Spectrochimico Acm, Vol. 4OA. No. I. pp. 75-79, 1984 Printed in Great Britain.

Covalent hydration of 5-substituted pyrimidines

JIM CLARK and GEORGE HITIRIS*

0584-8539184 $3.00 + 0.00 0 1984 Pergamon Press Ltd.

The Ramage Laboratories, Department of Chemistry and Applied Chemistry, University of Salford, Salford MS 4WT. U.K.

(Received 3 June 1983)

Abstract-5Substituted pyrimidines in which the substituent is electron-donating or weakly electron- withdrawing, form normal cations in aqueous acidic solutions. Those in which the substituent is strongly electron-withdrawing form 3,4-hydrated cations, which are usually rather prone to undergo ring cleavage reactions.

‘H NMR, ‘sC NMR and U.V. spectroscopy are used in the study.

INTRODUCTION

Many n-deficient heterocyclic compounds undergo reversible addition of water across one or more polarised C=N linkages [l, 33. Hydration is favoured by factors which increase the stability of a hydrate relative to the corresponding anhydrous species so many nitrogen heterocycles, such as quinazoline (l), exist essentially as resonance-stabilised hydrated cations (2-3) in aqueous solutions, but are essentially anhydrous as neutral molecules [4].

It was formerly believed that monocyclic hetero- cyclic compounds would not undergo covalent hyd- ration because the process would be energetically unfavourable as all aromatic resonance stabilisation

would be lost [4]. However, kinetics of deuterium exchange suggest that covalent hydration may be involved in reactions of some simple pyrimidines [5] and it has been shown that 5-nitro- [6], 5-methyl-[7], and 5-methylsulphinyl pyrimidine [7] form hydrated cations. More 5-substituted pyrimidines have now been examined to explore the extent of this phenom- enon and the factors which exert an influence.

DISCUSSION

Proton magnetic resonance spectra of a number of 5-substituted pyrimidines (4), in the form of neutral molecules in deuteriochloroform and in the form of cations in deuterium chloride/deuterium oxide sol-

HO H HO H

(1)

N/ I/\y X

'N I

(2) (3)

HOH

+H,O X

-Hz0

(5)

(6)

HOH

X

ution, are recorded in Table 1. The cation spectra fall neatly into two groups. In the first group are those

*Address for correspondence: Dr. G. Hitiris, Ionias 30, Nea which resemble the spectra of corresponding neutral Smymi, Athens, Greece. molecules, except for modest downfield shifts of the

Tab

le

1.

iH

NM

R

spec

tra

Che

mic

al

shif

ts

(6)

Com

poun

d

(4)

HZ

Neu

tral

m

olec

ulea

H,,

H,

5Sub

stitu

ent

HZ

H

,

Cat

ionb

H,

5Sub

stitu

ent

Stru

ctur

e of

ca

tion

X=H

C

9.28

’ 8.

82d*

’ 7.

43=

9.14

9.

45d

9.45

d 8.

34’

5; X

=H

X=B

rC

9.28

’~”

8.87

’ 9.

71

9.61

9.

61

5; X

=Br

X=

MeC

9.

05’*

ms”

8.

581.

m

2.31

m

9.41

9.

15

9.15

2.

45

5; X

=M

e X

=OM

eC

8.85

1%”

8.43

’ 3.

93

9.11

s 8.

96

8.96

4.

04

5; X

=OM

e

X=

SEt

J q,

J

= 7

.5

5; X

=SE

t 1.

34,

t, .I

=

7.5

9.57

hv”

1.41

, t,

J =

7.5

X

=CN

C

9.43

8.

41s

5.78

7.

49

7; X

=C

N

X=C

O,M

e 9.

37

9.30

4.

00

8.69

6.

44

7.79

3.

90

7; X

=CO

,Me

X=C

02H

C

9.4o

h 9.

24

8.64

6.

14

7.15

7;

X=C

O,H

X

=SO

,Et

9.31

9.

11

3.62

, q,

J

= 1

.5

8.60

6.

2 1

7.70

3.

37,

q, J

=

7.5

7;

X=S

O,E

t 1.

20,

t, J

= 7

.5

7.5

X=S

O,M

e’

9.4t

iv”

1.30

, t,

J

=

9.35

3.

40

8.60

6.

21

7.72

3.

29

9.34

’ 7;

X=S

O,M

e X

=SO

Me

9.10

3.

07

8.49

6.

20

7.38

2.

96

X=

SOM

e X

=NO

zk

7;

9.56

9.

54

8.71

6.

50

8.31

7;

X=N

O,

aIn

CD

CI,

un

less

st

ated

ot

herw

ise.

bW

ith

sodi

um

trim

ethy

lsily

lpro

pion

ate

as

inte

rnal

st

anda

rd,

unle

ss

stat

ed

othe

rwis

e.

CFo

r ne

utra

l m

olec

ule

spec

tra

in o

ther

so

lven

t se

e [

181.

dD

oubl

et,

J =

6.

eMul

tiple

t. ‘T

ripl

et,

J =

6.

sDio

xan

(r =

6.

4) a

s in

tern

al

stan

dard

. hI

n (C

D&

SO.

‘Fro

m

[7]

for

com

pari

son.

jln

D

,O.

kSim

ilar

valu

es

reco

rded

in

[6]

. ‘S

imila

r va

lues

re

cord

ed

in [

22].

mSi

mila

r va

lues

re

cord

ed

in 1

231.

“S

imila

r va

lues

re

cord

ed

in [

24].

. .

II _

,,,

_ L

___.

“,^

- ̂

_ --

-- -

Tab

le 2

. 13

C N

MR

sp

ectr

a

Com

poun

d (4

) C

2

Che

mic

al s

hift

? (p

pm)

Neu

tral

m

olec

uleb

C

atio

nc

C 4

/6

C,

Oth

ers

C,

C 4

16

C,

Oth

ers

X=

H

159.

1s

157.

0 12

1.0

X=H

* 15

9.5

157.

5 12

2.1

152.

2 15

8.8

125.

1 X

=Bre

15

6.6&

h 1S

7.8h

12

0.9h

X

=Me’

15

6.5s

15

7.0s

13

0.9s

14

3.2a

h 1S

3.6a

h lS

6(C

H,)

14

9.3

158.

1 13

6.4

16.4

(CH

,)

X=O

Me

1Sl.W

SS

8(O

CH

,)sJ

J 14

5.0

144.

3 15

5.7

S9.

0(O

CH

3)

X=S

Et

156.

0 15

6.9

133.

0 14

.4(C

HZ

) 22

.7(C

Ho)

X=

CN

e 16

0.3

160.

3 11

4.9

109.

6(C

N)

149.

7 13

6.7

116.

0 9S

.l(C

N)

70.0

X

=CO

,Me

161.

5 15

8.0

124.

4 16

4.1(

CO

) 52

.7(O

CH

,)

X=

C02

He

161.

0 15

7.7

124.

8 16

4.8(

CO

) X

=N

O,

162.

4h

1S2.

4h

143.

0h

aRel

ativ

e to

tet

ram

ethy

lsila

ne

unle

ss s

tate

d ot

herw

ise.

bi

n C

DC

l, un

less

sta

ted

othe

rwis

e.

In

DC

l/D,O

us

ing

diox

an a

s in

tern

al

stan

dard

(c

hem

ical

shi

ft 6

7.4

ppm

), u

nles

s st

ated

ot

herw

ise.

*N

eutr

al m

olec

ule

as n

eat

liqui

d an

d ca

tion

in a

queo

us

sulp

huri

c ac

id,

from

[ 1

11.

CN

eutr

al m

olec

ule

in D

MSO

-d,.

‘For

val

ues

in C

F,C

O,H

se

e [2

6].

sSim

ihu

valu

es r

ecor

ded

in [

22].

hS

imila

r va

lues

rec

orde

d in

[2S

].

78 JIM CLARK and GEORGE HITIRIS

signals which are consistent with simple proto- nation [IS], while those in the second group show more radical changes. The most obvious change in each spectrum of the second group is an upfield shift of about 3 ppm for the 4-proton signal. This is typical of the change in chemical shift of a heteroaromatic proton when covalent hydration occurs at the C=N linkage carrying that proton [9].

Thus Table 1 shows that when pyrimidine bears a

strongly electron-withdrawing mesomeric 5-sub- stituent the hydrated form of the cation is preferred (7;

X=CN, CO,H, CO,Me, SO,Me, SOMe, or NO,). Weak signals at low field, which suggest the presence of a small proportion (up to lo’:,,) of anhydrous cations in some cases show that the equilibrium is finely balanced.

When the substituent is electron-donating or weakly electron-withdrawing, the anhydrous form of the cation is the more stable (5; X=H, Me, Br, OMe or SEt).

Efforts to confirm the occurrence of covalently hydrated cations by 13C NMR spectroscopy were

largely frustrated by the lack of stability of the hydrates in strongly acidic solutions, although the method has been used successfully for bicyclic hetero- cycles [lo]. Spectra of neutral molecules and anhydr- ous cations were readily measured but the compounds whose cations underwent hydration were also prone to suffer ring cleavage. In the time needed to accumulate sufficient scans for a satisfactory spectrum, decompo- sition was usually well advanced and many unassig- nable peaks were present in the spectra.

Table 2 contains data on some neutral molecules (4) and anhydrous cations (5) and also the spectrum of the hydrated cation form of pyrimidine-5-carbonitrile (7; X=CN) which was reasonably stable. The chemical

shift of the 4-proton of the latter was 70 ppm, which agrees with those of similar carbinolamine pro- tons [lo], which have chemical shifts of about 7G75 ppm, but is incompatible with a ring opened product. Chemical shift changes caused by simple protonation of 5-substituted compounds (5; X=Me or OMe) correspond well with those shown by cor- responding protons of pyrimidine when the latter is protonated[ll, 121.

Ultraviolet spectra and ionisation constants re- inforced the evidence from ‘H NMR spectra. As expected, the compounds with strongly electron- withdrawing 5-substituents were weaker bases than pyrimidine, but the base-weakening effects of the substituents were much less marked than would be expected [13] unless some factor such as hydration was involved. Typical pK, values lay between 0.5 and 1.0 whereas compounds such as 5-nitro- or 5-methyl- sulphonylpyrimidine would be expected to have pK, values around -2. Ultraviolet spectra of the neutral molecule and cation forms of these compounds for which ‘H NMR spectra had indicated simple cation formation, were similar to each other as would be expected if the only change was protonation of the heteroatom [ 141. However, much bigger differences between neutral molecule and cation spectra were noted (Table 3) for those compounds which had been deemed to form hydrated cations, indicating that a change in conjugated system had occurred.

Dilute solutions of the pyrimidines, in aqueous buffers or acids with a wide range of pH values, were kept, and their U.V. spectra were measured at intervals. In general, the pyrimidines which formed normal cations were fairly stable over a wide pH range, but those which formed hydrated cations were unstable in both acidic and alkaline conditions. For example, in

Table 3. Ionisation and U.V. spectra

Compound

(4)

pK, and spread” PH

Ultraviolet spectra (i.,,, and Emax)b Neutral molecule H, Cation

X=HC X=Br X=Me X=OMe X=SEt X=CN

1.30 0.0 242(3.60)

-0.16+0.05 2.0 219(3.83) 261(3.35) -2.3 227(3.82) ?73(3.49) 2.03 + 0.03 4.1 252(3.43) 256(3.41) - 1.0 255(3.53) 1.36+0.06 3.4 221(3.77) 272(3.61) 266(3.24) - 1.1 227(3.87) 287(3.66) 0.93 f0.07 3.4 260(3.83) 300(3.17) - 1.1 27X(3.95) 337(3.13) 1.07 + 0.03 5.0 221(3.83) 245(3.14) 250(3.17) -2.1 27513.77)

X=C02Me

X=CO,H X=SO,Mee

255(3.07) 275(2.59) 0.95 * 0.04 3.0 221(3.62) 241(3.26) 245(3.25) _

252(3.12) 280(2.87) 7.0d 245(3.30) 275(2.71) _

0.97 f 0.04 5.0 24013.06) 243(3.06) 277(2.63)

1.1 228(3.48) 278(3.52)

1.1 225l3.58) ‘27(3.57) 1.5 26513.68)

X=SOMe~ 0.42 f 0.04 5.0 X=NOlf

247i3.44) ‘69i3.69j 0.72 f 0.03 7.0 237(3.90) -2.0 305(3.83)

aMeasured spectrophotometrically. bInflections in italics. ‘pK,from A. ALBERT, R. GoLDACREand J. PHILLIPS, J. them. SW. 2240 (1948) and U.V. spectra from M.V.P. Bo&RLAi%Dand

H.F.W. MCOWE, J. them. Sot. 3716 (1952). dAnion. ‘From [21]. ‘From [6] confirmed in our laboratories.

Covalent hydration of 5-substituted pyrimidines 79

our hands, 5nitropyrimidine decomposed very rapidly as a 10m4 molar solution at pH 13 and was about half decomposed after I h on 0.001 N-hydrochloric acid, or 2 h in sulphuric acid of H, - 2 (all at 25”C), although it is stated to be stable under acidic conditions [6].

Clearly a tautomeric electron withdrawing 5-sub- stituent, which increases the polarisation of the CN linkages in neutral molecules and cations, facilitates both the attack of the weak nucleophile water, to give a hydrate, and the subsequent ring cleavage. Still further degradations follow the ring cleavage step. 1,3,5- Triazine, which can be regarded as an extreme example of a 5-substituted pyrimidine is rapidly destroyed in cold water [ 151.

EXPERIMENTAL

Most of the S-substituted pyrimidines were synthesised by uublished methods t5-unsubstituted I-161. 5-bromo-fl71. 5- hethoxy-[17], 5icyano-[ 181, 3-e&ylthio-[ 17j, -’ 5- methoxycarbonyl-[19], 5-carboxy-[20], 5-methylsulphonyl- [21] and 5-nitro-[6]). 5-Methylpyrimidine was a commercial sample.

‘H NMR spectra were measured on a Perkin-Elmer R32 90 MHz instrument at normal probe temperature. Neutral molecules were examined as solutions in CDCI, or (CD&SO with tetramethylsilane as internal standard. Cation spectra were run on solutions of the pyrimidines in 20 % DC1 in D,O with dioxan (6 = 3.6 ppm) or sodium trimethylsilyl- propionate as internal standard.

13C NMR spectra were measured on a Varian CFT 20 instrument at normal probe temperature. Neutral molecules were examined as solutions in CHCI, or (CD&SO with tetramethylsilane as internal standard.“Cation spectra were run on solutions of the pyrimidines in 20 % DC1 in D,O with dioxan (67.4 ppm) as internal standard. Assignments were made with the aid of off-resonance spectra, additivity re- lationships and chemical shift changes on protonation.

pK,values were measured spectrophotometrically and U.V. spectra were measured on a Unicam SP 800 instrument using solutions of the pyrimidines in aqueous hydrochloric acid or aqueous buffer solutions.

Acknowledgements-We thank Mr. A. E. Cunliffe for pK, values and U.V. spectra, Miss Shiela Bogle for ‘H NMR spectra and Mrs. L. Phillips for r3C NMR spectra. We also thank Dr. 0. Meth-Cohn for valuable discussions on the ‘% NMR spectra.

Cl1

[i]

[41

c51

C61

c71

C81

[91

Cl01

Cl11

[121

Cl31

E::]

WI

[I71

Cl81

[ii]

[::]

v31

v41

c251

WI

REFERENCES

A. ALBERT and W. L. F. ARMAREGO, Adv. heterocycl. Chem. 4, 1 (1965). D. D. PERRIN, Adu. heteorcycl. Chem. 4, 43 (1965). A. ALBERT, Angew. Chem., Int. Ed. 6,919 (1967). A. ALBERT, W. L. F. ARMAREGO and E. SPINNER, J. them. Sot. 2689, 5267 (1961). A. R. KATRITZKY, M. KINGSLAND~~~ 0. S. TEE, Chem. Commun. 289 (1968). M. E. C. BIFFIN, D. J. BROWN and T.C. LEE, J. them. Sot. C 573 (1967). D. J. BROWN, P. W. Fo~~and M. N. PADDON-ROW, J. them. Sot. C 1452 (1968). T. J. BATTERHAM, NMR Spectra ofSimple Heterocycles, p. 14. Wiley, New York (1973). A. ALBERT, T. J. BATTERHAM and J. J. MCCORMACK, J. them. Sot. B 1105 (1966); J. CLARK, J. them. Soc.C 1543, (1967); J. CLARK and W. PENDERGAST, J. them. Sot. C 1751 (1969); J. CLARK, J. them. Sot. C 313 (1968). H. EWERS, H. GUNTHER and L. JAENICKE, Angew. Chem., Int. Edn 14, 354 (1975). R. J. PUGMIRE and D. M. GRANT, J. Am. them. Sot. 90, 697 (1968). E. BREITMAIER and K. H. SPOHN, Tetrahedron 29,1145 (1973). J. CLARK and D. D. PERRIN, Q. Rev. 18, 295 (1964). D. D. PERRIN, Adu. heterocycl. Chem. 4, 44 (1965). C. GRUNDMANN and A. KREUTZBERGER, J. Am. them. Sot. 76, 5646 (1954). H. BREDERECK, R..GOMPPER, H. G. SCHUH and G. THEILIG. Annew. Chem. 71. 753 (1959). H. BRED~RE~K, R. GoMPPErtand~H. HERLINGER, Chem. Ber. 91, 2832 (1958). S. GRONOWITZ, B. NORRMAN, B. GEZSTBLOM, B. MATHIASSON and R. A. HOFFMAN, Ark. Kemi 22, 65 (1964). M. ROBBA, An& Chim. 5, 351 (1960). S. GRONOWITZ and J. RYE, Acta them. scand. 19, 1741 (1965). D. J. BRowNand P. W. FORD, J. them. Sot. C 568 (1967). T. TSUJIMOTO, C. KOBAYASHI and Y. SASAKI, Chem. pharm. Bull. , Tokyo 27,691 (1979). J. RIAND, M. T. CHENON and N. LUMBROS(FBADER, Org. Magn. Rex 9, 572 (1977). 0. P. SHKURKO and V. P. MAMAEV, Khim. Geterotsikl. Soedin. 526 (1978). G. W. H. CHEESEMAN, C. J. TURNER and D. J. BROWN, Org. Magn. Res. 12, 212 (1979). J. RIAND, M. T. CHENON and N. LUMBROS~BADER, J. Am. them. Sot. 99, 6838 (1977).