotope effect was found in the
hydrolysis of N-acetylimidazole (kH O/kD O ) 2.7).4 The
2
2
solvent isotope effect is consistent with a water reaction.
The restriction of water in the reactant would be an
important kinetic factor because the translational en-
tropy of water molecules required for solvation of the
transition state would not then be lost. The resonance
(22) Bennet, A. J .; Wang, Q. P.; Slebocka-Tilk, H.; Somayaji, V.;
Brown, R. S.; Santarsiero, B. D. J . Am. Chem. Soc. 1990, 112, 6383.
(23) Curran, T. P.; Borysenko, C. W.; Abelleira, S. M.; Messier, R.
J . J . Org. Chem. 1994, 59, 3522.
(30) Fee, J . A. Ph.D. Thesis, University of Southern California, 1967.
The ratio of the rate constants for hydrolysis and exchange (khyd/kex
)
in the alkaline hydrolysis of N-(3,3-dimethylbutyryl)imidazole at 50%
hydrolysis is >60.

2876 J . Org. Chem., Vol. 62, No. 9, 1997
Lee et al.
substituted imidazole) is consistent with rate-determin-
ing nucleophilic attack by OH-.31-33 Therefore, if the
enhancement of C-N bond breaking is a factor in
producing the abnormal steric acceleration effects, as is
likely, then the hydrolysis reactions are concerted (XI),
and a stable tetrahedral intermediate does not exist.
group is very good, then bond breaking might begin
before the intermediate can become symmetrical, as in
XI. In that case, an anionic tetrahedral intermediate
would be metastable or the reaction could be concerted,
i.e., nucleophilic attack and bond breaking would occur
simultaneously. Williams39 has suggested that concerted
reactions might be more common than supposed. The
examples are, however, cases where the leaving group
is especially good, such as acyl chlorides.
CH3
O
The pKa of neutral imidazole is 14.5, which is only
slightly less than that of methanol (15.5).13,40 The high
pKa of the imidazole leaving group would conventionally
be thought to require the existence of a tetrahedral
intermediate in the OH- reaction. Staab had suggested
in 1956 that N-acetylimidazolium ion breaks down via a
unimolecular decomposition.3 That suggestion proved
not to be compatible with the D2O solvent isotope effect,
∆S* value, and other experimental evidence.4 Interaction
of solvent or other nucleophiles with the developing
acylium ion would have a stabilizing effect in the transi-
tion state. Thus, a concerted reaction could result. In
reactions of a neutral N-acylimidazole, a unimolecular
decomposition is much less likely than with the proto-
nated species, so reaction with a nucleophile would be of
increased importance. A key factor in giving rise to a
concerted reaction would then be enhancement of the
ease of C-N bond breaking.
Factors must exist which make C-N bond breaking
exceptionally favorable; N-acetylimidazole undergoes
alkaline hydrolysis with a second-order rate constant kOH
that is 20-fold larger than that of p-nitrophenyl acetate,
even though the pKa of p-nitrophenol is only 7.4,5 The
nucleophilic reactions of acyl derivatives are generally
dependent on the basicity of the leaving group.41 There-
fore, the large difference in reactivity with these types
of compounds, even with a leaving group ∆pKa of 7.5 pKa
units, indicates that factors other than the pKa of the
leaving group are operative. The partial negative charge
on N-3 of N-acylimidazoles will facilitate hydrogen bond-
ing of a water molecule (eq 4). Stabilization of the partial
negative charge on the leaving group will then enhance
C-N bond breaking. The opposed resonance will also
restrict the resonance involving N-1 and the carbonyl
group,42 so that the carbonyl is reactive. These factors
could, in turn, lead to high reactivity and a concerted
process, which would be promoted by relief of strain in
the transition state. The novel reactions of these sub-
stituted N-acylimidazole derivatives have, therefore,
provided considerable insight into the structural factors
that will permit rapid hydrolysis of acyl derivatives.
δ–
N
N
C
C
CH3
H
H
CH3
O
OH
δ–
XI
Likewise, the reactions of N-acetylimidazole and N-
acetylimidazolium ion with trifluoroethoxide ion are
either concerted or, if a tetrahedral intermediate is
formed, the intermediate cannot be sufficiently stable to
be at equilibrium with respect to proton transfer.34
It is generally accepted that most hydrolytic reactions
of acyl derivatives proceed via tetrahedral intermediates,
i.e., the reactions involve addition of a nucleophile to the
carbonyl group to give the intermediate followed by
elimination to give products or to regenerate the reac-
tants.35 Reactions of esters of aliphatic alcohols in water
enriched with 18O give 18O incorporation into the carbonyl
group of the ester.35-37 Incorporation of 18O is consistent
with the formation of a symmetrical tetrahedral inter-
mediate that undergoes breakdown to reactants (eq
5).35-37 It must also be shown that the tetrahedral
OH
C
O
C
(5)
+ H218O
OR′
products
R
OR′
R
18OH
intermediate lies on the pathway to products, and that
has only been accomplished in a few cases.2,38 A reason-
ably stable intermediate would very likely be formed
when the leaving group is poor. However, if the leaving
(31) The â1g of -0.28 is similar to that for acetate esters of
substituted phenols with which it has been considered that nucleophilic
attack of OH- at the carbonyl is the rate-determining step. Bruice,
T. C.; Fife, T. H.; Bruno, J . J .; Brandon, N. E. Biochemistry 1962, 1, 7.
J encks, W. P.; Gilchrist, M. J . Am. Chem. Soc. 1968, 90, 2622.
(32) Reference 2a, pp 510-513.
(33) The â1g of -0.44 for alkaline hydrolysis of N-aryl â-lactams has
been attributed to rate-limiting formation of a tetrahedral intermedi-
ate. Procter, P.; Gensmantel, N. P.; Page, M. J . Chem. Soc., Perkin
Trans. 2 1982, 1185. Blackburn, G. M.; Plackett, J . D. J . Chem. Soc.,
Perkin Trans. 2 1972, 1366.
Ack n ow led gm en t. This work was supported by a
grant from the National Science Foundation. Com-
pound VI was prepared by Milton H. Werner.
(34) (a) Oakenfull, D. G.; J encks, W. P. J . Am. Chem. Soc. 1971,
93, 178. (b) Oakenfull, D. G.; Salvesen, K.; J encks, W. P. J . Am. Chem.
Soc. 1971, 93, 188.
(35) Reference 2b, pp 22-24
J O960508D
(36) Bender, M. L. J . Am. Chem. Soc. 1951, 73, 1626.
(37) Bender, M. L.; Thomas, R. J . J . Am. Chem. Soc. 1961, 83, 4189.
(38) For an example, see: Fedor, L. R.; Bruice, T. C. J . Am. Chem.
Soc. 1965, 87, 4138. Bender, M. L.; Heck, H.d’A. J . Am. Chem. Soc.
1967, 89, 1211.
(39) Williams, A. Acc. Chem. Res. 1989, 22, 379. Williams, A. Adv.
Phys. Org. Chem. 1992, 27, 1.
(40) Ballinger, P.; Long, F. A. J . Am. Chem. Soc. 1960, 82, 795.
(41) Reference 2b, pp 58-60. Kirsch, J . F.; J encks, W. P. J . Am.
Chem. Soc. 1964, 86, 833, 837.
(42) N-1 of N-acetylimidazole has a net positive charge of 0.475+
while the carbonyl carbon has a net positive charge of 0.287+ according
to the molecular orbital calculations of ref 25.