NH-Acidities of Some Sterically Hindered Ureas

Article abstract of DOI:10.1039/a608619e

Introduction of an N-methyl group in to ethyl N-methylhydantoate causes a fourfold decrease in the rate of base-catalysed exchange of the N-H proton; a second methyl group restores the rate to close to that of the N-unsubstituted hydantoate; the latter ef

Full text of DOI:10.1039/a608619e

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220 J. CHEM. RESEARCH (S), 1997
J. Chem. Research (S),
1997, 220–221†
NH-Acidities of Some Sterically Hindered Ureas†
Ivan G. Pojarlieff,*a Iva B. Blagoeva,a Anthony J. Kirby,b Bozhana P. Mikhovaa and
Ergun Atay‡a
aInstitute of Organic Chemistry, Centre of Phytochemistry, Bulgarian Academy of Sciences, ul.
Acad. G. Bonchev block 9, 1113 Sofia, Bulgaria
bUniversity of Chemical Laboratory, Lensfield Road, Cambridge CB2 1EW, UK
Introduction of an N-methyl group in to ethyl N-methylhydantoate causes a fourfold decrease in the rate of base-catalysed
exchange of the N-H proton; a second methyl group restores the rate to close to that of the N-unsubstituted hydantoate;
the latter effect is observed for N-phenylhydantoates.
Proton exchange in amides and ureas is of continuing interest
to biochemistry.1 The introduction of methyl groups into
compounds 0–3, shown below, leads to unusual reactivities
towards base-catalysed cyclization in the most heavily substi-
tuted esters 3: these include both a change of mechanism and
the loss of the acceleration due to the gem-dimethyl effect.2
This prompted a study of the NH-acidity of these compounds
as a measure of the nucleophilicity of the ureido groups in
this series of ureidoesters.
the ionic product of water, as 10ꢀ14. Because of poor solu-
bility, spectra had to be run in 5:1 (v/v) water–acetonitrile. In
this solvent mixture pKw is little different from that of pure
water [14.33 in 20% (w/w) MeCN at 25 °C]3 and, in view of
the remaining uncertainties, refinements were considered
unwarranted. 3-PUE is still less soluble and 50% aqueous
MeCN was used. In this medium pKw differs considerably3
from 14 and the respective pK values were calculated as
above only for the sake of comparison.
As far as the ring-closure reaction is concerned, the results
in Table 1 show that differences in reactivity between com-
pounds 1 and 3, in both the MUE and PUE series, cannot be
attributed to the different basicity of the ureide anions.
2-MUE, with one methyl group at the 2 position, is con-
siderably less acidic than 1-MUE, with no methyl group. This
is not likely to be simply an inductive effect; in a Z-conforma-
tion on the ester side of the urea molecule, an extra methyl
group can be expected to hinder the solvation of the nega-
tively charged oxygen in the anion. The reversal of this trend
in compounds 3 is most likely due to a steric effect: strain
relieved by twisting the dialkylamino group out-of-plane
diminishing amide conjugation. This should make the NH
proton more acidic because of increased conjugation within
the secondary amide group. Strong acidifying effects upon
N-methyl substitution of secondary acylureas have been
observed.4
R4
O
NR2
2
R4
R3
O
R2
H
R3
R4
2
3
1
R1
5
N
5
R3
EtO21C
4
0-MUE
H
H
H
H
H
3NR1
N
4
1-MUE Me
2-MUE Me Me
R2
H
O
3-MUE Me Me Me
1-PUE Me
3-PUE Me Me Me
MUE, R1 = Me
PUE, R1 = Ph
MH, R1 = Me
PH, R1 = Ph
H
H
Rates of base-catalysed hydrogen exchange were measured
by means of dynamic NMR. The collapse of the methyl
doublet due to the NH–CH3 coupling in the w-methyl hydan-
toates and the broadening of the NH peak of the w-phenyl
esters with changing pH were monitored in buffers.
These exchange phenomena are due to the processes
shown in Scheme 1.
O
O
kOH
kd
H
+ OH–
+
H2O
R
N
R
N–
R1
The less heavily substituted ethyl hydantoates have been
5
8
R1
prepared by Kav´alek and St´erba. Esters 2 and 3, however,
cyclized rapidly in the presence of moisture and had to be
prepared under strictly anhydrous conditions, as described in
the Experimental section.
O
O
kα
kβ
Hα
Hβ
+ OH–
R
N
R
N
Experimental
Me
Me
Melting points are uncorrected. 1H NMR spectra were recorded
on a Bruker WM-250 instrument. pH Values were measured with
a Radiometer pH M 84 Research pH-meter using a GK 2401 C
electrode.
Scheme 1
Pseudo-first-order rates of hydrogen exchange, kexch, were
obtained as described in the Experimental section. In the pH
region where exchange phenomena could be observed,
spectra had to be recorded rapidly as cyclization to hydantoin
is a competing reaction. To calculate the second-order rates,
kOH = kexch/aOH, aOH was taken as antilog (pH ꢀ14), where pH
is the glass-electrode value measured in the buffer containing
the correct amount of acetonitrile. The acidity constant was
obtained as
Materials.sInorganic reagents and buffer components were of
analytical-reagent grade and used without further purification.
Buffer solutions were prepared with CO2-free water, to 0.03
M
total
Table 1 Rates of base-catalysed hydrogen exchange in ethyl
hydantoates and pKNH estimates in 5:1 (v/v) water–acetonitrile at
19 °C
Compound
pH
kexch/sꢀ1
kOH/dm3 sꢀ1 molꢀ1
pK
In 5:1 (v/v) water–acetonitrile
k
0-MUEa
1-MUE
9.84
9.43
12
4.0
11.5
5.5
11
2.5
6.3
12.2
1.7Å105
1.6Å105
18.8
18.8
KNH
=
OH Kw
kd
9.84
2-MUE
10.21
10.45
9.43
6.90
7.19
3.6Å104
19.45
with kd, the diffusion-controlled rate for the protonation of
the ureide anion, being taken as 1010 dm3 sꢀ1 molꢀ1 and Kw,
3-MUE
1-PUE
9.3Å104
7.9Å107
19.0
16.1
*To receive any correspondence (e-mail: ipojarli@gate.orgchm.
acad.bg).
†This is a Short Paper as defined in the Instructions for Authors,
Section 5.0 [see J. Chem. Research (S), 1997, Issue 1]; there is there-
fore no corresponding material in J. Chem. Research (M).
‡Formerly Denis T. Tashev of ref. 2.
In 1:1 (v/v) water–acetonitrile
1-PUE
3-PUE
7.44
7.44
4.5
5.8
1.6Å107
2.1Å107
16.8
16.7
aFor 3-NH we obtained kOH = 1.3Å106 dm3 sꢀ1 molꢀ1, pK = 17.9.

View Article Online
J. CHEM. RESEARCH (S), 1997 221
Table 2 1H NMR spectra of ureido esters and hydantoins in 5:1 (v/v) water–acetonitrile [HD2CCN (d 1.94) as reference, splittings in Hz
in parentheses]
Compounds
1-Me
2-H
2-Me
3-Me
5-H
5-Me
OCH2Me
OCH2Me
MUE and PUEa
0-MUE
3.780d (6.1)
3.955s
2.553d (4.6)
2.595d (4.5)
2.596d (4.4)
2.550d (4.5)
4.092q (7.2)
4.095q (7.2)
4.073q (7.1)
4.034q (7.2)
4.111q (7.2)
1.149t (7.2)
1.152t (7.2)
1.141t (7.2)
1.133t (7.1)
1.156t (7.2)
1.122 (7.2)
1-MUE
2.805s
2.691s
2.706s
2.967s
2.913
2-MUE
4.073q (7.1)
1.266d (7.1)
1.261s
3-MUE
1-PUE
4.032s
3-PUEc,d
1.327s
MH and PHa
0-MH
2.834
3.917s
2.836s
2.738s
2.757s
2.929s
2.862s
2.836s
2.811s
2.853s
3.910s
1-MH
3.973q (7.0)
1.278d (7.0)
1.257s
2-MH
3-MH
4.100s
1-PHe
1.408s
3-PHc
aSee formulae for numbering in esters and hydantoins. bd 5-Ph: o-H 7.185, m-H 7.266, p-H 7.064; NH 8.03. cIn 50% H2O–CD3CN v/v.
dd(NH) 7.98. ed (3-Ph) 7.25m (3 H), 7.47m (2 H).
concentration, and the ionic strength was adjusted with KCl to
0.1 . CD3CN was 99% from Aldrich.
kexch = k = kaǹkb were obtained by means of approximate solu-
tions;6 line-intensity methods for cases with slow7 and fast8
exchange were preferred. The values for the rate constants were
then refined by means of complete line-shape-analysis simula-
tions.9 In the case of PUE, line-broadening of the NH signal was
monitored: kexch = p(W*ꢀW0), where W* is the line-width of the
exchange-broadened signal and W0 the width in the absence of
observable exchange. Following the recommendations of Perrin et
al.,10 instrument inhomogeneity was compensated for by subtract-
ing the width of a line of the ester methyl triplet from every NH line
width.
We thank the National Foundation for Scientific Research
of Bulgaria for funding this research and the Bulgarian Aca-
demy of Sciences and The Royal Society for travel funds. We
thank also Dr N. Vassilev for help with the CLSA program.
M
Ethyl Hydantoates.sGeneral procedure. A slight excess (8%) of
methyl or phenyl isocyanate was added to the freshly distilled
amino ester (5 mmol) in dry benzene (5 ml) under ice cooling. The
mixture was stirred for 15 min at 0 °C and then for 1 h at room
temperature. Where the products precipitated they were filtered
off and washed with dry benzene and hexane, otherwise the reac-
tion mixture was evaporated to dryness and the solids recrystallized
from dry benzene. The yields of pure esters were 86–96%.
Compounds 0-MUE, 1-MUE and 1-PUE were prepared by the
above procedure and were identified by comparison with the mps
and NMR parameters described in ref. 4.
Ethyl 2,3-dimethyl-5-phenylhydantoate (2-PUE) had mp
95–96.5 °C; dH (CDCl3) 1.27 (t, 3 H, MeCH2OCO), 1.45 (d, 3 H,
MeCH), 2.98 (s, 3 H, MeN), 4.19 (q, 2 H, CH2OCO), 5.09 (q, 1 H,
CHNMe), 6.54 (s, 1 H, HNPh), 7.03–7.38 (m, 5 H, Ph) (Found: C,
62.51; H, 7.48; N, 11.14. C13H18N2O3 requires C, 62.38; H, 7.25; N,
11.19%).
Ethyl 2,2,3-trimethyl-5-phenylhydantoate (3-PUE) had mp
108.5–110 °C; dH (CDCl3) 1.23 (t, 3 H, MeCH2OCO), 1.43 (s, 6 H,
Me2CH), 3.00 (s, 3 H, CH3N), 4.18 (q, 2 H, CH2OCO), 6.33 (s, 1 H,
HNPh), 7.01–7.36 (m, 5 H, Ph) (Found: C, 63.55; H, 7.51; N, 10.87.
C14H20N2O3 requires C, 63.61; H, 7.62; N, 10.60%).
Hydantoates 2-MUE and 3-MUE were obtained in situ as
described below.
Received, 24th December 1996; Accepted, 28th February 1997
Paper E/6/08619E
References
1 C. L. Perrin, Acc. Chem. Res., 1989, 22, 268.
2 I. B. Blagoeva, D. T. Tashev and A. J. Kirby, J. Chem. Soc., Perkin
Trans. 1, 1989, 1157; I. B. Blagoeva, D. T. Tashev and A. J. Kirby,
unpublished results.
Dynamic NMR.sThe ready cyclization of the ureido esters
limited the time and the pH region (below 7 for PUE and below
10.5 for MUE) available for recording the spectra. Table 2 lists the
NMR parameters for the esters and the product hydantoins. The
final solutions were prepared by mixing 0.4 ml of the aqueous
buffer (formate, acetate, phosphate, borate or carbonate) with 0.1
ml of an ester CD3CN solution (0.1 g in 1 ml). Esters 2-MUE and
3 U. Mandal, S. Bhattacharya and K. K. Kundu, Indian J. Chem.,
1985, 24A, 191.
8
4 J. Kav´alek, J. Jirman, V. Mach´acek and V. St´erba, Collect. Czech.
Chem. Commun., 1987, 52, 1992 and references cited therein.
8
5 J. Kav´alek and V. St´erba, Collect. Czech. Chem. Commun., 1986,
51, 375.
3-MUE were prepared in situ by mixing equal amounts of 10ꢀ3
M
6 V. S. Dimitrov in Recent Developments in Molecular Spectroscopy,
ed. B. Jordanov, M. Kirkov and P. Simova, World Scientific,
Singapore, 1988, p. 476.
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CD3CN just before recording the spectra. In the case of MUE,
spectra for the 5-Me doublet could be taken before and after
coalescence in solutions of various pH. The relaxation time, T2, in
each spectrum was determined from the band width at half inten-
sity of the 3-methyl signal. For 0-MUE one of the lines of the
ethoxymethyl group was used, adding the difference of this line and
a line of the 5-Me signal at slow exchange. Estimates of
7 R. Ku¨spert, J. Magn. Reson., 1982, 47, 91.
8 V. D. Dimitrov, Org. Magn. Reson., 1974, 6, 16.
9 D. S. Stephenson and D. Binsch, J. Magn. Reson., 1978, 32, 145;
QCPE, 1978, 11, 365.
10 C. L. Perrin, E. R. Johnson, C. P. Lollo and P. A. Kobrin, J. Am.
Chem. Soc., 1981, 103, 4691.