Electroreduction mechanism of 2-thiopyrimidine derivatives

Electroreduction mechanism of 2-thiopyrimidine derivatives

Bioelectrochemistry and Bioenergetics 6 (1979) 263-271 J. Electroanal. Chem. 104 (1979) 263-271 @ Elsevier Sequoia S.A., Lausanne - Printed in Italy ...

392KB Sizes 0 Downloads 39 Views

Bioelectrochemistry and Bioenergetics 6 (1979) 263-271 J. Electroanal. Chem. 104 (1979) 263-271 @ Elsevier Sequoia S.A., Lausanne - Printed in Italy

283 - Electroreduction Mechanism of 2-Thiopyrimidine Derivatives. Part II. Correlation with Electronic S t r u c t u r e Indices b y MONIKA WRONA and MACIEff GELLER University of Warsaw, Institute of Experimental Physics, Department of Biophysics, 93 Z.wirki & \u o2-o89 \u Poland

Summary The experimentally observed changes in the electroreduction mechanism of 2-thiopyrimidine derivatives were interpretated on the basis of their electronic structure, calculated by the CNDO/2 and HOCKEL methods. For some of the examined compounds a linear correlation has been found between the experimental measurement of the electron acceptor properties of molecules (represented by a polarographic potential U~ Red) and the theoretical computation of the energy of the lowest unoccuppied molecular orbital (LUMO). For the same compounds it was also found that U~ Red linearly correlates with the N3=C4 bond order and the electronic charge distribution on N3 and C~ but not with other bond orders and charges. These results confirm the experimental data, indicating that the Ns=C4 bond is the electroactive centre of the molecules considered.

Introduction In a previous paper 1 we reported studies on the polarographic reduction of some methylated derivatives of 2-thiopyrimidine.

R2 I. P~=R2=H II. RI=CH3,R2=H III. RI=R2 =CH3

IV. R~=Rz=CH3

264

Wrona and Geller

Polarographic studies of compounds I - I V afford information a b o u t their tautomeric structure and an influence of position of methylation 'on potentials involved in the electrode reduction process. We have found that 2-thiopyrimidine (I) exists in aqueous solution in thione form, and that this form is readily reduced b y a mechanism very similar to parent pyrimidine and other 2 - s u b s t i t u t e d pyrimidines. 2-8 Initial I e-, I H + a t t a c k is directed on the N s = C 4 bond ; free radicals formed dimerize or undergo further I e - reduction to 3,4-dihydropyrimidine. F o r 4,6dihydro-2-thiomethylpyrimidine the electroreduction mechanism is completely changed and more complicated. 1 Initial electron attack is directed on C-2 position and as a result, the sulfur substituent is eliminated during the electroreduction process. The reduction of compound IV occurs at potentials more negative than in the case of the parent pyrimidine as well as its 2-thione derivatives. It follows that during the electroreduction of molecule IV, the selective elimination of the sulfur substituent, without simultaneous reduction of the pyrimidine ring, is not possible. However, on the basis of experimental data it is not possible to find out whether the elimination of the sulfide group is the result of direct reduction of the C~-SR bond or reduction of the C 2 = N double bond adjacent to the sulfur substituent and its subsequent chemical elimination. In the case of the latter mechanism, the rate of the electrode process should be affected b y the rate of the HSCH3 elimination (usually dependent on pH). This t y p e of mechanism was observed during the electroreduction of 4-thiomethyluracil derivatives. 6 Since no kinetic effect was observed for compound IV it is difficult to p i n - p o i n t the actual mechanism. In this paper we have tried to explain the observed phenomena and changes in the electroreduction mechanism of the examined compounds I - I V on the basis of their electronic structure. Also, we have tried to correlate the observed changes of the electron acceptor properties, represented b y polarographic potential of reduction, U~ Red, with a theoretical electron acceptor evaluation i.e. the energy of the lowest unoccupied molecular orbital L U M O ~ for the compounds I - I V and some other pyrimidines, reducible b y a similar mechanism. This t y p e of correlation is of special interest since LUMO energy has been correlated with the chemical and biochemical activity of molecules, s Polarographic potential U~ Red for the reversible process, diminished b y the difference of the solvation energy of products and reactants, is a measure of the electron affinity of the molecules. ~ In fact it is necessary to take into account electron-transfer reversibility, adsorption and proton participation in the rate-determining step, since these factors can seriously alter the potentials associated with redox processes. The reliability of the correlations of U~ R~d with LUMO energy also depends on the calculations and measurements having been made on identical molecular species. Unfortunately, theoretical calculations are usually based on a neutral idealized gas-phase molecule and a reversible electron-transfer process. Nevertheless, the U~R~dvalues, even for the irreversible reduction processes can be used to estimate qualitatively the acceptor properties of molecules and can be correlated with LUMO energy for a series of

Reduction of 2-Thiopyrimidines Derivatives. II.

265

closely related compounds, undergoing reduction via the same mechanism2 In this case, the assumption is made that the electrode kinetics parameters, the solvation effects, the adsorption effects and the protonparticipation are relatively constant or operate uniformly for members of such series. The usefulness of such correlations has been emphasized by m a n y investigators, 9-1. especially because we have very limited possibilities of determining electron-affinity of organic compounds. ~ To obtain experimental results more suitable for correlation with the theoretical indexes of reactivity one can perform polarographic studies in aprotic, organic solvents. However, when studying biological compounds we are interested in obtaining information on the electron donor or acceptor properties in conditions similar to biological ones. For this reason water buffered solutions are the best model for the biological medium of living cell.

Experimental All experimental data are referred to results described in previous paper. 1

Quantum mechanically calculated electronic indices Acceptor properties of molecules are characterised by energies of the LUM0. The lower the LUM0 energy, the better the acceptor properties of a molecule. This is only an approximation because of the assumption that the reduction process does not change the lower, doubly occupied molecular orbitals. The LUM0 orbital (~r) is given in the following form NA

nl

= X

X

c,joo

where X e is the atomic orbital centered on the atom i. The index j numbers the atomic orbitals of the atom i ; n~ is the number of atomic orbitals centered on this atom. In the CND0/2 and HOCKEL methods, which have been employed in this study, the density of the unpaired electron in the atom i contributed by the LUM0 is given by

Z I c,r~ I

j~

(2)

Thus, the absolute values of the coefficient [Cilt01 may be suitable to estimate the electroactive sites of a molecule. It should be borne in

266

Wrona and Geller

mind t h a t in the H0CI~EL method, or in the case of ~-LUMO for the first row atoms in the CNDO/2 approach, ni equals I. The possibility of reduction of the bond i-j can be estimated b y the change of the respective b o n d - o r d e r (p~i) due to the addition of one or two electrons to the LUMO. The lower the decrease of the bond-order, the higher the possibility of reduction. However, the classical b o n d - o r d e r values of the HfJCKEL m e t h o d cannot be applied with the CNDO/2 approach because of its non-invariant properties relative to the transformation of the coordinates. 18 The proper invariant properties have the TOP * index defined as: TOP (i-j) =

M

.,

~

~.

k=I

~mI

2nk Ck,(i) Ckb(j) S~b

(3)

b=I

where M is the n u m b e r of occupied molecular orbitals, ni, n1 are the numbers of atomic orbitals in atoms i and j, respectively ; nk is the n u m b e r of electrons on the k - t h molecular orbital and S~b is the overlap integral between X , and Xb. Change of TOP [A TOP(i-j)] due to the addition of one electron to the LUMO equals A TOP (i-j) = 2n

~

~

a~I

b~I

Cio~ Cibq) S~b

(4)

The strength of the bond i - j decreases when the terms for which

C ~ Q ~ S~ < o

(5i

dominate in the above summations.

Results and disoussion

Values of U~ Redfor the examined 2-thiopyrimidine derivatives I - I V and also for the parent pyrimidine and 2-oxopyrimidine are listed in Table I. Since the potential U~ Red for all these compounds is p H - d e p e n dent the data at p H 7 are selected for comparison because of the following reasons : a) all considered compounds are in neutral form, b) t h e y show a similar mechanism for the initial energy determining step. c) at p H 7 all compounds exhibit relatively weak adsorption effects, d) these conditions are most similar to a biological medium. * Total Overlap Population

Reduction of 2-Thiopyrimidines Derivatives. II.

267

Table i. Comparison of U89Red potentials and LUMO values for pyrimidine derivatives.

Molecule

Pyrimidine d 2-Oxopyrimidine d

2-Thiopyrimidine (I) 4, 6-Dimethyl-2-thiopyrimidine (II) 1,4,6-Trimethyl-2-thiopyrimidine (III) 4,6-Dimethyl-2-thiomethyl-pyrimidine (IV

PKxa

- - U ~ Red ( p H 7) b [Xr]

LUMO energy [eV]c

1.31 1.85 1.35

1.3o3 I.oSo 1.o18

O.ll 5 0.069 0.037

2.80

1.210

0.050

3.15

1.262

0.055

2.5 ~

1.58o

0.090

Symmetry of LUIV~O orbital

a p K 1 v a l u e s t a k e n f r o m R e f . 14 , 15 . b U'~Red at 0. 5 m M concen. c Calculated by the CBTDO/2 method. d U89 values taken from Ref. z.

The energies of LUMO, calculated using the CNDO/2 and I-IOCKEL methods, are listed in Table I and 2, respectively. Quantitatively, the results are similar. F r o m these tables it can be concluded t h a t the presence of a carbonyl or thione substituent at position 2 improves the electron acceptor properties of the molecule, the l a t t e r producing a significantly greater effect. Methylation of 2-thiopyrimidine at the C4, Ce, N1 a n d / o r Sz atoms increases the energy of the LUMO, decreasing the acceptor properties of the molecule. These results are in qualitative agreement with t h e changes of the observed potential U~4R~d. I n the case of compounds I - I n , there is a linear dependence of U~ R*d on the energy of the LUMO, presented in Fig. Ia. This confirms the conclusion t h a t all the three derivatives undergo reduction in the same manner. In view of this correlation it is also reasonable to predict t h a t the degrees of reversibility of the electron-transfer process for c o m p o u n d s I - n I are quite similar and t h a t changes in solvation energy a n d adsorption p h e n o m e n a are relatively constant for the compound I - n I . I n the case of compound IV this relation does not hold because of the different mechanism of reduction. The large deviations observed for pyrimidines and 2-ketopyrimidines, despite of a similar mechanism of reduction as for 2-thiopyrimidine, m a y be attributed to two factors. First, because of the parametrization difficulties, the results m a y be c o m p a r e d only within the group of closely related compounds. Secondly,

268

Wrona

6

6

and

Geller

6

6

d

~

~

0

d

d

d

o

c~

d

d

d

d

u'~

u-~

~

O~

0

o

o

o

6

o

0 0

O~ 0

~ ~

~ ~

O~ 0

o

d

d

d

o

I

I

I

I

I

I

I

I

I

0

0 oo

:D

5

#J

u~

',0

~

',D,

e,I

o

6

6

6

6

I

1

I

I

T II

I

2 o

~

d

d

d

d

d

0

-~o

I~ ,.~

,~

c~

I

o.g

oO

o

d

6

6

o

oo

~

~

I

I

I

d

6

6

o

d

,.o

~

I

I ~v 0

6

a I

..

A V

~ ~

N

~o

0

"~

0

d 0

0

R e d u c t i o n of 2 - T h i o p y r i m i d i n e s

Derivatives. II.

269

it should be borne in mind that differences in the reversibility, and/or solvation of the compounds, influence the values of Uv,R,d in a different manner. 0.04 0.06 0.08 9 ' Lu'mo energy

0.1

0.72

0.74

0.78

'N3-.C4 Bond order

-1.2

-1.1

-1.4

-1.3

>

' "

I

1/ Fig. I, Variation of potentials U~ Red with LUMO energies and N 8 ~ C4 m-electron b o n d order, calculated b y t h e CNDO/2 m e t h o d s for compounds I - I V . LUNIO emergies in e V.

The linear correlation of U~ Red with the energy of the LUMO is poor from a statistical point of view because it is based only on three experimental points. Nevertheless, there are additional facts supporting the above-mentioned conclusions. First, for the compounds (I-III) there is another linear dependence of U~ R'~ on the n-electron bond-order of N s = C , (see Fig. Ib) which is the electroactive center of those molecules. Secondly, the values of U~ R*dcorrelate both with pK1 of the protonation of N3 and with its electron net charge (Tables I, 3). Thirdly, in the case of derivatives I-III, the coefficients. C;. I of. the LUMO are. greatest for C4, Ce and Nz (see Table 2 and 3) indicating that the density of the unpaired electron is dominated in these three atoms and that the N3=C~ bond becomes weaker after reduction. Moreover, tile change of the bond-order of the N3=C4 bond due to reduction, in comparison with that of the Cs=Cs one, also demonstrate its greater susceptibility to reduction than the latter (see Table 2). The properties of the LUMO for 4,6-dimethyl-2-thiomethylpyrimidine (IV) can somewhat clarify the mechanism of its reduction. Symmetry of this orbital is a-type and the values of the coefficients Cf~ indicate that the major density of the unpaired electron is located in the C2 and S~. atoms. It suggests the C2-SR bond is an electroactive center of the molecule. The calculated value A TOP(C2-SR ) amounts to --o.21. Hence, this bond becomes weaker after reduction. These theoretical results support the conclusion that the observed elimination of mercaptan is due to the immediate reduction of the C2-SR bond rather than to the reduction of the C2=N double bond, followed by the former reaction.

270

Wrona

and Geller

O~ e,I

~~.

o'~ ~0

0 0

0 0 ~,

6

6

6

6

6

0 e~

~ ~

P'~ ,~0

O~ 0

~'~ Ox

o

d

6

6

d

~

~0

0

0

6

o

6

6

o

H

~

0

0

0

6

6

o

o

o

0 u~

~ u~

t~ ~

oh ,~.

el

6

6

6

o

o

o ~J

I

I

I

I

I

.-.k

o

I

I

I

I

I

0

[

~>

0 0

~

0

0

0

0

6

6

o

o

o

J

6

6

6

6

6

o

6

6

6

6

0

~

e~

f'~

o~

6

6

6

6

6

o

6

6

6

6

I

I

I

I

? ~

o

I

0

?

I

[

I

I

,A 0

V

o

I o 0 ,.c:l

o~

0

~

o

.

~,.~

0

0

Reduction of 2-Thiopyrimidines Derivatives. II.

271

I n v i e w of t h e f a c t t h a t f o r all t h e c o m p o u n d s c o n s i d e r e d a p r e p r o t o n a t i o n of t h e d e p o l a r i z e r s e e m s t o p l a y a role in t h e e l e c t r o d e process, p r o b a b l y a b e t t e r c o r r e l a t i o n of U~4Rea w i t h t h e t h e o r e t i c a l r e a c t i v i t y i n d e x e s m i g h t be a t t a i n e d if t h e c a l c u l a t i o n s w e r e c a r r i e d o u t f o r t h e p r o t o n a t e d f o r m of p y r i m i d i n e . U n f o r t u n a t e l y , c a r e f u l s t u d i e s of t h e p r o b l e m are v e r y difficult, b e c a u s e t h e r e l i a b i l i t y of t h e r e s u l t s are s t r o n g l y d e p e n d e n t on t h e p o s i t i o n of t h e a d d i t i o n a l p r o t o n .

Acknowlegments T h e a u t h o r s t h a n k P r o f . D. SHUGAR for v a l u a b l e discussion of t h e m a n u s c r i p t . T h i s w o r k w a s s u p p o r t e d b y t h e Polish A c a d e m y of Sciences w i t h i n t h e p r o j e c t o9.7.1.

References

preceding p a p e r

1

1V~. WRONA, S.

2 3

D.L. SMITH and P.J. ELVING, J. Am. Chem. goc. 84 (1962) 2741 ]3. CZOCHRALSI~A.and D. SHUGAR, Biochim. Biophys. Acta 281 (1972) I ]3. CZOCHRALSKA., M. WRONA and D. SI-IUGAR, Bioelectrochem. Bioenerg. 1 (I974) 4 ~ iV[. \u J. GizlEWlCZ and D. SHUGA.R, Nucleic Acid Res. 2 (1975) 2209 IV[. "VVRONAand ]3. CZOCHRA.LSKA,J. Eleclroanal. Chem. Interfacial Electrochem. 48 (1973) 433 C-. ]3RIEGLEB, Angew. Chem. 76 (1964) 326 ]3. PULLMAN and A. PULLMAN, Quantum Biochemistry, John Wiley & Sons, New York (1963) R. ZAHRADNIK and C. PARKANYI, Talanta 12 (1965) 1289 P.J. ELVlNG and ]3. PULLMAN, Advances in Chemical Physics, J. Prigogine (Editor), Interscience, New York (I96I), Vol. 3, p. I E.S. PYSH and N.C. YANG, J. Am. Chem. Soc. 85 (1963) 2124 G. DRYHURST and P.J. ELVlNO, Talanla 16 (1969) 855 J. K&UFMANN, Int. J. Quantum Chem. 4 (1971) 205 D.J. ]3ROWN, The Pyrimidines, Interscience, New Yolk (1962) ]3. STANOVNIK and M. TISLER, Arzneim. Forsch. 14 (1964) lOO4

4

5 6

8 9 10 11 12 13 14 15