Thorpe-Ingold effects in cyclizations to five-membered and six-membered rings containing planar segments. The rearrangement of N(1)-alkyl-substituted dihydroorotic acids to hydantoinacetic acids in base

Article abstract of DOI:10.1039/b400248b

While the gem-dimethyl effect (GDME) is quantitatively similar for cyclizations to cyclopentane and cyclohexane rings and their homomorphs, in systems containing planar segments the GDME is stronger for the formation of five-membered rings. Planar pentagons have smaller angles than planar hexagons and their formation is helped by the decrease in the potential internal bond angle caused by substituents, as suggested by Thorpe and Ingold for small rings. The phenomenon is illustrated with crystal structure data on five-membered hydantoins and six-membered dihydrouracils containing four-atom planar segments. Such a Thorpe-Ingold effect explains the rearrangement in base of N-alkyl substituted dihydroorotic acids 1 to hydantoinacetic acids 3. The reaction involves initial hydrolysis to N-(N-alkylcarbamoyl)aspartic acids 2 and their subsequent cyclization. The unsubstituted N-carbamoylaspartic acid 2a is stable in 1 M KOH, the N(1)-methyl and ethyl compounds 2b and 2c are in equilibrium with the hydantoinacetic acids 3, while the cyclization of the N(1)-isopropyl and cyclohexyl derivatives 2d and 2e is irreversible. Experimental data on equilibria and pK_as for ionization of the carboxy and NH groups allow equilibria and rates involving the N-unsubstituted compounds to be estimated and compared with those for the N-alkyl derivatives. The strongest effect is observed on the equilibrium [3^2-]/[2^2-], where substitution of H by methyl increases K 600-fold. In vitro the kinetic regioselectivity for acid catalyzed cyclization of N-carbamoylaspartic to hydantoinacetic acid against dihydroorotic acid is only 10:1. This, together with the weaker acidity of the remote carboxyl group, favours cyclization to dihydroorotic acid under biological conditions.

Full text of DOI:10.1039/b400248b

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Thorpe–Ingold effects in cyclizations to five-membered and
six-membered rings containing planar segments. The rearrangement
of N(1)-alkyl-substituted dihydroorotic acids† to hydantoinacetic
acids in base
Jose Kaneti,a Anthony J. Kirby,b Asen H. Koedjikova and Ivan G. Pojarlieff
a Institute of Organic Chemistry, Bulgarian Academy of Sciences, ul. Acad. G. Bonchev block 9,
Sofia 1113, Bulgaria. E-mail: ipojarli@orgchm.bas.bg
b University Chemical Laboratory, Cambridge, UK CB2 1EW
Received 9th January 2004, Accepted 17th February 2004
First published as an Advance Article on the web 10th March 2004
While the gem-dimethyl effect (GDME) is quantitatively similar for cyclizations to cyclopentane and cyclohexane
rings and their homomorphs, in systems containing planar segments the GDME is stronger for the formation of
five-membered rings. Planar pentagons have smaller angles than planar hexagons and their formation is helped
by the decrease in the potential internal bond angle caused by substituents, as suggested by Thorpe and Ingold
for small rings. The phenomenon is illustrated with crystal structure data on five-membered hydantoins and
six-membered dihydrouracils containing four-atom planar segments. Such a Thorpe-Ingold effect explains
the rearrangement in base of N-alkyl substituted dihydroorotic acids 1 to hydantoinacetic acids 3. The reaction
involves initial hydrolysis to N-(N-alkylcarbamoyl)aspartic acids 2 and their subsequent cyclization. The
unsubstituted N-carbamoylaspartic acid 2a is stable in 1 M KOH, the N(1)-methyl and ethyl compounds 2b and
2c are in equilibrium with the hydantoinacetic acids 3, while the cyclization of the N(1)-isopropyl and cyclohexyl
derivatives 2d and 2e is irreversible. Experimental data on equilibria and pKas for ionization of the carboxy and NH
groups allow equilibria and rates involving the N-unsubstituted compounds to be estimated and compared with those
for the N-alkyl derivatives. The strongest effect is observed on the equilibrium [32؊]/[22؊], where substitution of H by
methyl increases K 600-fold. In vitro the kinetic regioselectivity for acid catalyzed cyclization of N-carbamoylaspartic
to hydantoinacetic acid against dihydroorotic acid is only 10 : 1. This, together with the weaker acidity of the remote
carboxyl group, favours cyclization to dihydroorotic acid under biological conditions.
to have been analyzed in detail. A convenient point of reference
is the parent cycloalkane. Equilibrium constants for the formal
cyclizations of alkanes and gem-dimethylalkanes calculated
Geometry of normal rings and the Thorpe–Ingold
effect
The Thorpe–Ingold or gem-dimethyl (more generally dialkyl)
effect is defined by the increase in both rate and equilibrium
constants of cyclization reactions resulting from the introduc-
tion of substituents in the linking chain. The original concept
of Thorpe and Ingold referred to the reduction of the angle
between the relevant ring atoms in the open-chain reactant
resulting from compression by the substituent(s).1 However,
alkyl substitution also favours the formation of normal (five to
seven-membered) rings, where this reduction in bond angle is
no longer obviously beneficial because the original tetrahedral
angles are preserved in the ring. The broader term gem-di-
methyl2 or gem-dialkyl effect3 was coined,‡ and the effect
explained in terms of increased strain and a reduced entropy of
rotation in the open-chain compound.4 Quantitatively the effect
on the formation of normal rings varies considerably, and
depends on the type of reaction as well as on the position of the
substituent(s) in the chain.5
from thermodynamic data show very similar increases in stabil-
ity for cyclopentane and cyclohexane (around 70§ for substi-
tution at C(3)).7 Similarly Warren and coworkers8 have shown
that in competitive cyclizations to tetrahydrofurans and pyrans
the GDME is of equal importance. However, some systems
show a significantly stronger GDME for the formation of five
membered rings. The lactonizations of o-hydroxyalkylbenzoic
acids (Scheme 1) present such an example.5b
These variations can often be understood in terms of tight-
ness or looseness of the transition state and of specific inter-
actions in the transition state involving the substituent.5b,6 Data
for the gem-dialkyl effect in the formation of five-membered vs.
six-membered rings are available for many systems but seem not
Scheme 1
A second example is provided by the relative rates of acid
catalyzed cyclization of hydantoic9 and 2-ureidopropionic
acids5a (Scheme 2).
This difference in behaviour, of compounds resembling the
cyclic alkanes on the one hand and the lactones of benzoic acid
and cyclic ureides on the other, can be rationalized by the inter-
† The numbering of dihydroorotic acid differs from that of di-
hydrouracils due to priority of the carboxy group. For easier com-
parison with the parent ring systems we use 1-alkyldihydroorotic acid to
denote 3-alkyl-2,6-dioxohexahydropyrimidine-4-carboxylic acid and 1-
alkylhydantoinacetic acid to denote (3-methyl-2,5-dioxo-imidazolidin-
4-yl)-acetic acid.
‡ The effect is not limited to gem-substitution.
§ The number given in Table 14 of ref. 7 is incorrect.
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 0 9 8 – 1 1 0 3
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4
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Table 1 Ring geometries in hydantoins and dihydrouracilsa
(a) Mean internal angles (Њ) at apex atoms
Ring atom
N(1)
C(2)
N(3)
C(4)
C(5)
C(6)
Hydantoinsb
112.3 1.2
122.0 1.7
107.6 0.9
116.7 0.9
111.5 1.0
125.2 1.6
106.9 0.6
115.3 1.3
101.2 1.1
109.9 1. 9
Dihydrouracilc
109.7 1.6
(b) Average torsion angles (Њ)
Hydantoins
1234
2.8 2.2
1234
2345
3.3 2.8
2345
3451
3.5 3.4
3456
4512
3.4 3.4
4561
5123
3.3 2.7
5612
Dihydrouracils
6123
9.3 4.0
11.7 4.7
5.7 4.6
34.8 6.6
50.6 6.0
39.2 7.5
a Averages are for compounds containing the hydantoin or dihydrouracil ring without spiro or fused linkages to other rings. Data from the
Cambridge Crystal Structure Data Base. b From 37 structures. c From 32 structures.
intramolecularly catalyzed hydrolysis of maleamic acids (which
involves cyclization to the anhydrides). Introduction of one and
two methyl groups increases the rate by factors of 30 and 1.5 ×
104 respectively, reflecting substantial decreases in the prospect-
ive internal bond angles at the alkene carbons.11
The rearrangement of 1-alkyl-substituted
dihydroorotic acids to hydantoinacetic acids in base
We report a strong Thorpe–Ingold effect on the formation of
Scheme 2
five-membered rings from the rearrangement of dihydroorotic
vention of the original Thorpe–Ingold effect in the second case.
to hydantoinacetic acids in KOH solutions: which occurs on
This arises from the geometrical requirements imposed by the
alkylation of N(1) of the dihydrouracil ring (Scheme 3).
presence of planar segments of conjugated sp2-hybridized
atoms. von Baeyer suggested many years ago that cyclopentane
is strainless because the tetrahedral bond angles at carbon
(∼109Њ) match those of a regular pentagon (108Њ). In an irregu-
lar pentagon, as long as it is planar, the sum of the angles
remains fixed at 540Њ. When the intrinsic bond angles of some
of the atoms are 120Њ—there are four such atoms in the cases
cited above—the sum of bond angles exceeds 540Њ. With conju-
gation enforcing local regions of planarity the conflict can be
resolved by a combination of ring puckering and decreases in
some or all bond angles. The latter course is helped by the
Thorpe–Ingold effect, which thus favours cyclization more
strongly.
The opposite situation prevails in six-membered rings. A ten-
dency to planarity demands ultimately the 120Њ bond angles of
a regular hexagon, and thus atypically large angles at tetra-
hedral centres. This is borne out by the X-ray structural data on
hydantoins and dihydrouracils shown in Table 1.
The averaged internal bond angles of hydantoins are all
considerably reduced, that at C(5) by 8Њ compared with the
standard tetrahedral angle, while the torsion angles (Table 1(b))
indicate that the ring is essentially planar. Although the average
values for the angles at C(5) and C(6) in dihydrouracils are close
to tetrahedral these derive mainly from compounds with one or
two substituents at these atoms. In the parent dihydrouracil the
angles are 112.6Њ and 110.3Њ, respectively.10 The torsion angles
for the six-membered rings show that there is considerable
puckering involving the tetrahedral carbon atoms, and even the
two amide groups are slightly twisted with respect to each other
(torsion angle 1234).
Scheme 3
The change in behaviour in aqueous alkali is quite
spectacular. Dihydroorotic acid 1a is readily hydrolyzed to
N-carbamoylaspartate dianion 2a, which is stable under the
conditions. The hydrolysis products 2b and 2c of the methyl and
ethyl derivatives slowly cyclize, to form equilibrium amounts
of the dianion of hydantoinacetate 3. And the formation of
hydantoinacetate 3 is so fast for the secondary alkyl derivatives
2d and 2e that the process followed by UV appears superficially
as a direct conversion of 1d (e) into 3d (e).
The rate increase in the cyclization of the dianion of
N-carbamoylaspartic acid (k23 of Scheme 3) was found to be
ca. 40 when R = H was substituted for Me—a value comparable
to the maleamic acid case quoted above.
Results
The alkaline hydrolysis of 1-alkyldihydroorotic acids 1 has been
studied previously,12 to assess the effect on rates of an axial
carboxylate group. (This conformational preference is the result
of allylic strain: in the parent acid the COOH group is more or
A measure of the Thorpe–Ingold effect on the formation of
five-membered rings with five planar atoms is founded in the
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 0 9 8 – 1 1 0 3
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less equally axial and equatorial.) When the study was extended
to include R = isopropyl and R = cyclohexyl the reaction stud-
ied by UV appeared to show a direct conversion into the corre-
sponding hydantoic acid 3. This could in principle have resulted
As expected, in 0.1–1 M KOH the hydrolyses of the
N-isopropyl and N-cyclohexyl-dihydroorotic acids 1d and 1e,
and the formation of the hydantoinacetic acids 3d and 3e are
apparently first order in [OHϪ]:
from intramolecular attack of carboxylate anion on the C᎐O at
position 4, perhaps helped by buttressing by the neighbouring
secondary alkyl group.
᎐
V = k12[12؊][OHϪ] and V = k23[22؊][OHϪ].
However, this pathway is not consistent with the observed
kinetics. In 0.1–1 M KOH dihydroorotic acids 1 exist as the
dianions (Scheme 3). The rate of formation of 3 shows a first
order dependence on [OHϪ]: an intramolecular reaction of the
dianion of 1d would be independent of hydroxide concen-
The kinetics are revealed as being of the second order when the
unproductive ionizations are accounted for,
kcor = k1k3/kϪ1.
1
tration. Furthermore, a H NMR study of the course of the
The cyclizations of the N-methyl and N-ethyl-carbamoylacetic
acids 2b and 2c are too slow for a pH–rate profile to be meas-
ured, so rates were measured in 1 M KOH. To check the kinetic
order a pH–rate profile for the cyclization of the ethyl derivative
2c was obtained at 50 ЊC, and reaction found to be first order in
[OHϪ] (see Fig. 1).
reaction with 1d revealed transient formation of the intermedi-
ate N-(1Ј-isopropylcarbamoyl)aspartic acid 2d. Finally, when
solutions of the hydrolyzed products 2 of methyl and ethyl
derivatives 1b and 1c were left to stand they slowly cyclized,
forming equilibrium mixtures of 2 and 3.
The course of the rearrangement is thus that outlined in
Scheme 3, involving base catalyzed nucleophilic attack of the
urea NH2 on the carboxylate group. In the case of 1b and 1c the
two consecutive reactions are well separated in time and separ-
ate pseudo first order rate constants could be obtained from
the decrease in absorbance of 12؊ at λmax = 240 nm and the
subsequent increase in absorbance at 232 nm (λmax for 3b and
3c). The isopropyl and cyclohexyl derivatives 2b and 3b, on the
other hand, cyclized much faster so that this simple treatment
was no longer possible: the rate constants were obtained by
curve fitting of the variation of absorbance with time to the
integrated first order rate equation for two consecutive
reactions.
The preferred mechanism13 of alkaline hydrolysis of di-
hydrouracils and hydantoins (shown in Scheme 4) is character-
ized by two parallel modes of decomposition of the tetrahedral
intermediate T؊, catalyzed by water and OHϪ respectively.
Fig. 1 Plots of the observed pseudofirst order rates, sϪ1, against
[KOH] at 50.0 ЊC: open circles hydrolysis of 1c, k1 = 1.25 × 10Ϫ3 dm3
molϪ1 sϪ1; filled circles cyclization of 2c, k2 = 3.07 × 10Ϫ4 dm3 molϪ1 sϪ1
.
Measuring the equilibria for cyclization of the carb-
amoylaspartic acids 2b and 2c also provided the rate constants
(k32) for hydrolysis of hydantoinacetic acids 3b and 3c, because
kobs23 = k23 ϩ k32.
Scheme 4
The full set of kinetic data is shown in Table 2. Two sets of
rate constants are presented for comparison. For each com-
pound the first column presents the apparent second or first
order rate constant determined in 1 M KOH. However, our
earlier work12 indicates that the observed hydrolysis rates, k12,
of the parent dihydroorotic acid 1a and its N-methyl derivative
1b in 1 M KOH are determined mainly by k1, the rate constant
for formation of the tetrahedral intermediate. For the remain-
ing compounds the OHϪ catalyzed breakdown of the tetra-
hedral intermediate (k1k3/kϪ1) is rate determining at 1 M KOH.
The latter mechanism is the one for which rate constants could
be obtained in all cases, and these are given in parentheses in
Table 2. These rate constants are readily obtained from the
experimental second order rate constants and pKNH: from eqns.
The steady state approximation affords the following rate
equation for the forward reaction:
(1)
where kcor is the observed first-order rate constant corrected for
unproductive ionization at 3-NH:
(2)
(1) and (2), under conditions where [OHϪ] >> Kw/KNH
:
In the region of pH 10–14 1a and 3a exhibit pH-rate profiles
for kcor in which the slope changes from 1 to 2, then back to 1,
due to rate determining k1k2/kϪ1, k1k3/kϪ1 and k1 respectively.
Upon increasing the substituent size in 1,6-disubstituted di-
hydrouracils the term second order in [OHϪ], k1k3/kϪ1, tends to
become dominant throughout the pH region.12 This is the case
for compounds like 1,6-dimethyldihydrouracil and 1-ethyl-di-
hydroorotic acid 1c. Similarly the formation of 1,3,5,5-tetra-
methylhydantoin (stable in base up to 1 M KOH) from the
corresponding hydantoic acid is second order in [OHϪ] (based
on neutral substrate), consistent with a transition state carrying
two negative charges.14
k1k3/kϪ1 = (k12 or k32)KNH/Kw
(3)
The pKNH-values for 1 and 3 measured for this purpose appear
in Table 3.
The data obtained for the equilibrium:
K2Ϫ = [32؊]/[22؊]
(4)
in the case of the N-methyl and N-ethyl derivatives, b and c,
make an estimate of equilibrium with the N-H compounds a of
particular interest. This is possible because constants for two of
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 0 9 8 – 1 1 0 3
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Table 2 Rate constants for the hydrolysis of dihydroorotic acid and hydantoinacetic acid and the cyclization of N-carbamoylsuccinic acid in 0.1–1
M KOH (I = 1.0 M, KCl) at 25.0 ЊC, and k1k3/kϪ1-values according to eqn. (1) (in parentheses)
k12 dm3 molϪ1 sϪ1
k32 dm3 molϪ1 sϪ1
(dm6 molϪ2 sϪ1
R
(dm6 molϪ2 sϪ1
)
krel = ko/kx
k23 dm3molϪ1 sϪ1
krel = kx/ko
)
krel = ko/kx
H
CH3
C2H5
(CH3)2CH
C6H11
2.21 × 10Ϫ3 a (9.78d)
5.09 × 10Ϫ4 a (0.0783)d
3.32 × 10Ϫ4 a (0.0200)d
2.50 × 10Ϫ5 (0.0022)
2.58 × 10Ϫ5
1 (1)
2.7 × 10Ϫ7 b
1.15 × 10Ϫ5
3.78 × 10Ϫ5
1.62 × 10Ϫ4
2.22 × 10Ϫ4
1
43
140
600
2.88 × 10Ϫ5 c (0.91)
2.00 × 10Ϫ6 (0.047)
2.52 × 10Ϫ6 e (0.048)
1
4.3 (125)
6.7 (490)
88 (4400)
14 (19)
a Apparent first order rate constant in 1 M KOH sϪ1 b Calculated value, see text. c Interpolated from a temperature dependence study from ref. 15.
.
The pH–rate profile in the same paper indicates that this value, measured as the apparent bimolecular k32 in 0.1 M KOH, applies to the third order
k1k3/kϪ1 reaction. d Ref. 12. e Value inaccurate because of the large equilibrium constant.
Table 3 Acidity constants for dissociation at NH of hydantoinacetic
acids and dihydroorotic acids at 25.0 ЊC and I = 1.0 M (KCl)
acid is a step in the “de novo” biosynthesis of pyrimidine
bases.19 An intriguing point, recently reexamined,20 is that in
mineral acids the opposite regioselectivity is observed: cycliz-
ation proceeds by attack of the ureido NH2-group on the
1-CO2H to give hydantoinacetic acid, the only product isolated
by Nyc and Mitchell.21 The new interpretation20 is that in the
chemical reaction, attack on the distant carboxyl is hindered by
a strong hydrogen bond between the two carboxy groups, which
reduces the flexibility of the chain. Attack on the 1-CO2H takes
place in acid because the geminal ureido is favourably disposed.
It was also postulated that this hydrogen bond is broken in the
enzyme active site. From 1H vicinal coupling constants assigned
from specifically deuterium-labeled 2a we have estimated22 that
the conformations with the carboxy groups gauche account for
less than 60% of the neutral form in D2O—not consistent with
stabilization by a strong hydrogen bond. In contrast the popu-
lation of conformations with the ureido and 4-CO2H gauche
is 90%, so that proximity in forming the six-membered ring
should not be problem. Further, we showed previously17 that in
HCl solutions the cyclization of N-carbamoylaspartic acid
actually gives both products, with a kinetic regioselectivity
[3a] : [1a] of no more that 10 : 1, much less than the thermo-
dynamic preference discussed above.
Compound
pKNH
Compound
pKNH
3a
3b
3c
3d
9.50
9.63
9.72
9.97
1aa
1bb
1cb
1d
11.60
12.22
12.25
12.06
a Ref. 16. b Ref. 12
the equilibria of the thermodynamic cycle shown in Scheme 5
are available.
Scheme 5
At biological pH, near 7, both carboxy groups are ionized.
Because carboxylate anions are poor electrophiles reaction
must involve the neutral CO2H group. Since the more distant
carboxy group is a 30-times weaker acid more of it will be
present in the neutral CO2H form near pH 7, thus over-riding
the kinetic selectivity. The conclusion from chemical reactivity
data is thus that dihydroorotic acid is the preferred product at
neutral pH, so that enzyme catalysis is not in fact working
against strong intrinsic regioselectivities upon cyclization of
N-carbamoylaspartic acid.
K13 between dihydroorotic acid and hydantoinacetic acid was
determined17 in HCl at 70 ЊC, while the equilibrium K23
between carbamoylaspartic acid and dihydroorotic acid could
be set up enzymatically18 around pH 7 at 36 ЊC. As all the
necessary pKa-values involved are known, the equilibrium con-
stants between the various ionization states can be calculated.
The equilibrium data at 70 ЊC were corrected to 25 ЊC, as
described in the footnote of Table 4. (pKa-values for the carb-
oxy groups of N-carbamoylaspartic acid, and its equilibrium
constant, were determined at 36 ЊC, while the remaining pKa-
values were measured at 25 ЊC: this difference is ignored.) The
equilibrium data—experimental and estimated—are summar-
ized in Table 4.
The effect of N-substituents
Cyclizations of ureido acids are observed even in alkaline solu-
tion in fixed molecules or highly encumbered systems like
o-ureidobenzoic acid23 or 2,2,3,5-tetramethylhydantoic acid.14
Remarkably, just two substituents of the size of carboxymethyl
and isopropyl in the 1,5-position of hydantoin are enough to
make the ring stable in 1 M KOH. There is abundant evidence,
for example in the acid catalyzed cyclization of ureido acids,
Discussion
Intrinsic regioselectivity of cyclization of N-carbamoylaspartic
acids
The cyclization of N-carbamoylaspartic 2a to dihydroorotic
Table 4 Equilibrium constants for the cycle on Scheme 5
Equilibrium (compound)
Ko
K1Ϫ/2Ϫ molϪ1
K2Ϫ
krel
[1a]/[2a]
[3a]/[1a]
[3a]/[2a]
[3b]/[2b]
[3c]/[2c]
135a
80c
1.51 × 106 a
K1Ϫ =20d
3.8 × 10Ϫ6 b
2500
9.5 × 10Ϫ3 e
5.7
15
1.08 × 104 b
3.02 × 107
2.13 × 1010
8.05 × 1010
1
600
1600
a Ref. 18; from equilibrium achieved enzymatically at pH around 7 (dilute solutions) and pK1a = 3.10, pK2a = 2.83, pK2a– = 4.32 obtained at 37 ЊC and
I = 0.5 M. b pK1a– = 11.60. c Determined17 at 70 ЊC and corrected for a temperature of 25 ЊC by assuming ∆F = ∆H and Cp constant. d pKCOOH3a
3.70.18 e pKNH3a– from Table 3.
=
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 0 9 8 – 1 1 0 3
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that substitution at N(1) in the product causes the greatest
accelerations (krel-values obtained by comparison with the
corresponding unsubstituted ureido acids):24,25,5a
spectra were recorded on a Bruker Spectrospin WM 250
instrument (chemical shifts in ppm against TMS, couplings in
Hz), and UV measurements made using Unicam SP 800 UV
and Carl Zeiss Jena UV VIS spectrophotometer provided with
a thermostatted cell compartment, wavelengths in nm. Melting
points were taken on a Kofler block.
Agami and Couty26 have identified strong Thorpe–Ingold
effects due to N-alkyl substitution facilitating the formation
of 1,3-oxazolidin-2-ones or oxazolidin-2,5-diones compared to
the N-unsubstituted compounds. AM1 calculations showed
decreases in the C–NR–C angle of the open-chain reactant
when R = Me, leading Agami et al.27 to the conclusion that a
classical Thorpe–Ingold effect operates to favour ring-closure
upon N-methyl substitution.
Materials
Inorganic reagents and buffer components were of analytical
grade and were used without further purification. Potassium
hydroxide and buffer solutions were prepared with CO2-free
distilled water. The preparation of 3-alkyl-2,6-dioxo-hexa-
hydropyrimidine-4-carboxylic acids 1b,c, and d has been
described previously.29
A very strong such effect is observed on the equilibrium
hydantoinacetic acid
N-carbamoylaspartic acid [32؊]/[22؊]
(Table 4), where an N-methyl shifts the equilibrium by a factor
of 600. This seems too large to be simply a bond-angle effect:
the relative rates of similar acid-catalyzed cyclizations (Schemes
2 and 5) show that rate increases for substitution at the nitrogen
atom are much larger than that at C(5), even though significant
reductions of bond angles occur at both centres (data of
Table 1); and the substantial increase caused by N-substitution
in the rate of formation of the 6-membered ring shown in
Scheme 6 involves no bond-angle reduction. Studies of
rotational barriers around partial double bonds indicate28 that
in ureas considerable strain accumulates in the ground state
upon N-substitution. This is released upon cyclization as one
pair of the eclipsing groups is incorporated in the ring, as
explained by Allinger4 for the case of substituted hexanes.
3-Cyclohexyl-2,6-dioxohexahydropyrimidine-4-carboxylic
acid 1e. The parent 2-cyclohexylaminosuccinic acid mono-
amide was prepared as previously described.30 This was con-
verted into the N-ethoxycarbonyl derivative by dissolving the
mono-amide (0.5 g, 2.23 mmol), followed by 1 ml of ethyl
chloroformate, in 10 ml of dry triethylamine. After standing
for 2 hours at 50 ЊC the triethylamine was removed and the
residue dried in vacuo at 50 ЊC. The residual 1 g was treated for
4 h under reflux with sodium ethoxide (7 mmol) in 5 ml of
dry ethanol. The precipitate formed under cooling was filtered
rapidly to avoid moisture and washed with dry ethanol. The
solid was dissolved in a 3 ml of cold water and acidified with
HCl (Congo Red), then the precipitate filtered and recrystal-
lized from ethanol yielding 1e (180 mg, 34%), mp 234–235 ЊC.
(Found: C, 54.97; H, 6.70; N, 11.73. Calc. for C11H16N2O4: C,
54.99; H, 6.71; N 11.66%); δH (DMSO-d6) 1.0–1.8 (10 H,
m, (CH2)5), 2.566 (1 H, d, J44 16.6, J4e5 < 1.5, 4e-H), 2.851
(1 H, dd, J44 16.6, J4a5 7.2, 4a-H), 4.052 (1 H, s, broad unresol-
ved, 1Ј-H), 4.220 (1 H, d, J4a5 7.2, J4e5 < 1.5, 5-H), 10.055 (1 H,
s, NH).
Scheme 6
(3-Alkyl-2,5-dioxo-imidazolidin-4-yl)-acetic acids 3. The
In the absence of special effects on the transition state the
rate increases upon cyclization or decreases upon ring-opening
should be smaller than those for equilibrium: this is borne out
by the data in the final 4 columns of Table 2 (which compare
N–Me with N–H). The rate increase on cyclization is larger
than that on ring opening, which suggests a transition state
closer to the cyclic form. The hydrolyses of compounds a and b
allow a comparison of six versus five-membered ring behaviour.
When the apparent second order rate constants for hydantoin-
acetic acids 3 are compared to the first order constants for di-
hydroorotic acids 1 in 1 M KOH the decrease is larger for the
five-membered ring. As explained above, however, the data for
formation and hydrolysis of the hydantoinacetic acids refer to
the doubly negatively charged transition state,¶ so that it is more
appropriate to compare them with the third order rate con-
stants k1k3/kϪ1 for hydrolysis of 1. The latter exhibit a very large
decrease upon substitution of H for Me, which has been inter-
preted previously12 as an “inverse” GDME on ring opening.
The same trend is observed when the size of the N-substituent is
increased further (Table 2).
3-alkyl-2,6-dioxohexahydropyrimidine-4-carboxylic acid
1
(0.44 mmol) was dissolved in 20 ml of hydrochloric acid diluted
1 : 1 with water and refluxed for two hours. The residue was
evaporated to dryness and the residue recrystallized from
ethanol. Data for these compounds are summarized in Table 5.
1H NMR in DMSO-d6. The CH2 protons and the 4-H proton
formed an ABX system. The data for these protons were
obtained from the analysis of this system. 1b. 2.741 (3 H, s,
Me), 2.760 (2 H, octet, ∆νAB 11.1 Hz, JAB 17.1, JAX 4.7, JBX 4.3,
CH2), 4.160 (1 H, t, J 4.5, 4-H), 10.73 (1 H, s, NH), 12.76 br
(CO2H). 1c. 1.022 (3 H, t, J 7.1, Me), 2.767 (2 H, octet, ∆νAB
10.7 Hz, JAB 17.2, JAX = JBX = 4.5 CH2), 3.040 (1 H, sextet,
J 14.1, J 7.1, CHHN), 3.415 (1 H sextet, J 14.1, J 7.1, CHHN),
4.251 (1 H, t, J 4.5, 4-H), 10,74 (1 H, s, NH), 12.58 (1 H, s,
CO2H). 1d.|| 1.123 (3 H, d, J 6.9, Me), 1.169 (3 H, d, J 6.9, Me),
2.765 (2 H, octet, ∆νAB 7.2 Hz, JAB 17.0, JAX 4.6, JBX 4.0, CH2),
3.869 (1 H, septet, J 6.9), 4.199 (1 H, t, J 4.3, 4-H). 1e. 1.0–1.8
(10 H, m, (CH2)5), 2.822 (2 H d (J 3.4) CH2), 3.494 (1 H, t
unresolved, 4-H), 4.225 (1 H, br, 1Ј-H), 10.73 (1 H, s, NH),
12.55 (1 H, br, CO2H).
Increasing the size of the substituent from methyl to isopro-
pyl or cyclohexyl exhibits substantial effects on the rates of
cyclization of the N-alkylcarbamoylaspartic acids to hydanto-
inacetic acids (see columns 4 and 5 of Table 2)
Determination of pKas for dissociation at NH
pKa-values were determined spectrophotometrically in
a
series of buffers at 25.0 ЊC using the absorptions of the anions:
λmax ≅ 234 nm for N-alkylhydantoinacetic acids and 238 nm
for N-alkyldihydroorotic acids. pH-values were measured
using a Radiometer pH M 84 Research pH-meter, equipped
with a GK 2401 C electrode standardized at pH 6.87, 4.01 and
9.18.
Experimental
Unless otherwise stated IR-spectra are for Nujol mulls, using a
Bruker IFS 113v instrument, and frequencies in cmϪ1. 1H NMR
¶ Actually triply charged if the charge of the carboxylate group not
involved in the reaction is also taken into account.
|| Spectrum taken on a 400 MHz instrument.
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 0 9 8 – 1 1 0 3
1102

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Table 5 Data for (3-alkyl-2,5-dioxo-imidazolidin-4-yl)-acetic acids 3
Compound (formula)
Yield (%)a
Mp/ЊC
Found (%) (required)
C
H
N
3b C6H8N2O4
3c C7H10N2O4
3d C8H12N2O4
3e C11H16N2O4
92
91
92
90
184–185
190–191
196–197
199–200
41.79 (41.86)
45.21 (45.16)
48.11 (47.99)
55.01 (54.99)
4.75 (4.68)
5.38 (5.41)
6.01 (6.04)
6.90 (6.71)
16.24 (16.28)
15.02 (15.05)
13.89 (13.99)
11.72 (11.66)
a Of recrystallized product.
Kinetic measurements
Acknowledgements
Reactions were followed using stoppered cells, in the temper-
ature-controlled cell holder of the spectrophotometer or in
sealed vials at 25.0 ЊC. The reaction was initiated by adding
20 µl of a 0.05 M solution of the substrate in UV-grade meth-
anol to 2.75 ml of the KOH solution. The ionic strength was
maintained at 1 M with KCl.
We thank the Bulgarian Academy of Sciences and the Royal
Society for research and travel funds.
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O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 0 9 8 – 1 1 0 3
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