JOURNAL OF CHEMICAL RESEARCH 2007 249
Fig. 3
Fig. 4
d 149.1 ppm corresponds to the doublet CH signal at d 8.74
ppm. Compound 10 shows three peaks corresponding to
the four aromatic protons and its 13C NMR spectrum shows
11 resolved carbon signals: Four in the sp3-carbon region,
six in the aromatic carbon region and the carbonyl signal at
d 151.8 ppm.
(30–45°C) are measured spectrophotometically by monitoring
the formation of 7-HOAt, HOBt, and 4-HOAt anions 14–16 at
l = 286, 317 and 275 nm respectively. The product 13 shows
that compounds 9, 10 and 11 undergo morpholinolysis of the
ester group rather than the amide moiety indicating that -OAt
-
or OBt is the leaving group while –NEt2 is the non leaving-
one. The reaction obeys a clean second-order rate law, Eqn (2)
and Eqn (3), where [Subs] and [Morph] are the concentrations
of N,N-diethyl carbamate ester (9, 10 or 11) and morpholine,
respectively.
The reaction of N,N-diethyl carbamoyl chloride with
1-hydroxypyrrolidin-2,5-dioneinthepresenceoftriethylamine
under the previous conditions gave diethylcarbamic acid 2,5-
dioxopyrrolidin-1-yl ester 12 as indicated from its elemental
analysis and IR and NMR spectrum (Tables 1 and 2). The 1H
NMR spectrum of compound 12 shows two triplet peaks at
d 1.20 and 1.29 ppm corresponding to the two CH3 groups.
It also shows a singlet peak at d 2.81 and a multiplet peak
at 3.39 ppm corresponding to the four CH2 groups. Similarly,
the chemical shift of both N,N-diethyl groups is affected by
the anisotropic effect of the carbonyl group. The IR spectrum
of 12 shows 2 peaks at 1759 and 1742 cm-1 corresponding
to N–CO–O and the NC=O respectively. The 13C NMR
spectrum of 12 shows five resolved carbon signals in the sp3-
carbon region, and two carbonyl signal at d 151.2 and 170.1
ppm corresponding to the N–CO–O and N–C=O respectively,
indicating the only expected form, which is the O-acyl form.
Compounds 9–11 are presumably in the O-acyl form rather
than the N-acyl one17,18 because their carbonyl absorptions
occur at wave numbers near to that of compound 12. This
comes also from the coincidence of their 13C nmr carbonyl
group values in the range d 151.8–154.2 ppm with that of 12
at d 151.2 ppm confirming the O-acyl form.
Rate = kY [Sub]
kY = k2 [Morph]
(2)
(3)
The second-order rate constant, k2, summarised in Table 3 are
obtained from a straight line plot of kY vs five to six [Morph],
where kY is the pseudo-first-order rate constant. This indicates
that the titled reactions are not amine catalysed. Thus, the
morpholinolysisreactionispresumablyproceedingconcertedly
which is in agreement with the typical mechanism of an ester
and an amide. Table 3 reveals that the rate enhancement found
of 11 (4-HOAt carbamate) relative to 9 (7-HOAt carbamate)
and HOBt analogs 10 (HOBt carbamate) is in harmony with
the order of pKa values of the liberated leaving groups.7
Accordingly, this is consistent with increasing the stability
of the leaving group anion liberated from 11 than 9 than 10
and is thus reflected in the faster morpholinolysis rate for 11
than for the corresponding 9 and 10. Furthermore, the ratios
k4-HOAt, 11/k7-HOAt, , k7-HOAt, /kHOBt, 10, k4-HOAt, 11/kHOBt,
9 9 10
The reaction of the aryl carbamate derivatives of 1-hydroxy-
7-azabenzotriazole (7-HOAt) 9, 1-hydroxybenzotriazole
(HOBt) 10, or 1-hydroxy-4-azabenzotriazole (4-HOAt) 11 with
morpholine in acetonitrile afforded N,N-diethylmorpholine-
4-carboxamide 13 (Scheme 1). The same product was also
directly synthesised by the reaction of N,N-diethyl carbamoyl
chloride with morpholine in methylene chloride. The elemental
analysis of compound 13 indicates the replacement of the
ester groups of compounds 9, 10, and 11 by the morpholin-
1-yl group via a nucleophilic acyl substitution reaction.
The IR spectrum of 13 shows a sharp peak at 1638 cm-1,
corresponding to the C=O group. The 1H NMR spectrum of 13
shows one triplet at d 1.10 ppm corresponding to the two CH3
groups, one multiplet centred at d 3.19 ppm corresponding to
the four N–CH2 groups (two CH2–N of morpholinyl moiety
and two CH2 of N,N-diethyl moiety), and one triplet peak at d
3.67 ppm corresponding to the two O–CH2 groups.
Interestingly, no difference is detected in the chemical shifts
of both N,N-diethyl group protons which is in correspondence
with the energy minimised calculation of compound 13
utilising PM3/MOPAC,15 where the two ethyl groups are far
from the cone field of the carbonyl group, Fig. 4.
at all temperatures are in the ranges (3.15–3.93), (1.37–1.70)
and (4.6–6.10) respectively, Table 4. This indicates that the
absence, the presence and the position of pyridine-N-atom as
well as the pKa of the leaving group have important effects
on rates. Although, k11/k9 ratio is comparatively large, the pKa
difference of the leaving groups is quite small. Conversely,
k9/k10 is lower, yet the pKa difference is quite large. However,
the k11/k10 ratio is higher than the other ratios while the
difference of pKa is relatively large. These data are presumably
explained by the following concepts: the presence of the
pyridine N-atom increases the rates of 11 and 9 more than
10 that contains no such atom, although the difference in pKa
values is quite high. The position of the pyridine N-atom is
responsible for the increase in the rate of 11 more than for 9,
i.e. proximity effect of pyridine N-atom to the reaction centre,
although the difference in pKa is small, Table 4.
Further support for the concerted mechanism is provided
by the high negative entropy of activation (Table 3), which
is similar to that reported for the reaction of substituted
benzylamines with N-ethyl thiocarbamates in acetonitrile.12
This predicts a proton transfer in the transition state and
suggests a hydrogen bond by internal base catalysed process
to form a four cyclic transition state (structure 17#). The
relatively small DH# values with large negative DS# values in
The reactions of N,N-diethyl carbamates 9–11 with
morpholine in acetonitrile at different temperatures
PAPER: 07/4491