Structure-reactivity relationships in the rate of esterification by acetylimidazole: The influence of the second hydroxy group and of the length of the N-ω-hydroxy-n-alkyl chain in 3-(N-methyl, N-ω-hydroxy-n-alkyl)ammo-2-tert-butylpropan-1-ols

Article abstract of DOI:10.1039/a608033b

Enforced intramolecular hydrogen bonding facilitates intramolecular general base catalysis in the acetylation of a family of α,ω-amino alcohols by acetylimidazole, and the site of acetylation when there are two hydroxy groups is determined by the relative ease of intramolecular hydrogen bonding rather than by intermolecular steric effects.

Full text of DOI:10.1039/a608033b

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Structure–reactivity relationships in the rate of esterification by
acetylimidazole: the influence of the second hydroxy group and of
the length of the N-ù-hydroxy-n-alkyl chain in 3-(N-methyl,
N-ù-hydroxy-n-alkyl)amino-2-tert-butylpropan-1-ols
a
,a
b
Annemieke Madder, Pierre J. De Clercq* and Howard Maskill
a
University of Gent, Department of Organic Chemistry, Krijgslaan, 281 ( S4) , B-9000 Gent,
Belgium
Department of Chemistry, Bedson Building, University of Newcastle upon Tyne,
b
Newcastle upon Tyne, UK NE1 7RU
a
b
Enforced intramolecular hydrogen bonding facilitates
intramolecular general base catalysis in the acetylation of a
family of á,ù-amino alcohols by acetylimidazole, and the
site of acetylation when there are two hydroxy groups is
determined by the relative ease of intramolecular hydrogen
bonding rather than by intermolecular steric effects.
Table 1 Half-lives (23 ЊC), activation enthalpies, activation entro-
c
d
pies and second-order rate constants (25 ЊC) for the alcoholysis of
AcIm by 1, 2a–5a, 2b and 3b in acetonitrile
‡
‡
Ϫ1
Ϫ4
3
∆
H /kJ
Ϫ∆S /J K
mol
k2/10 dm
mol
Ϫ1
Ϫ1
Ϫ1 Ϫ1
t /min
₁
mol
s
₂
e
1
2
3
4
5
2
198
f
721
151
f
35.3
—
33.1
23.7
—
180
—
195
219
—
14.9
—
6.0
21.2
—
35.3
21.3
a
a
a
a
b
Recently, in the context of developing a non-enzymic catalyst
for the cleavage of esters and amides, we studied the influence
of 2-substitution on the rate of esterification of 1,3-amino-
e
1
alcohols by acetylimidazole (AcIm) in acetonitrile. In accord
80
150
32.2
35.6
184
177
with an intramolecular GBC mechanism, the enforced intra-
molecular hydrogen bonding in the 2-tert-butyl substituted
compound 1 led to a modestly increased rate constant at room
3b
a
Determined by NMR spectroscopy for the pseudo-first-order reaction
Ϫ3
b
2
–4
(0.05 mol dm amino alcohol in ten-fold excess over AcIm). Esti-
Ϫ1 c Ϫ1
temperature compared with 3a. Because of the aprotic nature
of the solvent acetonitrile, one may expect a further rate
enhancement by inclusion of an extra hydroxy group that could
serve to facilitate the formation of the oxyanion via intra-
molecular hydrogen bonding. The presence of this second
hydroxy group in the reactant, however, would also reduce the
basicity of the amino group, but this effect will depend on the
length of the methylene chain between the hydroxy group and
mated probable error ±4 kJ mol . Estimated probable error ±14 J K
Ϫ1
d
e
mol
. Determined by UV spectrophotometry (see text). These new
and preferred results for 1 and 3a are slightly different from those
reported earlier. Estimated at longer than 100 h.
1
f
4a,5c
an intramolecular hydrogen bond, i.e. 4a > 3a ӷ 2a and 5a.
One may expect that the changing basicity of the amino group
due to the changing number of methylene groups separating it
(
5
the amino group.
from the hydroxy group) will have an effect upon the ease of
formation of the hydrogen bond. However, there is also a con-
formational effect upon the ease of formation of the intra-
molecular hydrogen bond and hence upon the rate of acyl
transfer. According to this analysis, the very low reactivity of 2a
is due to both/either (i) the diminished basicity of the amino
group (through the inductive effect of the OH) and/or (ii) the
inefficient geometrical arrangement for an intramolecular pro-
ton transfer (proton transfer along a linear hydrogen bond
In order to understand better these structure–reactivity rela-
tionships, we decided to study (i) the influence of the methylene
chain length upon the reactivity of acetylation by acetylimid-
azole of a series of ω-(N,N-dimethylamine)-n-alkanols 2a–5a
and (ii) the relative reactivity in the same reaction of amino
diols 2b and 3b, in which a second hydroxyalkyl group is
incorporated into the 2-tert-butylamino alcohol 1.
CMe3
7
would require a four-membered ring). In the case of 5a, only
the latter geometrical effect could be responsible for its low
reactivity (i.e. an unfavourable seven-membered ring is required
for a linear intramolecular proton transfer) since the inductive
effect of the hydroxy group upon the base strength of the amino
group will have been rendered negligible by the intervening five
methylene groups. The higher reactivity of 4a compared with 3a
is not unexpected since the former has both the more basic amino
group and can accommodate the linear proton transfer within a
NMe2
OH
NMe2
OH
N:
Me3C
(
)n
(
)n
HO
OH
1
a
2 n = 0
b
3
4
5
n = 1
n = 2
n = 3
8
The half-lives of the pseudo-first-order esterification reac-
tions of 2a–5a at 23 ЊC were determined by H NMR spec-
troscopy (500 MHz) using the amino alcohols in excess (Table
). Inspection of the results reveals that the position of 5a in the
observed order of reactivity and the difference between 4a and
a on the one hand and 2a and 5a on the other (4a > 3a ӷ 2a
and 5a) do not correspond with expectation based solely upon
the basicity of the amino groups, i.e. 5a > 4a > 3a > 2a.
favourable six-membered ring.
1
In order to gain further insight into the mechanism of esteri-
fication of 3a and 4a by AcIm in acetonitrile the activation
parameters were determined. For this purpose, pseudo-first-
order reaction rates of the esterification were measured by
monitoring the decrease in UV absorbance at 270 nm due to
AcIm. The reactions were run in duplicate over at least five half-
lives with the amino alcohol present in large excess (160–1300-
fold). Second-order rate constants were measured in the normal
1
3
6
Instead, the order of reactivity follows the ease of formation of
J. Chem. Soc., Perkin Trans. 2, 1997
851

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δ–
minimized geometry of the tetrahedral intermediate originating
Me
H
O
from the reaction of 2b, the most reactive in the series 1, 2b
+
9
δ
O
Me
and 3b.
N
Me
Im
Acknowledgements
4
a–TTS
A. Madder thanks the National Fund for Scientific Research
Fig. 1 Transition state for reaction of 4a with acetylimidazole
(NFWO, Belgium) for a position as Research Assistant. The
National Fund for Scientific Research (Belgium) is thanked for
financial assistance to the laboratory and for a research grant
(Krediet aan Navorsers 1993–1994).
References
1
2
I. Steels, P. J. De Clercq and H. Maskill, J. Chem. Soc., Chem.
Commun., 1993, 294.
For examples of the hydrolysis of AcIm involving amino alcohols, see
(
(
a) D.G. Oakenfull and W. P. Jencks, J. Am. Chem. Soc., 1971, 93, 178;
b) D. G. Oakenfull, K. Salvesen and W. P. Jencks, J. Am. Chem. Soc.,
1
971, 93, 188; for examples of esterification of amino alcohols with
AcIm, see (c) L. Anoardi and U. Tonellato, J. Chem. Soc., Chem.
Commun., 1977, 401.
For a recent review on hydrogen bonding, see F. Hibbert and
J. Emsley, Adv. Phys. Org. Chem., 1990, 26, 255.
For studies of intramolecular hydrogen bonding in some substituted
amino alcohols, see (a) A. M. De Roos and G. A. Bakker, Rec. Trav.
Chim. Pays-Bas, 1962, 81, 219; (b) M. G. Zaitseva, S. V. Bogatkov and
E. M. Cherkasova, Zh. Obs. Khim., 1964, 35, 2056; (c) A. F. Casy and
M. M. A. Hassan, Can. J. Chem., 1969, 47, 1587; (d) R. Mathis,
M.-T. Maurette, C. Godechot and A. Lates, Bull. Soc. Chim. Fr., 1970,
Fig. 2 Energy-minimized geometry of the tetrahedral intermediate
originating from reaction of 2b with AcIm. Hydrogen-bond distances
are given in pm.
3
4
way at five temperatures in the range of 25–65 ЊC and the com-
puted activation parameters are shown in Table 1. Inspection of
the results reveals that the higher reactivity of 4a compared
with 3a is entirely due to its much lower activation enthalpy.
However, note that the enthalpic stabilisation of the transition
state from 4a is offset to some extent by a less favourable
entropy of activation compared with the transition state from
3
047; (e) P. Gilli, V. Bertolasi, V. Ferrelti and G. Gilli, J. Am. Chem.
Soc., 1994, 116, 909; ( f ) J. Hine and M. N. Khan, Ind. J. Chem., Sect.
B, 1992, 31, 427.
5
6
For studies on the basicity of amino alcohols, see (a) S. V. Bogatkov,
V. N. Romaslov, N. I. Kholdyakov and E. M. Cherkasova, Zh. Obsch.
Khim., 1959, 39, 247; (b) S. V. Bogatkov, E. Y. Skobeleva and E. M.
Cherkasova, Zh. Obsch. Khim., 1966, 36, 138; (c) B. A. Koralev,
M. A. Mal’tseva, A. I. Tarasov and V. A. Vasnev, Zh. Obsch. Khim.,
3
a, i.e. there is some degree of compensation between the activ-
ation entropy and the activation enthalpy. The former is
somewhat more negative for 4a compared with that for 3a due
to the more ordered chair-like transition state geometry (see
Fig. 1, 4a–TTS) which, in turn, allows the less strained
arrangement for better development of new bonds in concert
with the cleavage of the old ones, and hence the appreciably
lower enthalpy of activation of 4a.
1
974, 44, 833; (d) G. Stevens, S. Chen, P. Huyskens and S. De Jaegere,
Bull. Soc. Chim. Belg., 1991, 100, 493.
The following pK values in water have been reported for the conju-
a
gate acids of 1,2-, 1,3-, 1,4- and 1,5-amino alcohols: 9.50, 10.09,
10.38 and 10.61 respectively (see ref. 5d); the relative order follows the
reduced influence of the inductive effect of HO as the chain
lengthens.
The hydrogen is not counted in the ring size designation in accord
with a linear proton transfer.
Six-membered ring transition states are particularly favoured for
linear hydrogen transfers: (a) E. A. Dorigo and K. N. Houk, J. Am.
Chem. Soc., 1987, 109, 2195; (b) P. Camilleri, C. A. Marby, B. Odell,
H. S. Rzepa, R. N. Shepard, J. J. P. Stervart and D. J. Williams,
J. Chem. Soc., Chem. Commun., 1989, 1722.
Fig. 2 shows the minimum energy conformation of several low-
energy conformations found. Geometry calculated using Macromodel
V3.0: W. C. Still, F. Mohamadi, N. G. J. Richards, W. C. Guida,
M. Lipton, R. Liskamp, G. Chang, T. Hendrickson, F. DeGunst and
W. Hasel, Department of Chemistry, Columbia University, New
York, NY 10027, USA.
The half-lives for the pseudo-first-order reactions of 2b and
3
b were also determined as in the a series (Table 1). Very signifi-
7
8
cantly, selective esterification of the more hindered primary
hydroxy group located on the tert-butyl substituted fragment
was observed in both cases. This is wholly in accord with our
analysis above; the preferred reaction is of the hydroxy group
which is involved in the enforced intramolecular hydrogen
bonding. Scrutiny of the results for 1, 2b and 3b (Table 1) sug-
gests that the diminished basicity of the amino groups due
to the incorporation of the second hydroxyalkyl residues in
9
2
b and 3b almost cancels out the rate enhancements due to
the cooperative involvement of the second hydroxy group
through hydrogen bonding required by the regioselectivity.
Enthalpies and entropies of activation were also determined
for 2b and 3b (as described above) and are shown in Table 1.
However, whilst they are qualitatively as expected, they provide
no new insights into the mechanism. Fig. 2 shows the energy-
Paper 6/08033B
Received 27th November 1996
Accepted 12th March 1997
8
52
J. Chem. Soc., Perkin Trans. 2, 1997