N-(Hydroxyalkyl)-uracils are the simplest formal analogs of nucleosides and their structure and properties
are attracting increasing attention of researchers. A method has been developed for the synthesis
of l-(hydroxyalkyl)-uracfls by alkylation of the potassium salt of uracil with esters of chloroalkyl alcohols
in dimethyl sulfoxide medium [i]. N-(fi-Hydroxyethyl)-uracfls have been synthesized by the reaction of
uracil and ethylene carbonate [2]. We have developed a method of synthesizing 3-(hydroxyethyl)-uracils by
the reaction of chlorohydrins with sodium salts of uracils in water [3].
The present investigation is devoted to the elucidation of the nature of the hydrogen bond in N-(hydroxyethyl)-
6-methyluracils. In N-(hydroxyalkyl)-uracils we might expect the appearance of a hydrogen
bond between the OH groups of the hydroxyalkyl radical of the C = O groups of the pyrimidine ring, as well
as between the NH groups of the lactam form of the pyrimidine ring and the C = O groups in mono-N-(hydroxyalkyl)-
uracfls. A more substantial role in the strengthening of the crystal lattice of N-(hydroxyalkyl)-
uracils is played by the second type of bond. This is confirmed by the fact that replacement of the hydrogen
atom in the NH group in the molecules of uracil and 6-methyluracil by a hydroxyalkyl radical lowers
the melting points of these compounds by approximately 100 ~ (Table 1), despite the possibility of the appearance
of a hydrogen bond C = O . . . HO. The introduction of a second N-hydroxyalkyl radical also
sharply lowers the melting point (by 80-90~ From Table 1 it is evident that the meltingpoints of N-(hydroxyalkyl)-
uracils approximately coincide with the melting points of the corresponding N-(alkyl)-uracils.
This is a confirmation of the fact that the OH group of the hydroxyalkyl radical does not participate in a
strong intermolecular hydrogen bond, which might significantly increase the strength of the crystal lattice.
For uracils that do not possess OH groups, the intermolecular association in the crystalline phase arises
on account of the hydrogen bond C = O . . . HN. This is confirmed by the data of x-ray diffraction study.
Thus, in the case of 1-methyluracil a hydrogenbond arises between the hydrogen atom at N 3 and the carbonyl
group in the 4-position of the pyrimidine ring [7]
CHs
I
N O
/ \/
NH... O
\/ II
0 . . 9 HN 1
o/\N / J
ctts
On the basis of the IR spectrum, the formation of a C = O . . . HN bond has been demonstrated for a
number of other heteroeyclie compounds possessing a CONHCO group [8].
Table 2 presents the values of the valence vibrations of the C = O, OH, and NIt groups of the investigated
and certain model compounds in the crystalline phase, as well as in solutions. For uracils in the
crystalline state, the vibrations of the C = O groups appear in the form of two bands, 1640-1690 and
A. E. Arbuzov Institute of Organic and Physical Chemistry, Academy of Sciences of the USSR.
Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. i0, pp. 2200-2206, October,
1971. Original article submitted December 30, 1969.
9 1972 Consultants Bureau, a division of Plenum Publishing Corporation, 227 West 17th Street, New York,
N. Y. 10011. All rights reserved. This article cannot be reproduced for any purpose whatsoever without
permission of the publisher. A copy of this article is available from the publisher for $15.00.
2080
TABLE i. Melting Points of N-(Hydroxyalkyl)-uracils and
Their N-(Alkyl)- Analogs
Compound Mp, ~
Uracil [4] . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3-Methyluracil [4] . . . . . . . . . . . . . . . . . . . . . . . . . .
1,3- Dimethylur acil [4] .......................
3-Ethyluracil [4] . . . . . . . . . . . . . . . . . . . . . . . . . . .
1-Ethyluracil [4] . . . . . . . . . . . . . . . . . . . . . . . . . . .
1,3- Diethyluracil [4] . . . . . . . . . . . . . . . . . . . . . . . .
1- (B - Hydroxyethyl)- uracil [1] . . . . . . . . . . . . . . . . . .
3- (/3- Hydroxyethyl)- uracil [5] . . . . . . . . . . . . . . . . . . .
1,3- Bis- (B-hydroxyethyl)- uracil [2] . . . . . . . . . . . . . . .
1,3- Bis- (8, y- dihydroxypropyl)- uracil [3] . . . . . . . . . . . .
1- (B- Chloroethyl)- uracil [2] . . . . . . . . . . . . . . . . . . . .
1-(n- Butyl)- uracil [1] . . . . . . . . . . . . . . . . . . . . . . . .
1- (4- Hydroxybutyl)- uraciI [1] . . . . . . . . . . . . . . . . . .
6-Methyluracil [4] . . . . . . . . . . . . . . . . . . . . . . . . . .
3, 6- Dimethylttracil [4] . . . . . . . . . . . . . . . . . . . . . . .
1,3, 6- Trimethyluracil [4] . . . . . . . . . . . . . . . . . . . . .
1-Ethyl- 3, 6- dimethyluracil [4] . . . . . . . . . . . . . . . . . .
3- Ethyl- 1, 6- dimethyluracil [4] . . . . . . . . . . . . . . . . . .
3- Ethyl- 6- methyluracil [4] . . . . . . . . . . . . . . . . . . . .
1,3- Diethyl- 6- methyluracil [4] . . . . . . . . . . . . . . . . . .
3- (B- Hydroxyethyl)- 6- mcthyluracil [3] . . . . . . . . . . . . .
1- (/3- Hydroxyethyl)- 3, 6- dimethyluraciI . . . . . . . . . . . .
1,3- Bis- (B-hydroxyethyl)- 6- methylur acil [3j . . . . . . . . .
3- (B- Hydroxyethyl)- 1,6-dimethyluracil [6] . . . . . . . . . .
3- (/3, y -Dihydroxypropyl)- 6- methyluracil [3] . . . . . . . . .
3- (B-Chloroethyl)- 6- methyluracil [6] . . . . . . . . . . . . .
1,3- Bis- (/~ - chloroethyl) -6 -methyluracil [6] . . . . . . . . . .
318
233
121-122
173-174
147.5
14-15
141-143
171.5-173
152.5-153
165-166.5
163-165
100-103
124-126
313-315
263-265
111-112
110-112
i12-I14
2O6
52-53
205.5-207
134-136
111-112
112-115
175.5-176.5
196-197
71-72
1705-1740 cm -I. The band VNH of the pyrimidine ring lies in the region of 3050-3260 cm -I. Certain heterocyclic
compounds containing the CONIICO group have two bands in the region of the ~ vibrations, ~ 3100
and 3200 em -1, in the solid state [8]. The higher frequency band belongs to the valence vibrations of the
bound NH group. The nature of the band 3100 cm -I has not been elucidated. In the case of N-hydroxyMkyl
derivatives of uracil in the solid state, the band ~3100 cm -I is always present. Sometimes, as in the case
of 3-(fl-hydroxyethyl)-5-bromo-6-methyluraci[, two bands are present, 3100 and 3170 em -~. In the case
of N-alkyiuraeils, the band 3100 em -I should be assigned to the valence vibrations of the bound NH groups,
since it disappears entirely in 1,3-disubstituted uracils.
In dilute solutions of uracils in dioxane, CHCI3, and CCI 4, the bands of the free C = O groups are observed,
and in the last two solvents the bands of the nonbonded NH groups as well.
The frequencies of the valence vibrations of the NH group in uracil and its derivatives have been
studied specially [9]. The valence vibrations of the C = O groups of N-(fl-hydroxyethyl)-6-methyluraeils
in the crystalline state and in solution appear in the same regions as for 3-methyl- and 1,3-dimethyl-6-
methyluracils (see Table 2).
To determine the position of the valence vibrations of the nonbonded OH groups and the possibility of
an intramoleeular hydrogen bond, we took the IR spectra of dilute solutions of N-(fl-hydroxyethyl)-6-methyluracils
in CCI 4. On account of the extremely low solubility of the compounds in CCI 4, this could be done
only for 1,3-disubstituted-6-methyluracils. In the IR spectrum of l-(fi-hydroxyethyl)-3,6-dimethyluracil
(concentration of the solution less than 0.0001 M) in the region of the valence vibrations of OH, two bands
are observed - a narrow intense peak at 3635 cm -I and a broader intense peak at 3435 cm -I (Fig. la). With
decreasing concentration of the solution, the intensity of the band 3435 cm -I decreases, while that of the
band 3635 cm -i increases (Fig. ib). Consequently, the absorption at 3635 cm -I belongs to the vibrations
of the nonbonded OH group, while the band 3435 cm -i belongs to the vibrations of the OH group bonded by
an intermolecular hydrogen bond. For l-(fi-hydroxyethyl)-3,6-dimethyluracil, we can represent the following
most probable types of intermolecular hydrogen bond:
2081
t~
O
OO
bO
TABLE 2. Frequencies of the Valence Vibrations of the C = O, NH, and OH Groups
Compound
I-(B -Hyd=oxyethyl)- 3, 6-dimethyluracil ...........
1 - (8-Hydroxyethyl)- 3, 6- dimethyl- 5- bromourac il ....
3 - (8 - Hydrox yethyl )- I, 6- dim ethylur acil ...........
3-(8- Hydroxyethyl)- I, 6- dimethyl- 5- bromouracil ....
i, 3- Bis- (8-hydroxyethyl)" 6- methylur acil ..........
i, 3- Bis- (8-hydroxyethyl)" 6- methyl- 5- bromour acil . .
3-(8- Hydroxyethyl)- 6- methyluracil ............
39- (B-Hydroxyethyl)- 6- methyl- 5-bromour acil ......
3-(8-H)droxypropyl)- 6-methyluracil ...........
3-(8, ~-Dihydroxypropyl)- 6- methylur acil .........
3- (/B, 7-Dih)/droxypropyl) -6 - methyl -5 -bromour acil . .
i, 3 - Bis- (8 - hydro xyethyl)- ur acil ...............
Uracil [i0] ............................
6-Methyluracil .........................
1-Meth~lnracil [10, 11] . . . . . . . . . . . . . . . . . . . .
1.3- Dimethyluracil [10, 12] . . . . . . . . . . . . . . . . .
3-Methyluracil [10-12] . . . . . . . . . . . . . . . . . . . .
3,6- Dimethyluraeil . . . . . . . . . . . . . . . . . . . . . . .
2-Hydroxypyrimidine [11] . . . . . . . . . . . . . . . . . .
4-Hydroxypyrimidine [11] . . . . . . . . . . . . . . . . . .
3- (B - Chloroethyl )- 6- metbylurac il [6] . . . . . . . . . . .
Crystalline phase u, cm "1
C=O
t665--1700
1640--1670; t700--1705
t640--t690
t630--t660; 1690--t720
1640--1690
t630--t650; t700
1645--t660; 1720
1620--1660; t7t0--1740
t640--1660; t730
t670--t680; t720--1725
1670--t680; t710--t720
1640--t670; t690
1670--1715
1640--1700; t7t0--t730
t675--t695
i665; t712
1630; 1705
t620--t720
1647; t733
t684; t7t6
1610--1670; t730--t740
N]:I
3092
3100; 3t69--3170
3100
3t00
3090--3100
3100
3395 :~
3~2 :~
3200
3t95
3200; 3257
3t00
OH
3430
3480
3380--3390
3430--3440
3480--3520
3360--3400
3480
3359--3360
3500--3580
3250--3300
3200--3230;
3350--3370
3320--3380
uC= O of solution, cm -~
t665; t700 *
t670; 1710 *
167s *
1665; 1700--173C
1660; 1700--t730~
t665--1670; 1700--I730
t698; 1720
t689; t7t3 $
t670; 17t2
t677; t727
1765 $
1721 *
* Solution in CC14.
"~ Solution in dioxane; the second band is overlapped by the absorption 'of the solvent.
:~ Solution in CHC1 s.
uOH of solution
in CC14,
C1TI "1
3435; 3635
3485; 3635
3485
35t0
3490; 3635
3515; 3635
0
II
HOCH~CHzN/
\
I
CI%
0 Clts 0
11 ~ tl
/-- ~'--0 . HOCH~CH~N / N/--'"
I I x,(..
CHs CH2CH~0H CHs
B
-CH~ CHs
I 0 I
N II N
='~/=0 . . .HOCH~CHsN\/ ~=0
l
CH~
A
CH~ 0
--N /\
HsC / ~ 'N} /% O... HO--CH~
CH2 C[H 2
I ,
XI
o
c
A characteristic peculiarity of the intermolecular bond in the investigated compounds is the fact that it is
observed in very dilute solutions at concentrations less than 0.0001 M. A selection cannot be made among
the structures A-C on the basis of the shift of v C = O, since the position of the two bands v C = O changes
negligibly in the transitions from solid to solution.
r
O0
fO0
~Jo
<
fO0
50
I I I
r J I
d300 3000
d
I I . - ~
I I
J~O0 3800 Cl~l -I
Fig. i. IR spectra of solutions in
CCI 4 in the region of the valence
vibrations of the OH groups: a, b)
l-(/3-hydroxyethyl) -3,6-dimethyluracil
; c, d) l-(fi-hydroxyethyl)-
3,6-dimethyl-5-bromouracil; e, f)
1,3-his-(fl-hydroxyethyl)-6-methyluracil,
a, c, e) At C ~ 0.0001 M;
b, d, f) after two to four dilutions of
the solution.
The introduction of bromine into the 5-position of l-(fl-hydroxyethyl)-
3,6-dimethyluracil leads to a shift of the band into
the regions of the valence vibrations of the C = O and OH groups.
In CCI 4 solution, the band 1665 cm -I is shifted by 5 em -I, while
the band 1700 cm -t is shifted by i0 cm -I into the more high-frequency
region. In the region of the vibrations of OH, just as in
the nonbrominated product, there are two bands - the band of the
free OH group 3635 cm -I and the band of the bound OH group 3485
cm -I. The decrease in the intensity of the band 3485 cm -i with
dilution (Fig. ic, d) indicates the intermolecular character of the
hydrogen bond formed. The shift of the band of the bound OH group
of l-(p-hydroxyethyl)-3,6-dimethyl-5-bromouracil into the highfrequency
region in comparison with l-(fl-hydroxyethyl}-3,6-
dimethyluracil is an indication of weakening of the hydrogen bond,
probably on account of a decrease in the negative charge of the
oxygen of the carbonyl group. As we go from dilute solutions of
l-(fl-hydroxyethyl)-3,6-dimethyluracil and its bromo derivative to
crystalline samples, the band of the free OH groups disappears
entirely, while the bands of the bound OH groups practically do not
change their shape and position. Evidently in the crystalline state
the same type of hydrogen bond is also preserved as in solution.
For 3-(~-hydroxyethyl)-l,6-dimethyluracil and its 5-bromo
derivatives, which are structural isomers of the compounds discussed
above, only the band of the vibrations of the bound OH
group - at 3485 and 3510 em -I, respectively - is observed in dilute
solutions. The picture of the absorption and the position of the
maximum do not depend on the concentration. This indicates that
the OH group of the hydroxyethy[ radical is bonded by an intramolecular
hydrogen bond of the D or E type
0 . . . HO--CH~ 0
R II R !J
,-o )=o....o
HsC / \ N/ - - R~H, Br HaC / N
I I
CHs CHa
D E
2083
The intramolecular bond is weakened when bromine is introduced into the 5-position of the pyrimidine ring
(a 25 cm -t shift of the band into the high-frequency region). A consideration of the Stewart-Briegleb model
shows that the intramolecular hydrogen bond~ are the most profitable for all the 3-(fl-hydroxyethyl)-uracils
studied. Evidently in the crystalline state also, intramolec~ttar hydrogen bonds OH . . . O = C are realized
in these compounds. Then, for crystalline 3-(fi-hych~oxyethyl) -, 3-(fl-hydroxyethyl)-5-bromo-, and 3-(fihydroxypropyl)-
6-methyluracils, the following types of hydrogen bonds can be represented:
o... HO--CHR' R'CH OH B'CH OH
R /\s-- H~ cm 6 cH~ 6 II, I_o. I!
H3 \N/-- "" [ CH8 0 H ..0~- ~NH.o.
H...O= R I I
CH~ N t
|
! l
R CH--0H... 0
R=H2 Br; R'=H, CH3
Considering the data of x-ray diffraction study of 1-methyluracil [7], we should recognize the first
type of association as more probable.
An investigation of the shift u C = O in solution and in the crystalline state does not permit selection
to be made of the carbonyl with which the intramolecular hydrogen bond is formed.
In the IR sepctr a of solutions of 1,3-bi s- (/3-hydroxyethyl)- and 1,3-bis ,(fl -hydroxyethyl) -5 -bromo-6 -
methyluracils in CC14 (~0.00003 M), two bands are observed: the band of the vibration of the nonbonded OH
group 3635 cm -1 and the bands of the bound OH groups 3490 and 3515 cm -t, respectively. Further dilution
does not change the relative intensities and positions of the bands (Fig. le, f). This indicates that the OH
group of the 3-fl-hydroxyethyl radical is bonded by an intramolecular hydrogen bond, while the 1-fl-hydroxyethyl
radical does not participate in a hydrogen bond in dilute solutions. In crystalline samples of 1,3-bis-
(fi-hydroxyethyl)- and 1,3-bis-(fl-hydroxyethyl)-5-bromo-6-methyluracils, the OH group of the 3-fl-hydroxyethyl
radical evidently participates in an intramolecular hydrogen bond, while the OH group of the
1-fl -hydroxyethyl radical participates in intermolecular associations.
In the case of 3-(fi,~/-dihydroxypropyl)-6-methyluracil, the presence of the second OH group opens up
the possibility for the formation of an intermolecular hydrogen bond, including polymer association. This
leads to complication of the picture of the IR spectrum in the region of the vibrations of the OH groups and
to an increase in the strength of the crystal lattice, and consequently, to an increase in the melting point.
EXPERIMENTAL METHOD
In the work we used analytically pure samples, produced according to [3, 13]. 3-(~-Hydroxyethyl)-
1,6-dimethyl-5-bromouracil was produced by the reaction of 3-(fl-hydroxyethyl)-6-methyl-5-bromouraeil
and CH3I in the presence of an equimolar amount of NaOH in water in a sealed ampoule at i00-ii0 ~ . After
3 h of heating, the ampoule was cooled, opened, the precipitated crystals filtered off, dried, and reerystallized
twice from benzene with an addition of activated charcoal. The yield of the uracil was 87~ of the
theoretical; mp 153-154 ~ Found: C 36.34; H 4.27; N i0.42~0. CsHIiN203Br. Calculated: C 36.5; H 4.18;
N 10.65%.
The IR spectra were taken on a UR-10 spectrometer. Crystalline samples were taken in the form of
suspensions in liquid petrolatum. The spectra of dtoxane solutions (C ~ 0.01 M) were taken in a euvette (i
mm). On account of the very poor solubility of N-(fi-hydroxyethyl)-uracils in CC14, the solutions were prepared
as follows. A weighed 0.i g sample of the compound was placed in a flask, i00 ml of CCI 4 was added,
and the mass was brought to boiling. The solution!, cooled to room temperature, was filtered to remove
the undissolved substance (approximately 0.06-0.09 g). In the case of 1,3-bis-(fi-hydroxyethyl)-6-methyl-
Uracil and 1,3-bis-(fi-hydroxyethyl)-6-methyl-5-bromouracil, the boiling solution was filtered, and the
spectra were taken in a cuvette warmed to 35-40 ~ Cuvettes i00 mm long were used to take the spectra
in the region of 3100-3700 cm -I, and euvettes 20 and 50 mm long in the region of 1620-1800 cm -i.
The authors would like to express their deep gratitude to R. R. Shagidullin, O. A. Raevskii, S. A.
Samartseva, N. V. Teptina, and A. V. Chernova, for their aid in the work.
2084
CONCLUSIONS
1. The IR spectra of N-(hydroxyalkyl)-uraeils were studied in the solid state and in solution.
2. The OH group of the hydroxyalkyl radical of 3-(fl-hydroxyethyl)-6-methyluracils participates in
an intramolecular hydrogen bond.
3. The OH group of the hydroxyethyl radical of 1-(fl-hydroxyethyl)-6-methyluracils participates in
an intermolecular hydrogen bond.
LITERATURE CITED
i. B.R. Baker and T. J. Schwan, J. Med. Chem., 9, 73 (1966).
2. M. Prystas and J. Gut, Coll. Czechosl. Chem. Comm., 27, 1054 (1962).
3. V.S. Reznik and N. G. Pashkurov, Izv. Akad. Nauk SSSR, Set. Khim., 1327 (1968).
4. D.J. Brown, The Pyrimidines, Interscience, New York-London (1962).
5. H. Tuppy and E. Kuchler, Monatsh. Chem., 95, 1698 (1964).
6. V.S. Reznik, Yu. S. Shvetsov, and N. G. Pashkurov, Izv. Akad. Nauk SSSR, Ser. Khim., 2811
(1968).
7. D.W. Green, F. S. Mathews, and A. Rich, J. Biol. Chem., 237, 3573 (1962).
8. N.A. Borisevich and N. N. Khovratovich, Zh. Prikl. Spektr., 7, 538 (1967).
9. J. Pitha and S. Vasickova, Coll. Czechosl. Chem. Comm., 30, 1792 (1965).
i0. K. Nakanishi, N. Suzuki, and F. Yamazaki, Bull. Chem. Soc. Japan, 34, 53 (1961).
ii. S.F. Mason, J. Chem. Soc., 4874 (1957).
12. M. Horak and J. Gut, Coll. Czechosl. Chem. Comm., 26, 1680 (1961).
13. V. S. Reznik and Yu. S. Shvetsov, Izv. Akad. Nauk SSSR, Ser. Khim., 1646 (1970).
are attracting increasing attention of researchers. A method has been developed for the synthesis
of l-(hydroxyalkyl)-uracfls by alkylation of the potassium salt of uracil with esters of chloroalkyl alcohols
in dimethyl sulfoxide medium [i]. N-(fi-Hydroxyethyl)-uracfls have been synthesized by the reaction of
uracil and ethylene carbonate [2]. We have developed a method of synthesizing 3-(hydroxyethyl)-uracils by
the reaction of chlorohydrins with sodium salts of uracils in water [3].
The present investigation is devoted to the elucidation of the nature of the hydrogen bond in N-(hydroxyethyl)-
6-methyluracils. In N-(hydroxyalkyl)-uracils we might expect the appearance of a hydrogen
bond between the OH groups of the hydroxyalkyl radical of the C = O groups of the pyrimidine ring, as well
as between the NH groups of the lactam form of the pyrimidine ring and the C = O groups in mono-N-(hydroxyalkyl)-
uracfls. A more substantial role in the strengthening of the crystal lattice of N-(hydroxyalkyl)-
uracils is played by the second type of bond. This is confirmed by the fact that replacement of the hydrogen
atom in the NH group in the molecules of uracil and 6-methyluracil by a hydroxyalkyl radical lowers
the melting points of these compounds by approximately 100 ~ (Table 1), despite the possibility of the appearance
of a hydrogen bond C = O . . . HO. The introduction of a second N-hydroxyalkyl radical also
sharply lowers the melting point (by 80-90~ From Table 1 it is evident that the meltingpoints of N-(hydroxyalkyl)-
uracils approximately coincide with the melting points of the corresponding N-(alkyl)-uracils.
This is a confirmation of the fact that the OH group of the hydroxyalkyl radical does not participate in a
strong intermolecular hydrogen bond, which might significantly increase the strength of the crystal lattice.
For uracils that do not possess OH groups, the intermolecular association in the crystalline phase arises
on account of the hydrogen bond C = O . . . HN. This is confirmed by the data of x-ray diffraction study.
Thus, in the case of 1-methyluracil a hydrogenbond arises between the hydrogen atom at N 3 and the carbonyl
group in the 4-position of the pyrimidine ring [7]
CHs
I
N O
/ \/
NH... O
\/ II
0 . . 9 HN 1
o/\N / J
ctts
On the basis of the IR spectrum, the formation of a C = O . . . HN bond has been demonstrated for a
number of other heteroeyclie compounds possessing a CONHCO group [8].
Table 2 presents the values of the valence vibrations of the C = O, OH, and NIt groups of the investigated
and certain model compounds in the crystalline phase, as well as in solutions. For uracils in the
crystalline state, the vibrations of the C = O groups appear in the form of two bands, 1640-1690 and
A. E. Arbuzov Institute of Organic and Physical Chemistry, Academy of Sciences of the USSR.
Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. i0, pp. 2200-2206, October,
1971. Original article submitted December 30, 1969.
9 1972 Consultants Bureau, a division of Plenum Publishing Corporation, 227 West 17th Street, New York,
N. Y. 10011. All rights reserved. This article cannot be reproduced for any purpose whatsoever without
permission of the publisher. A copy of this article is available from the publisher for $15.00.
2080
TABLE i. Melting Points of N-(Hydroxyalkyl)-uracils and
Their N-(Alkyl)- Analogs
Compound Mp, ~
Uracil [4] . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3-Methyluracil [4] . . . . . . . . . . . . . . . . . . . . . . . . . .
1,3- Dimethylur acil [4] .......................
3-Ethyluracil [4] . . . . . . . . . . . . . . . . . . . . . . . . . . .
1-Ethyluracil [4] . . . . . . . . . . . . . . . . . . . . . . . . . . .
1,3- Diethyluracil [4] . . . . . . . . . . . . . . . . . . . . . . . .
1- (B - Hydroxyethyl)- uracil [1] . . . . . . . . . . . . . . . . . .
3- (/3- Hydroxyethyl)- uracil [5] . . . . . . . . . . . . . . . . . . .
1,3- Bis- (B-hydroxyethyl)- uracil [2] . . . . . . . . . . . . . . .
1,3- Bis- (8, y- dihydroxypropyl)- uracil [3] . . . . . . . . . . . .
1- (B- Chloroethyl)- uracil [2] . . . . . . . . . . . . . . . . . . . .
1-(n- Butyl)- uracil [1] . . . . . . . . . . . . . . . . . . . . . . . .
1- (4- Hydroxybutyl)- uraciI [1] . . . . . . . . . . . . . . . . . .
6-Methyluracil [4] . . . . . . . . . . . . . . . . . . . . . . . . . .
3, 6- Dimethylttracil [4] . . . . . . . . . . . . . . . . . . . . . . .
1,3, 6- Trimethyluracil [4] . . . . . . . . . . . . . . . . . . . . .
1-Ethyl- 3, 6- dimethyluracil [4] . . . . . . . . . . . . . . . . . .
3- Ethyl- 1, 6- dimethyluracil [4] . . . . . . . . . . . . . . . . . .
3- Ethyl- 6- methyluracil [4] . . . . . . . . . . . . . . . . . . . .
1,3- Diethyl- 6- methyluracil [4] . . . . . . . . . . . . . . . . . .
3- (B- Hydroxyethyl)- 6- mcthyluracil [3] . . . . . . . . . . . . .
1- (/3- Hydroxyethyl)- 3, 6- dimethyluraciI . . . . . . . . . . . .
1,3- Bis- (B-hydroxyethyl)- 6- methylur acil [3j . . . . . . . . .
3- (B- Hydroxyethyl)- 1,6-dimethyluracil [6] . . . . . . . . . .
3- (/3, y -Dihydroxypropyl)- 6- methyluracil [3] . . . . . . . . .
3- (B-Chloroethyl)- 6- methyluracil [6] . . . . . . . . . . . . .
1,3- Bis- (/~ - chloroethyl) -6 -methyluracil [6] . . . . . . . . . .
318
233
121-122
173-174
147.5
14-15
141-143
171.5-173
152.5-153
165-166.5
163-165
100-103
124-126
313-315
263-265
111-112
110-112
i12-I14
2O6
52-53
205.5-207
134-136
111-112
112-115
175.5-176.5
196-197
71-72
1705-1740 cm -I. The band VNH of the pyrimidine ring lies in the region of 3050-3260 cm -I. Certain heterocyclic
compounds containing the CONIICO group have two bands in the region of the ~ vibrations, ~ 3100
and 3200 em -1, in the solid state [8]. The higher frequency band belongs to the valence vibrations of the
bound NH group. The nature of the band 3100 cm -I has not been elucidated. In the case of N-hydroxyMkyl
derivatives of uracil in the solid state, the band ~3100 cm -I is always present. Sometimes, as in the case
of 3-(fl-hydroxyethyl)-5-bromo-6-methyluraci[, two bands are present, 3100 and 3170 em -~. In the case
of N-alkyiuraeils, the band 3100 em -I should be assigned to the valence vibrations of the bound NH groups,
since it disappears entirely in 1,3-disubstituted uracils.
In dilute solutions of uracils in dioxane, CHCI3, and CCI 4, the bands of the free C = O groups are observed,
and in the last two solvents the bands of the nonbonded NH groups as well.
The frequencies of the valence vibrations of the NH group in uracil and its derivatives have been
studied specially [9]. The valence vibrations of the C = O groups of N-(fl-hydroxyethyl)-6-methyluraeils
in the crystalline state and in solution appear in the same regions as for 3-methyl- and 1,3-dimethyl-6-
methyluracils (see Table 2).
To determine the position of the valence vibrations of the nonbonded OH groups and the possibility of
an intramoleeular hydrogen bond, we took the IR spectra of dilute solutions of N-(fl-hydroxyethyl)-6-methyluracils
in CCI 4. On account of the extremely low solubility of the compounds in CCI 4, this could be done
only for 1,3-disubstituted-6-methyluracils. In the IR spectrum of l-(fi-hydroxyethyl)-3,6-dimethyluracil
(concentration of the solution less than 0.0001 M) in the region of the valence vibrations of OH, two bands
are observed - a narrow intense peak at 3635 cm -I and a broader intense peak at 3435 cm -I (Fig. la). With
decreasing concentration of the solution, the intensity of the band 3435 cm -I decreases, while that of the
band 3635 cm -i increases (Fig. ib). Consequently, the absorption at 3635 cm -I belongs to the vibrations
of the nonbonded OH group, while the band 3435 cm -i belongs to the vibrations of the OH group bonded by
an intermolecular hydrogen bond. For l-(fi-hydroxyethyl)-3,6-dimethyluracil, we can represent the following
most probable types of intermolecular hydrogen bond:
2081
t~
O
OO
bO
TABLE 2. Frequencies of the Valence Vibrations of the C = O, NH, and OH Groups
Compound
I-(B -Hyd=oxyethyl)- 3, 6-dimethyluracil ...........
1 - (8-Hydroxyethyl)- 3, 6- dimethyl- 5- bromourac il ....
3 - (8 - Hydrox yethyl )- I, 6- dim ethylur acil ...........
3-(8- Hydroxyethyl)- I, 6- dimethyl- 5- bromouracil ....
i, 3- Bis- (8-hydroxyethyl)" 6- methylur acil ..........
i, 3- Bis- (8-hydroxyethyl)" 6- methyl- 5- bromour acil . .
3-(8- Hydroxyethyl)- 6- methyluracil ............
39- (B-Hydroxyethyl)- 6- methyl- 5-bromour acil ......
3-(8-H)droxypropyl)- 6-methyluracil ...........
3-(8, ~-Dihydroxypropyl)- 6- methylur acil .........
3- (/B, 7-Dih)/droxypropyl) -6 - methyl -5 -bromour acil . .
i, 3 - Bis- (8 - hydro xyethyl)- ur acil ...............
Uracil [i0] ............................
6-Methyluracil .........................
1-Meth~lnracil [10, 11] . . . . . . . . . . . . . . . . . . . .
1.3- Dimethyluracil [10, 12] . . . . . . . . . . . . . . . . .
3-Methyluracil [10-12] . . . . . . . . . . . . . . . . . . . .
3,6- Dimethyluraeil . . . . . . . . . . . . . . . . . . . . . . .
2-Hydroxypyrimidine [11] . . . . . . . . . . . . . . . . . .
4-Hydroxypyrimidine [11] . . . . . . . . . . . . . . . . . .
3- (B - Chloroethyl )- 6- metbylurac il [6] . . . . . . . . . . .
Crystalline phase u, cm "1
C=O
t665--1700
1640--1670; t700--1705
t640--t690
t630--t660; 1690--t720
1640--1690
t630--t650; t700
1645--t660; 1720
1620--1660; t7t0--1740
t640--1660; t730
t670--t680; t720--1725
1670--t680; t710--t720
1640--t670; t690
1670--1715
1640--1700; t7t0--t730
t675--t695
i665; t712
1630; 1705
t620--t720
1647; t733
t684; t7t6
1610--1670; t730--t740
N]:I
3092
3100; 3t69--3170
3100
3t00
3090--3100
3100
3395 :~
3~2 :~
3200
3t95
3200; 3257
3t00
OH
3430
3480
3380--3390
3430--3440
3480--3520
3360--3400
3480
3359--3360
3500--3580
3250--3300
3200--3230;
3350--3370
3320--3380
uC= O of solution, cm -~
t665; t700 *
t670; 1710 *
167s *
1665; 1700--173C
1660; 1700--t730~
t665--1670; 1700--I730
t698; 1720
t689; t7t3 $
t670; 17t2
t677; t727
1765 $
1721 *
* Solution in CC14.
"~ Solution in dioxane; the second band is overlapped by the absorption 'of the solvent.
:~ Solution in CHC1 s.
uOH of solution
in CC14,
C1TI "1
3435; 3635
3485; 3635
3485
35t0
3490; 3635
3515; 3635
0
II
HOCH~CHzN/
\
I
CI%
0 Clts 0
11 ~ tl
/-- ~'--0 . HOCH~CH~N / N/--'"
I I x,(..
CHs CH2CH~0H CHs
B
-CH~ CHs
I 0 I
N II N
='~/=0 . . .HOCH~CHsN\/ ~=0
l
CH~
A
CH~ 0
--N /\
HsC / ~ 'N} /% O... HO--CH~
CH2 C[H 2
I ,
XI
o
c
A characteristic peculiarity of the intermolecular bond in the investigated compounds is the fact that it is
observed in very dilute solutions at concentrations less than 0.0001 M. A selection cannot be made among
the structures A-C on the basis of the shift of v C = O, since the position of the two bands v C = O changes
negligibly in the transitions from solid to solution.
r
O0
fO0
~Jo
<
fO0
50
I I I
r J I
d300 3000
d
I I . - ~
I I
J~O0 3800 Cl~l -I
Fig. i. IR spectra of solutions in
CCI 4 in the region of the valence
vibrations of the OH groups: a, b)
l-(/3-hydroxyethyl) -3,6-dimethyluracil
; c, d) l-(fi-hydroxyethyl)-
3,6-dimethyl-5-bromouracil; e, f)
1,3-his-(fl-hydroxyethyl)-6-methyluracil,
a, c, e) At C ~ 0.0001 M;
b, d, f) after two to four dilutions of
the solution.
The introduction of bromine into the 5-position of l-(fl-hydroxyethyl)-
3,6-dimethyluracil leads to a shift of the band into
the regions of the valence vibrations of the C = O and OH groups.
In CCI 4 solution, the band 1665 cm -I is shifted by 5 em -I, while
the band 1700 cm -t is shifted by i0 cm -I into the more high-frequency
region. In the region of the vibrations of OH, just as in
the nonbrominated product, there are two bands - the band of the
free OH group 3635 cm -I and the band of the bound OH group 3485
cm -I. The decrease in the intensity of the band 3485 cm -i with
dilution (Fig. ic, d) indicates the intermolecular character of the
hydrogen bond formed. The shift of the band of the bound OH group
of l-(p-hydroxyethyl)-3,6-dimethyl-5-bromouracil into the highfrequency
region in comparison with l-(fl-hydroxyethyl}-3,6-
dimethyluracil is an indication of weakening of the hydrogen bond,
probably on account of a decrease in the negative charge of the
oxygen of the carbonyl group. As we go from dilute solutions of
l-(fl-hydroxyethyl)-3,6-dimethyluracil and its bromo derivative to
crystalline samples, the band of the free OH groups disappears
entirely, while the bands of the bound OH groups practically do not
change their shape and position. Evidently in the crystalline state
the same type of hydrogen bond is also preserved as in solution.
For 3-(~-hydroxyethyl)-l,6-dimethyluracil and its 5-bromo
derivatives, which are structural isomers of the compounds discussed
above, only the band of the vibrations of the bound OH
group - at 3485 and 3510 em -I, respectively - is observed in dilute
solutions. The picture of the absorption and the position of the
maximum do not depend on the concentration. This indicates that
the OH group of the hydroxyethy[ radical is bonded by an intramolecular
hydrogen bond of the D or E type
0 . . . HO--CH~ 0
R II R !J
,-o )=o....o
HsC / \ N/ - - R~H, Br HaC / N
I I
CHs CHa
D E
2083
The intramolecular bond is weakened when bromine is introduced into the 5-position of the pyrimidine ring
(a 25 cm -t shift of the band into the high-frequency region). A consideration of the Stewart-Briegleb model
shows that the intramolecular hydrogen bond~ are the most profitable for all the 3-(fl-hydroxyethyl)-uracils
studied. Evidently in the crystalline state also, intramolec~ttar hydrogen bonds OH . . . O = C are realized
in these compounds. Then, for crystalline 3-(fi-hych~oxyethyl) -, 3-(fl-hydroxyethyl)-5-bromo-, and 3-(fihydroxypropyl)-
6-methyluracils, the following types of hydrogen bonds can be represented:
o... HO--CHR' R'CH OH B'CH OH
R /\s-- H~ cm 6 cH~ 6 II, I_o. I!
H3 \N/-- "" [ CH8 0 H ..0~- ~NH.o.
H...O= R I I
CH~ N t
|
! l
R CH--0H... 0
R=H2 Br; R'=H, CH3
Considering the data of x-ray diffraction study of 1-methyluracil [7], we should recognize the first
type of association as more probable.
An investigation of the shift u C = O in solution and in the crystalline state does not permit selection
to be made of the carbonyl with which the intramolecular hydrogen bond is formed.
In the IR sepctr a of solutions of 1,3-bi s- (/3-hydroxyethyl)- and 1,3-bis ,(fl -hydroxyethyl) -5 -bromo-6 -
methyluracils in CC14 (~0.00003 M), two bands are observed: the band of the vibration of the nonbonded OH
group 3635 cm -1 and the bands of the bound OH groups 3490 and 3515 cm -t, respectively. Further dilution
does not change the relative intensities and positions of the bands (Fig. le, f). This indicates that the OH
group of the 3-fl-hydroxyethyl radical is bonded by an intramolecular hydrogen bond, while the 1-fl-hydroxyethyl
radical does not participate in a hydrogen bond in dilute solutions. In crystalline samples of 1,3-bis-
(fi-hydroxyethyl)- and 1,3-bis-(fl-hydroxyethyl)-5-bromo-6-methyluracils, the OH group of the 3-fl-hydroxyethyl
radical evidently participates in an intramolecular hydrogen bond, while the OH group of the
1-fl -hydroxyethyl radical participates in intermolecular associations.
In the case of 3-(fi,~/-dihydroxypropyl)-6-methyluracil, the presence of the second OH group opens up
the possibility for the formation of an intermolecular hydrogen bond, including polymer association. This
leads to complication of the picture of the IR spectrum in the region of the vibrations of the OH groups and
to an increase in the strength of the crystal lattice, and consequently, to an increase in the melting point.
EXPERIMENTAL METHOD
In the work we used analytically pure samples, produced according to [3, 13]. 3-(~-Hydroxyethyl)-
1,6-dimethyl-5-bromouracil was produced by the reaction of 3-(fl-hydroxyethyl)-6-methyl-5-bromouraeil
and CH3I in the presence of an equimolar amount of NaOH in water in a sealed ampoule at i00-ii0 ~ . After
3 h of heating, the ampoule was cooled, opened, the precipitated crystals filtered off, dried, and reerystallized
twice from benzene with an addition of activated charcoal. The yield of the uracil was 87~ of the
theoretical; mp 153-154 ~ Found: C 36.34; H 4.27; N i0.42~0. CsHIiN203Br. Calculated: C 36.5; H 4.18;
N 10.65%.
The IR spectra were taken on a UR-10 spectrometer. Crystalline samples were taken in the form of
suspensions in liquid petrolatum. The spectra of dtoxane solutions (C ~ 0.01 M) were taken in a euvette (i
mm). On account of the very poor solubility of N-(fi-hydroxyethyl)-uracils in CC14, the solutions were prepared
as follows. A weighed 0.i g sample of the compound was placed in a flask, i00 ml of CCI 4 was added,
and the mass was brought to boiling. The solution!, cooled to room temperature, was filtered to remove
the undissolved substance (approximately 0.06-0.09 g). In the case of 1,3-bis-(fi-hydroxyethyl)-6-methyl-
Uracil and 1,3-bis-(fi-hydroxyethyl)-6-methyl-5-bromouracil, the boiling solution was filtered, and the
spectra were taken in a cuvette warmed to 35-40 ~ Cuvettes i00 mm long were used to take the spectra
in the region of 3100-3700 cm -I, and euvettes 20 and 50 mm long in the region of 1620-1800 cm -i.
The authors would like to express their deep gratitude to R. R. Shagidullin, O. A. Raevskii, S. A.
Samartseva, N. V. Teptina, and A. V. Chernova, for their aid in the work.
2084
CONCLUSIONS
1. The IR spectra of N-(hydroxyalkyl)-uraeils were studied in the solid state and in solution.
2. The OH group of the hydroxyalkyl radical of 3-(fl-hydroxyethyl)-6-methyluracils participates in
an intramolecular hydrogen bond.
3. The OH group of the hydroxyethyl radical of 1-(fl-hydroxyethyl)-6-methyluracils participates in
an intermolecular hydrogen bond.
LITERATURE CITED
i. B.R. Baker and T. J. Schwan, J. Med. Chem., 9, 73 (1966).
2. M. Prystas and J. Gut, Coll. Czechosl. Chem. Comm., 27, 1054 (1962).
3. V.S. Reznik and N. G. Pashkurov, Izv. Akad. Nauk SSSR, Set. Khim., 1327 (1968).
4. D.J. Brown, The Pyrimidines, Interscience, New York-London (1962).
5. H. Tuppy and E. Kuchler, Monatsh. Chem., 95, 1698 (1964).
6. V.S. Reznik, Yu. S. Shvetsov, and N. G. Pashkurov, Izv. Akad. Nauk SSSR, Ser. Khim., 2811
(1968).
7. D.W. Green, F. S. Mathews, and A. Rich, J. Biol. Chem., 237, 3573 (1962).
8. N.A. Borisevich and N. N. Khovratovich, Zh. Prikl. Spektr., 7, 538 (1967).
9. J. Pitha and S. Vasickova, Coll. Czechosl. Chem. Comm., 30, 1792 (1965).
i0. K. Nakanishi, N. Suzuki, and F. Yamazaki, Bull. Chem. Soc. Japan, 34, 53 (1961).
ii. S.F. Mason, J. Chem. Soc., 4874 (1957).
12. M. Horak and J. Gut, Coll. Czechosl. Chem. Comm., 26, 1680 (1961).
13. V. S. Reznik and Yu. S. Shvetsov, Izv. Akad. Nauk SSSR, Ser. Khim., 1646 (1970).
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