Patai S., Rappoport Z. 1997 The chemistry of functional groups. The chemistry of double-bonded functional groups / 1355 149

S

+

C C

H NH2

(11)

In unsymmetrically substituted thioketones, the thiocarbonyl group is often calculated92,39 to be significantly bent towards one of the substituents. The tilt (see Scheme 2) is consistently away from electropositive groups and towards electronegative ones. In general, the tilt found for thiocarbonyl compounds is smaller than that exhibited by the carbonyl analogs. This difference has been explained by Sudhakar and Chandrasekhar93 in terms of the energy differences between the thiocarbonyl n orbital and the carbonyl n orbital. Since the former lies higher in energy than the latter, tilt angles will no longer be determined by simple two-orbital interactions as in the case of carbonyl compounds, involving the carbonyl n orbital and a Ł orbital from the substituent, but by three-orbital and four-orbital interactions.

X Y

SCHEME 2

3.Structural aspects

a. Experimental structural data. (i) Structure. Clouthier and Moule100 have critically compiled and thoroughly discussed the available structural data for 5, 6, acetaldehyde, thioacetaldehyde, acetone, thioacetone and the formyl and thioformyl halides, X2CDY (X D F, Cl, Br, Y D O,S), ClC(O)F and ClC(S)F both in the ground and in various

excited states. This is a major reference in the field. Schaumann1 also provides relevant information on small carbonyl and thiocarbonyl molecules.

Mack and collaborators101 have used electron diffraction for the purpose of determining the structures of 4,4-difluoro-1,3-dithietane-2-one (13a) and 4,4-difluoro-1,3-dithietane-2- thione (13b).

The comparison of their results with data for the open-chain compounds dimethyldithiocarbonate, (CH3S)2CDO (14)102 and dimethyltrithiocarbonate (CH3S)2CDS (15)103 sheds light on the influence of cyclation on the structure and orbital interactions of thiocarbonyl compounds. A particularly important feature is the decrease in CDO and CDS bond lengths upon cyclation. This follows from the reduction of the S C(sp2) S angles

1376 M. T. Molina, M. Ya´nez,˜ O. Mo,´ R. Notario and J.-L. M. Abboud

(ca 8° in both cases) since, as pointed out in studies involving four-membered carbonyl compounds104, the two hybrids involved in the C(sp2) S bonds appreciably increase their p-character upon cyclation and, by orthogonality, that involved in the CDX (X D O, S) increases its s-character. Thus, in 13a and 13b, this carbon shows an enhanced electronegativity with respect to 14 and 15.

Brown and coworkers105 used microwave spectroscopy to determine the structure of propadienethione H2CDCDCDS (16) through the analysis of the rotational constants for several of its isotopomers (obtained by pyrolysis of cyclopenteno-1,2,3-thiadiazole and deuterated derivatives). The main structural parameters are shown in Scheme 3a. A most remarkable (and yet unexplained) feature is the fact that this molecule has a C2v geometry, while propadienone, H2CDCDCDO (17) is ‘kinked’105, as shown in Scheme 3b.

SCHEME 3

High-resolution FTIR studies of thioketene-H2, -HD and -D2 have allowed the determination of the rs molecular structures of thioketene106. On going from ketene to thioketene, a marked change in the methylene group geometry is observed, such that a small decrease in the CH bond length and a substantial reduction of the HCH angle (2.8°) occur. This was interpreted as an indication of a larger p-character of the C H bonds of thioketene. Relevant parameters for the couple thioketene/ketene are as follows: rs CH A˚ D 1.0796 36/1.0825 15 ; rs CC A˚ D 1.3144 24/1.3137 721 ;

rs CS A˚ D 1.5542 26 ; rs CO A˚ D 1.1620 721 ; <sD 119.7 30/121.56 15 .

(ii) Dipole moments. Table 12 summarizes experimental data for selected carbonyl and thiocarbonyl compounds. The first two sets present remarkable features: (a) In benzene

TABLE 12. Experimental dipole moments (in Debye units) for selected thiocarbonyl and carbonyl compounds

aReference 1, solution values.

bReference 107, benzene solution at 20.0 °C. c Reference 108, gas phase.

dReference 109, benzene solution at 30.0 °C.

solution at 20 °C, the dipole moment of 2-(methylamino)tropothione (18) is much higher than that of the carbonyl homolog while the opposite holds for the parent compounds. The situation is intriguing, because Machiguchi’s group107 has shown that under these experimental conditions 18 actually exists as a rapidly equilibrating mixture of the thione and ene-thiol (19) forms. Furthermore, because of the very different lengths of the CDO and CDS bonds, the comparison of the dipole moments is by no means straightforward. These problems call for further study. (b) As indicated by Brown105, the available results for the cumulene thione series display a pattern of alternance with the parity of the number of carbon atoms similar to that displayed by the carbonyl homologs. It is possibly related to the ‘even/odd’ factor relevant in the XDC (C)n CDY systems108. Data by Lumbroso and Cure´109 on benzamides and thiobenzamides are discussed below, in connection with the problem of internal rotations.

b. Rotational barriers. (i) C N internal rotation in thioamides. In general, the geometry of amides and thioamides tends to be planar owing to the contribution of the mesomeric form 20b.

This is also reflected in quite high rotational energy barriers, which surprisingly are greater for thioamide than for the amide analogues.

Ferreti and coworkers110 have carried out an analysis of over 300 crystal structures of species which contain the R(XD)C NR1R2 molecular fragment. In this survey it was found that, in the crystal, interor intramolecular forces can induce out-of-plane deformations of the fragment, so that the cis trans isomerization pathway involves a transition state 21b.

1378 M. T. Molina, M. Ya´nez,˜ O. Mo,´ R. Notario and J.-L. M. Abboud

These movements are well represented by a potential energy surface of two internal coordinates which represent the rotation around the C N bond and the degree of nitrogen pyramidalization, respectively. One of the most significant quantitative results is that the activation barrier for the cis trans isomerization is lower for amides than for thioamides. The available experimental data suggest, and the theoretical estimates point also in the same direction, that the nitrogen inversion barriers are larger for thioamides. The dipole moment analysis of amides and thioamides carried out by Lumbroso and Cure´109 showed that the C N rotational barriers for N, N-dimethylacetamide (MeCONMe2) and N, N- dimethylbenzamide (PhCONMe2) are also smaller than those of the corresponding sulfur analogs, N, N-dimethylthioacetamide (MeCSNMe2) and N, N-dimethylthiobenzamide (PhCSNMe2), respectively. From the mesomeric moments of these species it was concluded that these increases in the rotational barriers parallel the increase in the estimated contributions of mesomeric forms 20b. These results are in agreement with the ab initio calculations of Wiberg and Rablen83, who found that at the G2 level the rotational barrier of thioformamide is 2.0 kcal mol 1 higher than that of formamide. Similarly, the out-of-plane bending vibration is predicted to have a considerably higher frequency for thioformamide than for formamide and the corresponding potential much stiffer. This is also interpreted in terms of a greater contribution of the 20b mesomeric structure. Following the arguments given by Wiberg and Rablen83, this would imply that, quite unexpectedly, there is a greater transfer of charge from nitrogen to sulfur in thioformamide than from nitrogen to the oxygen atom in formamide. In the latter case the oxygen of the CDO group has a considerably large negative charge which comes essentially from the carbon atom. Hence, in amides the carbonyl carbon is electron deficient and the nitrogen lone pairs interacts with the carbon leading to a C N double bond character. In thioamides, the carbon is not electron deficient and the nitrogen charge is transferred to the uncharged sulfur atom. This charge allocation on sulfur requires very little energy due to the large size of this atomic system. This better conjugation of the amino group with the thiocarbonyl system was also postulated by Abboud and coworkers39 for both neutral and protonated thiocarbonyl compounds.

A semiempirical study of rotational barriers of various thioamides and thioureas was published by Feigel and Strassner111a and a careful, high level ab-initio study of formamide and thioformamide has been carried out by Chu and coworkers111b.

(ii) Methyl and alkyl rotations in thiocarbonyl compounds. As in the case of propionic acid112,113, ab initio MO calculations at the 3-21 C G(d) level predict that thiolpropionic acid adopts preferentially the syn conformation around the C˛ C bond. However, the estimated rotational barrier is higher for the thiocarbonyl compound, which is rationalized in terms of unfavorable steric interactions between the ˛-CH3 group and the C S bond. The greater van der Waals radius of the sulfur atom with respect to the oxygen atom renders these interactions greater in thiocarbonyl compounds than in carbonyl derivatives. The same sort of interactions explain the preference for skew forms as far as thionpropionic and dithiopropionic acids are concerned114, as well as the preference for a gauche conformation for thiolformate, thionformate and dithioformate115. In all cases the calculated rotational barriers for the latter species are also consistent with the importance of ˛-CH3 . . . S steric interactions.

As we have mentioned above, the eclipsed rotamers of thioacetamide and thioacetaldehyde were found to be114 the global minima of the corresponding potential energy surfaces at the MP4/6-311 C G(d,p) level. However, the rotational barrier is significantly lower (0.24 kcal mol 1) for thioacetamide than for thioacetaldehyde (22) (1.4 kcal mol 1). Since the -character of the CDS bond is higher in thioacetamide, it was assumed114 that staggered orientation of the methyl group is stabilized by increasing the polarization of the CDS bond.

c. Thiol thione tautomerism. (i) Thioformic acid. The simplest system which is susceptible of presenting a thiol/thione tautomerism is thioformic acid, and probably because of its simplicity it has received a great deal of attention. It is now well established that the thiol form 4a is more stable than the thione form 4c. Most ab initio calculations agree in predicting 4a to be about 3 kcal mol 1 more stable than 4c. Even when high level ab initio calculations are used116 this difference is still of the order of 3.1 kcal mol 1. It is important to emphasize that most of this energy difference has its origin in the much smaller zero-point vibrational energy of the thiol form. This is a direct consequence of replacing a O H bond by a S H linkage. Since the former has a harmonic vibrational frequency (ca 3500 cm 1) significantly higher than the latter (ca 2600 cm 1), the corresponding zero-point energy correction is about 1.9 kcal mol 1 higher. As we proceed in the present section this finding will be common, to all the thiol/thione tautomerisms.

It is, however, interesting to note that according to the calculations of Nguyen’s group117, the thione form 4c has a much smaller ionization energy than 4a. Accordingly, a reversed stability ordering is observed for the corresponding ionized species, and 4cCž turns out to be 22.0 kcal mol 1 more stable than 4aCž .

Another interesting problem related to the thiol/thione tautomerism in thioformic acid is the relative stability of the s-cis (4a) and s-trans (4b) conformers of the thiol form. As we have mentioned in the preceding section, the former is 0.7 kcal mol 1 more stable than the latter. A much larger energy difference is predicted to exist, at the ab initio level, between

However, similar estimations yield a s-cis/s-trans (24a/24b) energy gap in dithioformic acid, HC(DS)SH, almost equal to that predicted between forms 4a and 4b of thioformic acid. These significant differences were explained in terms of the relative degree of mesomerism within the C(DX)Y fragment (see Scheme 4) and the strength of the X. . .H(Y) intramolecular hydrogen bonding in the s-cis form. It is hard to believe, however, that the geometrical arrangements in formic or thioformic acid may favor the existence of an intramolecular hydrogen bond. To clarify this matter we have optimized the geometries of the thiol and thione forms of thioformic acid at the MP2/6-31 C G(d,p)

medium. In gas-phase and in nonpolar solvents the thiol form usually predominates, while either in polar solvents or in the solid state the thione form is usually more abundant. At the beginning of the nineties more evidence in the same direction as well as quantitative relative abundances of the different stable tautomeric forms have been reported.

For the particular case of 2- and 4-mercaptopyridines and 2-mercaptopyrimidines and by means of absorption UV-VIS spectroscopy, Stoyanov and collaborators122 have shown that polar solvents shift the thiol/thione tautomerism towards the thione form, while in dilute solutions of nonpolar solvents the thiol form predominates. However, one of the most significant contributions of this work122 is the observation of self-association. It also favors the thione forms and is followed by quantitative transformation of the thiol form into the corresponding symmetrical disulfides (see Scheme 6). More importantly thione-disulfide process is reversible in water, which can be of some relevance in biological systems.

N S S N

N S

H

H

S N

SCHEME 6

The most complete investigation on the thiol/thione tautomerism of thiopyridines and thiodiazines was carried out by Adamowicz and coworkers61,63,123, who presented combined theoretical and experimental IR spectroscopic studies of Ar and N2 matrix-isolated compounds for the whole series.

The ab initio calculated energies were obtained at the SCF level, followed by the evaluation of the second-order electronic correlation contribution with the many-body perturbation theory [SCFCMBPT(2)]. These calculations were performed on HF/3-21G(d) optimized geometries and include the zero-point vibrational energy corrections.

These authors also show that irradiation by UV light strongly influences the tautomeric equilibria for oxopyridines as well as for thiopyridines and thiodiazines. More importantly, this provided a reliable method to determine the relative abundance of thiol and thione

1382 M. T. Molina, M. Ya´nez,˜ O. Mo,´ R. Notario and J.-L. M. Abboud

forms. The thiol/thione experimental ratio was usually obtained by measuring the changes in the IR band intensities after several minutes of UV-vis irradiation of the matrix. Since for matrix-isolated compounds only intramolecular reactions may be expected, one may apply the formula

where I is the intensity of a band of the thiol form in the initial spectrum and IUV is the intensity of the same band after irradiation. Alternatively, a similar estimated ratio may be obtained from the sums of intensities of all the observed bands scaled by the sums of their theoretically predicted intensities,

From the aforementioned procedures the thiol/thione ratios summarized in Table 13 were obtained for these kinds of systems. It is noteworthy that 2-thiopyrimidine was found to exist in inert gas matrices exclusively in the thiol form124, while 3-thiopyrazine was found only in the thione form, since no trace of the SH absorption was observed123.

From the determination of the relative abundances of thiol and thione forms and assuming that in the gas phase the thermodynamic equilibrium exists between monomeric tautomers, it was possible to estimate the free energy differences between the tautomers, which are also given in Table 13.

The results summarized in Table 13 show a tendency of a decreasing thiol/thione ratio on going from 2-thiopyrimidine to 3-thiopyrazine. This tendency is also reproduced by the ab initio molecular orbital calculations and has been explained123 in terms of the ability of the sulfur atom to behave as a proton acceptor with respect to the endocyclic nitrogen atom of 2-thiopyridine or 2-thiopyrimidine. On the other hand, attachment of a proton to the sulfur atom yields an aromatic bonding structure which tends also to stabilize the system. In 3-thiopyrazine, on the contrary, the presence of two adjacent endocyclic nitrogen atoms enhances their ability to become proton acceptors and the thione form is favored. An intermediate situation corresponds to 4-thiopyrimidine where the two nitrogen atoms are separated by a CH group.

Although ab initio calculations reproduce qualitatively the aforementioned trends, it must be noted that there exist significant discrepancies from the quantitative point of view61 regarding the predictions of theory and experiment with regards to the relative

TABLE 13. Ratio of concentrations of the tautomeric forms [thiol]/[thione] for mercaptopyridines and mercaptodiazines ( G gives the free-energy differences between both tautomers, in kcal mol 1)

a2-Thiopyrimidine was found to exist only in the thiol form. b3-Thiopyrazine was found to exist only in the thione form.

stabilities of the thiol vs the thione forms. The particular case of 2-thiopyridine was already discussed in the previous section, but there are also significant differences as far as 4-thiopyrimidine and 3-thiopyrazine are concerned. In the latter case it can be seen that the only ab initio calculations available123 predict the thione form to be only 0.1 kcal mol 1 more stable than the thiol one, when experimentally only the thione form is observed. On the contrary, the considerably large stability of the thiol form of 2- thiopyrimidine estimated by Contreras and Alderete125 at the MP2/6-31 G(d) level seems to be consistent with the fact that only the thiol form is observed in the gas phase and in matrices. The predominance of the thiol form of 2-thiopyrimidine is also predicted by MNDO semiempirical calculations126.

These studies clearly show that the thiol form is systematically favored by the zeropoint energy corrections, which are 2.5 to 3.5 kcal mol 1 higher for the thione forms91a. This difference reflects mainly the large frequency gap between typical N H stretching

modes, which are observed at about 3400 cm 1123 , and the S H stretching displacements, usually observed for these systems around 2600 cm 1. This represents the most significant difference with respect to the corresponding carbonyl derivatives, where the enol form is only slightly favored (about 0.5 1 kcal mol 1) by the zero-point vibrational energy correction. Hence, in general, the replacement of oxygen by sulfur enhances the relative stability of the fully aromatic thiol forms61. Thus, while the [thiol]/[thione] ratio for 2- thiopyridine is about 30, for 2-pyridinone the [hydroxy]/[oxo] ratio was about 2.6123. Similarly, while the free energy difference between the thiol and thione forms of 2- thiopyridine and 4-thiopyrimidine are 2.4 š 0.1 kcal mol 1 and 1.1 š 0.1 kcal mol 1, respectively, for the oxygen analogs the free energy difference between the oxo and

hydroxy tautomers was estimated to be 0.3 and 0.14 kcal mol 1119 .

It must be also emphasized that UV-vis irradiation favors the formation of the thiol conformer. A typical example is provided by 3-pyridazine, which, as we have mentioned above, is found exclusively in the thione form. However, one hour of UV-vis irradiation ( > 330 nm) of matrix-isolated 3-thiopyrazine caused a nearly complete disappearance of the initial IR spectrum and the new observed spectrum fits well with the predicted spectrum of the thiol form, which was taken123 as evidence that the photoproduct is the thiol tautomer. A similar conversion of the thione tautomeric form into the thiol tautomer upon UV-vis irradiation was also observed for 2-thiopyridine63 and for 4-thiopyrimidine123.

When the thiol/thione tautomerism of 2-thiopyridine was studied in an amorphous, highly disordered, solid layer63, the observation of two broad bands of the IR spectrum at 2898 and 2412 cm 1, corresponding to the NH and the SH stretchings, confirmed the existence of both thiol and thione forms. Quite interestingly, in the crystalline state the molecules of 2-thiopyridine adopt only the thione form and appear bonded via pairs of N H. . .S hydrogen bonds forming cyclic dimers63. The predominance of the thione forms in condensed media is expected on the basis of the much higher dipole moments of these forms63,123. These experimental findings are consistent, for the particular case of 2-thiopyrimidine, with the ab initio self-consistent reaction field (SCRF) calculations of Contreras and Alderete125, who predicted the thione form to be 5.5 and 5.8 kcal mol 1 more stable than the thiol form in DMSO and water, respectively. It is worth noting that solvation effects are rather similar for thioand oxo-derivatives, since in general the oxo tautomers of oxoazines also have much larger dipole moments than the hydroxy forms127, so a reversal of stability is predicted in polar media, where the oxo form is usually more stable. These similarities apply also to other molecular properties. The SCRF study of 2- thiopyrimidine mentioned above125,126 showed that the introduction of a solvent reaction field has little effect on the structure of the thiol tautomer, whereas for the thione the change in the structure on going from the gas-phase to solution is rather significant,

1384 M. T. Molina, M. Ya´nez,˜ O. Mo,´ R. Notario and J.-L. M. Abboud

affecting essentially the C S bond which becomes 0.03 A˚ longer and the C N linkage which becomes 0.017 A˚ shorter. Similarly, in a SCRF study of 2-pyridone it was found127 that the solvent has little effect on the structure of the hydroxy form while changes in the molecular geometry of the keto tautomer (whose CDO bond lengthens by 0.01 A˚ while the C N bonds shorten by 0.005 A)˚ are sizeable. Similarly, for both carbonyl and thiocarbonyl derivatives large frequency shifts are calculated upon solvation. In both cases a red shift of about 40 cm 1 is predicted for the CDO and the CDS stretchings in going from the vapor phase to solution.

(iii) Thioguanines and thiopurines. Closely related to the tautomerism presented in the previous subsection are the tautomeric equilibria in the series of thioguanines and thiopurines. However, in the period of time under review, very few experimental studies have been reported for these systems and we are only aware of that of Santhosh and Mishra128, although some theoretical studies at the ab initio and semiempirical level have been published.

The structures and properties of the tautomers of 6-thioguanine were first investigated, at the ab initio level, by Leszczynski35. The geometries were optimized at the HF/3-21G(d) level and the final energies obtained at the MP2/6-31G(d) level. The most important conclusion of this work is that the most stable tautomer is the thione form 25a, while the thiol structure 25b is only 0.6 kcal mol 1 less stable. However, due to the large difference in dipole moments the alternative thione form 25c was predicted to be strongly stabilized in polar solvents. These results are in good agreement with the experimental work of Santhosh and Mishra128, who conclude that all the observed transitions of the electronic spectra of this molecule can be explained if one assumes that only the 25a and 25c thione species are present in solution. Furthermore, while at neutral or acidic pH the absorption peak observed near 340 nm can be unambiguously assigned to the 25a thione form, the peak observed near 320 nm at the alkaline pH seems to be due to the 25c thione form. Hence, Santhosh and Mishra128 conclude that in going from the neutral or acidic pH to the alkaline pH, the thione 25a is converted into the thione form 25c. Similar tautomers are found to be stable in solution for 6-thiopurine.

A more refined theoretical model was applied later by Alhambra and coworkers36 in a study of the stabilities of the different tautomers of 6-thioguanine and its protonated species. In this work geometry optimizations were carried out at the HF/6-31G(d) level and final energies were obtained at the MP2/6-311CCG(d,p) level. On the other hand, the effect of water on the tautomeric equilibrium was explored using a SCRF approach. In contrast with the conclusions of Leszczynski35, Alhambra’s group36 concluded that in the gas phase, 6-thioguanine is found predominantly in a thiol tautomeric form 25d (not