2-Acylidene-3,5-diaryl-2,3-dihydro-l,3,4-thiadiazoles and related compounds: a question of hypervalent S.. .O interactions

NARESH PANDYA, ANTHONY J. BASILE, AJAY K. GUPTA, PATRICK HAND, CINDY L. MACLAURIN, TAJ MOHAMMAD, ELAREF S. RATEMI, MARTIN S. GIBSON,' AND MARY FRANCES RICHARDSON'

Deparrment of Chemistry, Brock Universiry, St. Catharines, Ont., Canada L2S 3 A I

Received July 28, 1992

NARESH PANDYA, ANTHONY J. BASILE, AJAY K. GUPTA, PATRICK HAND, CINDY L. MACLAURIN, TAJ MOHAMMAD, ELAREF S. RATEMI, MARTIN S. GIBSON, and MARY FRANCES RICHARDSON. Can J. Chem. 71, 56 1 (1993).

A new synthesis of 1 by selective deacetylation of 2 is reported. The acylation step implied in earlier syntheses of 1 and related compounds is exemplified by direct acylations of 3 to give 4a and 46. Several new 2-acylidene-3-(2,4-di- bromophenyl)-5-phenyI-2,3-dihydro-1,3,4-thiadiazoles (11) and thioacylidene analogues (12) are described. The crys- tal structures of l l a , l l b , l l c , and l l d reveal a hypervalent interaction, ca. 2.45-2.7 A long, between the sulfur and carbonyl oxygen atoms. The dibromophenyl ring is nearly perpendicular to the thiadiazole ring plane in the crystal structures, and NMR data suggest that this conformation is maintained in solution. Molecular mechanics calculations show that the S...O interaction need only be a few kilocalories in order to_ stabilize the observed acylidene side chain configuration over other pcssible isomers. Crystals of l l a are triclinic, P1, with cell dimensions a = 12.937(2), b = 13.429(2), c = 13.489(2) A, a = 60.14(1)", P = 74.59(1)", y = 58.70(1)", Z = 4, and R = 0.044 for 3287 observed r$iections. Crystals of l l b are monoclinic, P2,/c, with cell dimensions a = 10.512(1), b = 12.084(2), c = 16.268(4) A, @ = 96.91(1)", Z = 4, R = 0.050 for 1938 observed refl~ctions. Crystals of l l c are monoclinic, P2,/c, with cell dimensions a = 17.492(4), b = 16.979(1), c = 14.962(1) A, P = 106.46(1)", Z = 8, R = 0.057 for 31 12 observed r~flections. Crystals of l l d are monoclinic, P2,/c, with cell dimensions a = 11.749(1), b = 8.533(1), c = 22.670(4) A, @ = 100.17(1)", Z = 4, and R = 0.059 for 2265 observed reflections.

NARESH PANDYA, ANTHONY J. BASILE, AJAY K. GUPTA, PATRICK HAND, CINDY L. MACLAURIN, TAJ MOHAMMAD, ELAREF S. RATEMI, MARTIN S. GIBSON et MARY FRANCES RICHARDSON. Can. J. Chem. 71, 561 (1993).

On decrit une nouvelle synthese du compose 1 realiske par une dCsacttylation selective du composC 2. L'etape d'acylation impliquee dans les syntheses anterieures du composk 1 et de ses composes apparentes est demontree par des acylations directes de 3 qui donnent 4a et 46. On decrit plusieurs nouveaux 2-acylidbne-3-(2,4-dibromophCnyl)-5-phCnyl-2,3-dih- ydro-l,3,4-thiadiazoles (11) et leurs analogues thioacylidbnes (12). Les structures cristallines des cpmposes l l a , 116, l l c et l l d rkvklent I'existence d'une interaction hypervalente, d'une longueur d'environ 2,45-2,7 A, entre le soufre et I'oxygkne du carbonyle. Dans les structures cristallines, le noyau dibromophenyle est pratiquement perpendiculaire au plan du noyau thiadiazole et les donnees de la RMN suggkrent que cette conformation est maintenue en solution. Des calculs de mkcanique moleculaire montrent qu'il suffit d'une interaction S...O de quelques kilocalories pour stabiliser la configuration observee pour la cha-he laterale par rapport aux autres isomkres possibles. Les 2ristaux du produit l l a sont tricliniques, groupe d'espace P1, avec a = 12,937(2), b = 13,429(2) et c = 13,489(2) A, a = 60,14(1)", P = 74,59(1)" et y = 58,70(1)", Z = 4 et R = 0,044 pour 3287 reflexions observees. Les cristaux du produit l l b sont mono- cliniques, groupe d'espace P l l / c , avec a = 10,512(1), b = 12,084(2) et c = 16,268(4) A, P = 96,91(1)", Z = 4 et R = 0,050 pour 1938 reflexions observees. Les crisiaux du produit l l c sont monocliniques, groupe d'espace P l l / c , avec a = 17,492(4), b = 16,979(1) et c = 14,962(1) A, P = 106,46(1)", Z = 8 et R = 0,057 pour 31 12 reflexions observkes. Les cristaux du produit l l d sont monocliniques, groupe d'espace Pl,/c, avec a = 11,749(1), b = 8,533(1) et c = 22,670(4) A, P = 100,17(1)", Z = 4 et R = 0,059 pour 2265 reflexions observees.

[Traduit par la rCdaction]

Introduction

We previously described syntheses of a number of 2-acy- lidene-3,5-diaryl-2,3-dihydro- 1,3,4-thiadiazoles such as 1 from a variety of substituted thiohydrazides (1) and 1,3,4- thiadiazolium salts (2). We now report a further synthesis of 1 by acidic hydrolysis of the acetylacetonylidene deriva- tive 2.

Compounds such as 1 can be regarded as acyl derivatives

/ N-N

' ~u thor s to whom correspondence may be addressed.

of methine bases, and, in our view, a reactive methine base is generated in situ in the earlier syntheses (1, 2) and then intercepted by the acylating agent present. We have now demonstrated the acylation step for a representative methine base 3 by reaction with two aroyl chlorides to give 4a and 4b. The enaminic character of 3 is further indicated by its reaction with iodomethane and with trichloroacetic acid to give 5 and 6, respectively, so providing a parallel with the benzothiazole series (3). We noted, however, that at- tempted acetylation of 7 gave dimer 8 although the parent thiadiazolium salt reacted normally to give 9. This behavior recalls that of methine bases in the 1,3,4-oxadiazole series, which form rearranged dimers on attempted acetylation (4). We tried to trap one such methine base, generated in situ, but obtained the rearranged dimer 10 (4).

2-Acylidene-3,5-diaryl-2,3-dihydro- 1,3,4-thiadiazoles (11) and the thioacylidene analogs (12) (5) are of interest from a number of points of view. Formally, geometrical isomerism is possible, yet in all syntheses to date only one isomer has

Can

. J. C

hem

. Dow

nloa

ded

from

ww

w.n

rcre

sear

chpr

ess.

com

by

119.

186.

160.

86 o

n 06

/03/

13Fo

r pe

rson

al u

se o

nly.

CAN. J . CHEM. VOL. 71, 1993

Ph + /

N-N

4a: R = phenyl

46: R = p-nitrophenyl

been isolated (6). We early suspected that these compounds possessed (Z) geometry and might be bicyclic as in 13 (5). We have since prepared a number of acyl compounds 11 (and thioacyl analogues 12) in which the methine proton is re- placed by alkyl in order to determine the overall geometry and the effect of alkyl size on the interatomic S-X (X = 0 , s ) distance and hence the extent of S.. .X interaction. This paper reports the crystal structures of four acyl compounds l l a - l l d and interprets the short S . . .O distance as a hyper- valent interaction that stabilizes the (Z) configuration.

Experimental section

Instrurnentatiorz The following instruments were used: Analect FX-6220 FT IR

spectrophotometer for IR spectra; Bruker WP-60 FT and WP-80 CW spectrometers for 'H NMR spectra (tetramethylsilane was used as an internal standard); DMS 100 UV-visible spectrophotometer for UV spectra (log 8 values given in parentheses); AEI MS30 double-beam instrument for mass spectra. Melting points are un- corrected.

Hydrolysis of 2 (7) Compound 2 (1) (50 mg, 0.15 mmol) was refluxed in concen-

trated HC1 (5 mL) for 50 min. When cool, the mixture was neu- tralized with 1 M NaOH solution, and the solid was collected. Crystallization from absolute EtOH gave 1 (20 mg, 45%), mp 147- 149"C, identified by mp and spectral correlation with a reference sample (1).

lla: R 1 = H , R 2 = M e 12a: R' = H, R2 = Ph

1 lb: R' = H, R2 = Ph 12b: R1 = Me, R2 = Ph

1 1 ~ : R' = Me, R2 = Ph 12~: R' = Et. R2 = Ph

11d: R' = E t , R 2 = P h

Can

. J. C

hem

. Dow

nloa

ded

from

ww

w.n

rcre

sear

chpr

ess.

com

by

119.

186.

160.

86 o

n 06

/03/

13Fo

r pe

rson

al u

se o

nly.

PANDYA E 3T AL. 563

Reactions of 2-betzzylidene-2,3-dihydro-3,5-diphet1yl-l,3,4- thiadiazole (3) (8)

(a) Acylation A solution of the methine base 3 (0.33 g, 1 mmol) in dry ben-

zene (10 d ) containing triethylamine (0.1 g, 1 mmol) and freshly distilled benzoyl chloride (0.14 g, 1 mmol) was refluxed under ni- trogen for 2.5 h. The triethylamine hydrochloride was filtered off and the filtrate was evaporated to give a brown solid (0.42 g). Pu- rified by chromatography on silica, the benzoyl derivative 4a crystallized from 95% ethanol as yellow prisms (0.39 g, 90%), mp 171-173 "C; UV (MeCN): 242 (4.28) and 387 (4.26) nm; IR (KBr): 1585 (C=O) cm-I; mass spectrum m/z: 432 (MC, base peak). Anal. calcd. for C28H20N20S: C 77.77, H 4.62, N 6.48; found: C 77.54, H 4.51, N 6.33.

Similarly prepared (2 mmol scale), the p-nitrobenzoyl deriva- tive 4b crystallized from chloroform-methanol as deep orange needles (0.74 g, 77%), mp 237-240°C; UV (MeCN): 248 (4.3 1) and 398 (4.16) nm; IR (KBr): 1595 (C=O) cm-I; mass spectrum m/z: 477 (M+, base peak). Anal. calcd. for C28H19N303S: C 70.44, H 3.98, N 8.81; found: C 70.28, H4.07 , N 9.01.

(b) Methylation A solution of 3 (0.5 g, 1.5 mmol) in Me1 (8 mL) was refluxed

for 72 h, and excess Me1 was then evaporated in vacuo. Crystal- lization from MeCN gave 2-(1 -phenethyl)-3,5-diphenyl- 1,3,4- thiadiazolium iodide (5) as a yellow crystalline solid (0.4 g, 56%), mp 233-235°C; UV (MeCN): 247 (4.32) and 285 (4.00) nm; 'H NMR (CD3CN) 6: 1.98 (d, J 7 Hz, 3H, CH,), 4.80 (q, J 7 Hz, 1 H, CH), and 7.26-8.06 (m, 15H, arom H); mass spectrum m/z: 342 (M' - HI). Anal. calcd. for C22H191N2S: C 56.17, H 4.04,127.02, N 5.96; found: C 55.99, H 4.1 I , 127.31, N 6.02.

(c) Reaction with trichloroacetic acid A solution of 3 (0.5 g, 1.5 mmol) in dry benzene (10 mL) con-

taining freshly distilled trichloroacetic acid (0.25 g, 1.5 mmol) was refluxed under nitrogen for 1.5 h. The solvent was evaporated in vacuo and the residual gum was crystallized from 95% EtOH to give 2-benzyl-2,3-dihydro-3,5-diphenyl-2-trichloromethyl- 1,3,4-thia- diazole (6) as a yellow crystalline solid (0.55 g, 81%), mp 45-50°C; UV (MeCH): 232 (4.22) and 342 (3.92) nm; 'H NMR (CDCI,) 6: 3 .70(d, J 16Hz, lH), 4.10(d, J 16Hz, lH), and7.10-7.75 (m, 15H, arom H); mass spectrum m/z: 328 (M+ - CHC1,). Anal. calcd. for C,,H,,Cl,N,S: C 58.86, H 3.79, N 6.24; found: C 59.15, H 3.88, N 6.26.

Attempted acetylation of 7 Compound 7 (8) (0.2 g, 0.7 mmol) was added in portions to a

stirred mixture of acetyl chloride (0.1 mL, ca. 1.4 mmol) and dry pyridine (3 d ) at O°C. The solution was stirred at O°C for 1 h, and then at room temperature for 4 h. The reaction mixture was poured into water and was extracted with chloroform. The combined or- ganic extracts were washed with water and dried (Na2S04). Evap- oration in vacuo gave a red solid (0.18 g), which was identified as 8 (8) by comparison with an authentic specimen (mp and mixture mp; 'H NMR spectrum).

2-(1 -Chloroacetonylidene)-2,3-dihydro-3,5-diphenyl-l,3,4- thiadiazole (9)

2-Chloromethyl-3,5-diphenyl-1,3,4-thiadiazolium perchlorate (8) (0.5 g, 1.3 mmol) was added in portions to a stirred mixture of acetyl chloride (0.15 mL, ca. 2.1 mmol) and dry pyridine (5 mL) at 0°C. The resulting dark red mixture was stirred at 0°C for 1 h, and then at room temperature for 30 min. The reaction mixture was poured into water (50 mL) and left overnight. The separated solid was filtered off, washed with water, and dried. Two crystalliza- tions from absolute EtOH gave 9 as a pale yellow crystalline solid (0.20 g, 47%), mp 142-146°C; UV (MeCN): 237 (4.3 1) and 369

(4.25) nm; IR (KBr): 1600 (C=O) c m ' ; 'H NMR (CDCl,) 6: 2.43 (s, 3H, CH,) and 7.38-8.13 (m, IOH, arom H); mass spectrum (rel. int.) m/z: 328 (M', 14%), and 103 (base peak). Anal. calcd. for C17H13CIN20S: C 62.19, H 3.96, N 8.53; found: C 62.34, H 4.09, N 8.50.

3,5-Diphenyl-2-methyl-] ,3,4-oxadiazolium perchlorate and 1 0 A mixture of N-phenylbenzohydrazide (1.0 g, 44 mmol) and

acetonitrile (0.3 mL, ca. 53 mmol) in acetic acid (2 mL) and 70% perchloric acid (1 mL) was refluxed for 5 min. When cool, water (20 mL) was added with stirring; the suspension cleared, and the oxadiazolium salt slowly separated as a white crystalline solid (1.5 g, 99%), mp 188-190°C (lit. (4) mp 191-192.5"C).

Treatment of this salt in acetonitrile with triethylamine, alone or in conjunction with acetic or benzoic anhydride, gave 3-(N',Nf- dibenzoyl-N-pheny1hydrazino)-5-methyl- 1 -phenylpyrazole (lo), identified by correlation of mp and spectral data with published values (4).

(a) l l c A stirred mixture of N'-(2,4-dibromopheny1)-N'-propionylben-

zothiohydrazide (1) (2.20 g, 5.0 mmol) and benzoic anhydride (6.0 g, 26.5 mmol) in MeCN (15 mL) was refluxed for 3 h. After cooling, 10% aqueous NaOH (75 mL) was added, and the mix- ture was stirred for 2 h. The separated solid was filtered off, washed with water, and dried. Crystallization from chloroform - light pe- troleum gave l l c as a light brown crystalline solid (2.0 g, 76%), mp 199-201°C; UV (MeCN): 237 and 380 nm; IR (KBr): 1595 (C=O) cm-'; 'H NMR (CDCl,) 6: 1.60 (s, 3H, CH,) and 7.30- 8.00 (m, 13H, arom H); mass spectrum (rel. int.) m/z: 526 (M', 4%) and 105 (base peak). Anal. calcd. for C23H,6Br2N,0S: C 52.27, H 3.03, N 5.30; found: C 51.96, H 3.04, N 5.05. Crystals were grown from ethyl acetate.

(b) l l d Similarly prepared (1.1 mmol scale), l l d crystallized from

MeCN as light brown prisms (0.425 g, 72%), mp 153-155°C; UV (MeCN): 238 (4.34) and 375 (4.21) nm; IR (KBr): 1595 (C=O) cm-'; 'H NMR (CDC1,) 6: 0.57 (t, J 7 Hz, 3H, CH,), 1.94-2.33 (m, 2H, CH,), and 7.39-7.92 (m, 13H, arom H); mass spectrum (rel. int.) m/z: 540 (M+, 9%) and 105 (base peak). Anal. calcd. for C24H18Br2N20S: C 53.14, H 3.32, N 5.17; found: C 53.09, H 3.32, N 4.99. Crystals were grown from acetonitrile.

(a) 12b To a stirred solution of 3-(2,4-dibromopheny1)-2-ethyl-5-phenyl-

1,3,4-thiadiazolium perchlorate (2) (0.5 g, 1.5 mmol) and thiob- enzoylthioglycollic acid (1.0 g, 4.7 mmol) in absolute EtOH (15 mL) was added triethylamine (0.3 mL). The resulting mixture was refluxed for 20 h. The solvent was evaporated in vacuo and the residue was dissolved in chloroform (75mL). The chloroform so- lution was washed with 5% aqueous NaOH (2 x 25 mL) and water (2 X 25 mL), then dried over Na2S04. Evaporation of chloroform and chromatography on silica gave 12b, which crystallized from chloroform-hexane as a brick-red crystalline solid (0.25 g, 48%), mp 303-304°C (dec. after changing colour to yellow-green at 185°C); UV (MeCN): 235 (4.40) and 447 (4.16) nm; IH NMR (CDCI,) 6: 1.70 (s, 3H, CH3) and 7.28-7.91 (m, 13H, arom H); mass spectrum (rel. int.) m/z: 542 (MC, 2%) and 103 (base peak). Anal. calcd. for C23H,6Br2N2S2: C 50.73, H 2.94, N 5.14; found: C 50.44, H 3.27, N 4.93. Crystals were grown from chloroform.

(b) 12c A stirred suspension of l l d (0.75 g, 1.4 mmol) and phosphorus

pentasulfide (0.8 g, 3.6 mmol) in dry benzene (25 mL) was re- fluxed for 30 min. The product was isolated as described for 12b.

Can

. J. C

hem

. Dow

nloa

ded

from

ww

w.n

rcre

sear

chpr

ess.

com

by

119.

186.

160.

86 o

n 06

/03/

13Fo

r pe

rson

al u

se o

nly.

CAN. J . CHEM. VOL. 71, 1993

TABLE I. Crystal data

1 l a l l b l l c 1 l d

Formula Formula weight Crystal size, mm Crystal system Space group Cell dimensions determined from 25

r:flections with: a , b, A c , A a , O

P, O

z Pcalc, PO? (g cm-7 IJ.3 cm- Reflections collected, max 28 Standard reflection, deviation

No. of reflections collected No. of unique reflections No. of observed reflections No. of parameters refined Final R, R,. Final shiftlerror, max Final difference map, max, min (e A-3) p in weighting scheme, [a2(F) + p ~ 2 ] - '

CZ2H ,,Br2N20S 514.23 - Monoclinic P 2 , l c

C23H16Br2N20S 528.26 0.34 X 0.15 X 0.11 Monoclinic P21lc

C,4H,8Br2N20S 542.29

" -

Monoclinic P 2 , l c

"Irregular; maximum dimension 0.3 mm.

Crystallization from absolute EtOH gave 12c as an orange-red crystalline solid (0.45 g, 58%), mp 265-268°C (dec. after dark- ening at 150°C); UV (MeCN): 232 (4.45) and 444 (4.09) nm; 'H NMR (CDC13) 6: 0.63 (t, J 7 Hz, 3H, CH,), 1.99-2.40 (m, 2H, CH2), and 7.30-7.94 (m, 13H, arom H); mass spectrum (rel. int.) m/z: 556 (Mf , 6%) and 103 (base peak). Anal. calcd. for C24H18Br2N2S2: C 51.61, H 3.22, N 5.01; found; C 50.83, H 3.21, N 4.76. Crystals were grown from acetonitrile.

Crystal structure determzrzations Crystals of l l c and l l d were obtained as described above; l l a

and 116 were prepared in previous work (1). Unit cell dimensions were determined from the angular setting of 25 reflections mea- sured with graphite-monochromatized MoKci radiation ( A = 0.7 1069 A). Intensities were measured by the o-28 technique at room temperature (293-298 K) with an Enraf-Nonius CAD4 sin- gle-crystal diffractometer and corrected for Lorentz and polariza- tion effects but not for absorption. The structures were solved by Patterson methods and refined by full-matrix least-squares tech- niques (116 and 116) or by block-diagonal least squares ( l l a and l l c ) with each block contaming all of the atoms in one indepen- dent molecule plus the sulfur and bromlne atoms in the second. Hydrogen atom positions were calculated. Anisotropic displace- ment parameters were assigned to all atoms except hydrogen in l l a , l l b , and l l d . The phenyl carbons and the hydrogens in l l c were refined with isotropic displacement parameters; the remaining atoms were refined with anisotropic displacement parameters. Scattering factors, including the real and imaginary parts of the anomalous scattering, were taken from the International tables for X-ray crystallography (9). The weighting scheme was w = [u2(F) + p F']-' with a value of p asslgned to minimize the variance as a function of reflection intensity. Programs used included SHELX- 76 ( lo) and ORTEP (1 1). The largest peaks and holes on the final difference maps (ca. ?1 e A - ~ ) were located near the bromines,

and are due to the lack of an absorption correction. The crystal data and experimental details are listed in Table 1. The final parame- ters are given in Tables 2-5.'

Molecular mechanics Molecular mechanics calculations were canied out with Chem3D

Plus (Cambridge Scientific Computing, Cambridge, Mass.), which implements Allinger's MM2 force field (12) with automatic n-calculation. A few new parameters were introduced and stan- dard parameters were modified slightly to reproduce the structure of l l a ; the full parameter set is given in the Supplementary Ma- terial.

Results and discussion Syntheses and characterization

Syntheses of l l a and l l b were described previously (1); compounds l l c and l l d were prepared from the corre- sponding N'-acyl-N'-(2,4-dibromopheny1)benzothiohydra-

'packing diagrams, anisotropic displacement parameters, hy- drogen atom positions, short contact distances, bond distances and angles in the phenyl rings and side chains, least-squares planes, and structure factor tables for l l a - l l d , as well as molecular me- chanics parameters and the results of the Cambridge Crystallo- graphic Database Search, may be purchased from: The Deposi- tory of Unpublished Data, CISTI, National Research Council Canada, Ottawa, Canada K I A OS2.

Packing diagrams and tables of hydrogen atom positions, short contact distances, and bond distances and angles have also been deposited with the Cambridge Crystallographic Data Centre and can be obtained on request from The Director, Cambridge C q s - tallographic Data Centre, University Chemical Laboratory, 12 Union Road, Cambridge, CB2 lEZ, U.K.

Can

. J. C

hem

. Dow

nloa

ded

from

ww

w.n

rcre

sear

chpr

ess.

com

by

119.

186.

160.

86 o

n 06

/03/

13Fo

r pe

rson

al u

se o

nly.

PANDYA ET AL. 565

TABLE 2. Fractional coordinates and displacement parameters for l l a

Atom x Y 7 ue:

TABLE 3. Fractional coordinates and displacement parameters for l l b

Atom x Y z Ueqn

Br(1A) Br(2A) S(A) O(A) N(1A) N(2A) C( 1 A) C(2A) C(3A) C(4A) C(5A) C(6A) C(7A) C(8A) (39.4) C(1OA) C( l I A) C( 12A) C(13A) C( 14A) C(15A) C( 16A) C(17A) Br(1B) Br(2B) S(B) O(B) NUB) N(2B) C(lB) C(2B) C(3B) C(4B) C(5B) C(6B) C(7B) C(8B) C(9B) C(1OB) C( l IB) C(12B) C(13B) C(14B) C(15B) C(16B) C(17B)

zide and benzoic anhydride. Of the corresponding thioacyl derivatives, 12a was prepared from thiobenzoylthioglyco1- lic acid and the required thiadiazolium salt by the literature method (2). This method was successfully extended to the preparation of 12b, although a small amount of PhCSOEt was also apparently formed. However, PhCSOEt emerged as the main product (IR, NMR, and mass spectral identification) recovered from the complex mixture obtained when a simi- lar synthesis of 12c was attempted. This compound was therefore prepared, though not in analytically pure condi- tion, from l l d and phosphorus pentasulfide (5); Lawesson's reagent ( l3) , as an alternative reagent to phosphorus penta- sulfide, proved unsuitable for this purpose. We did not ob-

"Uc, = 1 /3 CSU,,aTa,Ca,. a,.

tain crystals suitable for X-ray structure determinations for any of the thioacyl compounds.

As noted, we early suspected that compounds such as 1 and their thioacyl analogues possessed (Z) geometry and might even be bicyclic structures such as 13 (5). For com- pounds like 1 , our suspicions were aroused by the some- what low frequency (ca. 1600 cm-') observed for carbonyl absorption in the IR spectra (for similar quinoline deriva- tives 14 with R = Me or Et, the carbonyl absorption band is at 1635 cm-I (14)). For the thioacyl compounds, our sus- picions were based on mass spectra; for example, l l b shows m/z 105 (PhCO) as base peak, whereas 12a shows m/z 103 (PhCN) as base peak, with a peak at m/z 425 (12%) (M - PhCN) that suggests S-S interaction. Similar features are exhibited by compounds l l c and l l d , and by 12b and 12c, though the last does not show a detectable (M - PhCN) fragment.

Molecular structures The structures of l l a - l l d are shown in Figs. 1-4, and

important distances and angles are listed in Table 6. Bond distances lie within the range of values established for sim- ilar structural fragments (15). The six independent mole-

Can

. J. C

hem

. Dow

nloa

ded

from

ww

w.n

rcre

sear

chpr

ess.

com

by

119.

186.

160.

86 o

n 06

/03/

13Fo

r pe

rson

al u

se o

nly.

566 CAN. J. CHEM. VOL. 71. 1993

TABLE 4. Fractional coordinates and displacement parameters for l l c

Atom x

Br(1A) 0.19227(7) Br(2A) 0.19769(8) S(A) 0.4161(1) O(A) 0.4439(3) N(1A) 0.3662(4) N(2A) 0.3647(4) C(1A) 0.3971(4) C(2A) 0.4 149(5) C(3A) 0.4217(6) C(4A) 0.4146(6) C(5A) 0.3941 (8) C(6A) 0.3885(6) C(7A) 0.3903(4) C(8A) 0.3261(4) C(9A) 0.248 l(5) C(1OA) 0.2104(5) C(l1A) 0.2500(5) C(12A) 0.3285(5) C(13A) 0.3658(5) C(14A) 0.3910(4) C(15A) 0.3981(5) C(16A) 0.4232(4) C(17A) 0.4252(4) C(18A) 0.4894(5) C(19A) 0.4923(5) C(20A) 0.43 1 1 (5) C(21A) 0.3670(5) C(22A) 0.3636(5) C(23A) 0.3851(5) Br(1B) 0.08038(9) Br(2B) 0.36453(7) S(B) -0.1416(2) O(B) -0.1824(3) N(1B) 0.0052(4) N(2B) -0.0150(4) C(1B) -0.1301(5) C(2B) -0.2108(5) C(3B) -0.2471(6) C(4B) -0.2037(6) C(5B) -0.1240(6) C(6B) -0.0862(6) C(7B) -0.0894(5) C(8B) 0.0899(5) C(9B) 0.133 l(5) C(I0B) 0.2153(5) C( I 1 B) 0.2520(5) C(12B) 0.21 13(6) C(13B) 0.1286(5) C(14B) -0.0523(5) C(15B) -0.0477(5) C(16B) -0.1178(6) C(17B) -0.1182(5) C(18B) -0.1820(6) C(19B) -0.1855(8) C(20B) -0.1270(8) C(21B) -0.0630(6) C(22B) -0.0593(6) C(23B) 0.0252(6)

'U,, = 1 /3 HHU,n,*n,?a,

Y

0.48704(7) 0.16801(7) 0.5841(1) 0.6619(3) 0.4508(3) 0.4462(4) 0.5275(4) 0.6018(6) 0.6166(6) 0.5573(6) 0.4821(8) 0.4668(6) 0.5132(5) 0.3858(4) 0.3913(4) 0.3266(5) 0.2572(5) 0.2496(5) 0.3 152(4) 0.5189(4) 0.5364(5) 0.6149(5) 0.6437(4) 0.6880(4) 0.7203(5) 0.7068(5) 0.6639(5) 0.6300(5) 0.4750(5) 0.33024(7) 0.15489(9) 0.1348(2) 0.0902(3) 0.1648(4) 0.181 l(4) 0.1792(5) 0.1950(5) 0.2048(5) 0.1993(5) 0.1832(5) 0.1728(5) 0.1681(5) 0.1633(5) 0.2325(5) 0.2306(5) 0.1588(5) 0.0893(6) 0.0919(6) 0.1410(5) 0.1240(5) 0.0959(5) 0.0720(5) 0.0922(6) 0.0699(8) 0.0248(6) 0.0013(6) 0.0244(6) 0.1471(6)

. a,.

cules exhibit seyeral common features: a short S.. .O contact (2.463-2.691 A), essentially planar thiadiazole rings with the C(15)-C(16)-0 side chain deviating only slightly from the plane of the thiadiazole ring, and the dibromophenyl ring nearly perpendicular to the thiadiazole ring (N(1)-

TABLE 5. Positional parameters and equivalent isotropic displace- ment parameters for l l d

Atom x Y z ue;

Br(1) 0.37918(9) 0.28258(10) 0.44335(5) 0.070 Br(2) 0.46580(11) 0.90190(12) 0.38269(6) 0.103 S 0.0274(2) 0.0940(2) 0.3304(1) 0.046 0 0.0769(5) -0.0271(7) 0.2396(2) 0.064 N(1) 0.0843(6) 0.3280(9) 0.4008(3) 0.060 N(2) 0.1492(6) 0.3367(8) 0.3557(3) 0.059 C(1) -0.0592(6) 0.1692(9) 0.4359(3) 0.046 C(2) -0.1360(7) 0.0470(10) 0.4247(4) 0.065 C(3) -0.2070(8) 0.0048(11) 0.4649(4) 0.075 C(4) -0.2011(9) 0.0881(12) 0.5164(4) 0.074 c(5) -0.1254(8) 0.2123(12) 0.5293(4) 0.075 C(6) -0.0541(8) 0.2513(10) 0.4886(4) 0.062 (37) 0.0186(6) 0.2105(10) 0.3939(3) 0.047 C(8) 0.2257(7) 0.4665(10) 0.3603(3) 0.048 (39) 0.3284(7) 0.4647(8) 0.3978(3) 0.044 C(10) 0.4006(7) 0.5925(9) 0.4049(3) 0.051 C(11) 0.3653(8) 0.7249(9) 0.3724(4) 0.058 C(12) 0.2609(8) 0.7317(10) 0.3368(4) 0.063 C(13) 0.1887(8) 0.6045(12) 0.3301(3) 0.064 C(14) 0.1338(6) 0.2212(9) 0.3132(3) 0.050 C(15) 0.1880(7) 0.1999(10) 0.2641(3) 0.056 C(16) 0.1522(6) 0.0636(9) 0.2280(3) 0.045 C(17) 0.2090(6) 0.0245(9) 0.1753(3) 0.049 C(18) 0.2885(8) -0.0959(13) 0.1789(4) 0.080 C(19) 0.3365(8) -0.1394(14) 0.1283(5) 0.084 (320) 0.3072(8) -0.0609(12) 0.0766(4) 0.069 C(21) 0.2274(9) 0.0545(12) 0.0716(4) 0.078 C(22) 0.1774(8) 0.0992(11) 0.1200(4) 0.063 C(23) 0.2780(12) 0.3271 (18) 0.2395(6) 0.129 C(24) 0.3847(18) 0.2785(20) 0.2651(6) 0.164

N(2)-C(8)-C(9) torsion angles of 63.1-97.0"). The C(14)-C(15) and C(15)-C(16) distances, intermediate between single and double bond lengths, show that there is delocalization in the C(14)-C(15)-C(16)-0 moiety. However, the C(16)-0 distances are not significantly longer than the expected distance for a C=O bond (15).

The S . ..O contacts in all six independent molecules in l l a - l l d adhere closely to the geometry observed by Rosenfield, Parthasarathy, and Dunitz (16) for the approach of nucleophiles to divalent sulfur: the C(7)-S. ..O and S.. .O-C(16) angles of .= 16.5" and 100°, respectively, are consistent with a hypervalent interaction in which a pair of electrons from the carbonyl donates to a C-S a * orbital (16), or with u-bond coupling between a filled oxygen p-orbital with an empty sulfur d12-),2 orbital (17). Both bonding models explain the shift of the carbonyl stretching frequency to =1600 cm-I, and both are consistent with a structure lying along the reaction coordinate that connects the monocyclic 11 and the bicyclic 13 (1 8). The S.. .O distance varies with the substituents, and is longest when R' = H ( l l a , l lb) . Replacement of the methine proton by methyl ( l l c ) or ethyl (114 shortens the S...O distance by ca. 0.20 A. The short- ening can be interpreted in terms of steric crowding, as the N(2)-C(14)-C(15) and C(15)-C(16)-C(17) angles in- crease to accommodate the bulkier alkyl groups.

There are also trends in the C(15)-C(16) distance and C(14)-C(15)-C(16) angle with substituent: when R2 =

Can

. J. C

hem

. Dow

nloa

ded

from

ww

w.n

rcre

sear

chpr

ess.

com

by

119.

186.

160.

86 o

n 06

/03/

13Fo

r pe

rson

al u

se o

nly.

PANDYA ET AL. 567

FIG. 1. Independent molecules (a) A and (b) B in the structure of l l a .

methyl ( l la) , C(15)-C(16) is ca. 0.05 A shorter and C(14)-C(15)-C(16) is ca. 3" larger than when R' = phenyl (116, l l c , 116). These changes, which are due to elec- tronic effects, also affect the S...O distance so that it is nearly the same in l l a and l l b .

The orientation of the dibromophenyl ring nearly perpen- dicular to the thiadiazole plane was unexpected since phenyl rings do not normally twist greatly out of the plane of an- other delocalized ring system (e.g., note the N(1)- C(7)-C(1)-C(2) torsion angles in the present structures; Table 6). A search of the Cambridge Crystallographic Database (ref. 19; see supplementary information) yielded eight structures having 2-bromophenyl rings attached to

planar atoms in 5- or 6-membered rings. Of the eight, only one had a dihedral angle less than 50". That such a large di- hedral angle is maintained across a spectrum of different compounds is an indication that it reflects the most favor- able conformation of a 2-bromophenyl ring. This is an im- portant point since below we shall interpret NMR spectra in terms of the differing phenyl and dibromophenyl ring con- formations in 7, 11, and 12 and their corresponding non- brominated analogues.

Two of the structures ( l l a and l l c ) have two indepen- dent molecules in the asymmetric unit. This phenomenon occurs with reasonable frequency in lower-symmetry space groups (20), and sometimes the independent molecules have essentially identical conformations (2 1). The conformations of molecules A and B in l l c are quite different (note the N(1)-N(2)-C(8)-C(9), N( 1)-C(7)-C(l )-C(2), and C(15)-C(16)-C(17)-C(18) torsion angles in Table 6), whereas molecules A and B in l l a are essentially identical. We checked carefully for higher symmetry in l l a , espe- cially since there is a pseudo-monoclinic C-centred cell that can be derived from the triclinic cell. However, nominally equivalent reflections in the monoclinic cell did not have the same intensity, and the final structure showed that mole- cules A and B are not related by a monoclinic symmetry element.

In every structure, the C(12)-H and (or) C(13)-H groups in the dibromophenyl ring make short contacts with carbonyl oxygens in adjacent molecules. Some of these contacts are short enough to be regarded as C-H ... 0 hy- drogen bonds (22).

Molecular mechanics, isomerism, and conformations Molecular mechanics allows a semiquantitative estimate

of the relative energies of isomers and conformers of a given molecule. The accuracy of the calculated structure and the steric energy depend on the quality of the parameters, which are less well established for molecules such as l la - l ld than for simpler compounds. For example, the MM2 minimiza- tion of l l a gave structures with the dibromophenyl ring in- cluded at an angle of =32" with respect to the thiadiazole plane, and a corresponding energy of 1-5 kcal less than the observed conformation with the dibromophenyl ring per- pendicular to the plane. The final torsion angle of the di- bromophenyl ring depended on the parameters associated with the lone pair on N(1). The S...O and other distances varied with the orientation of the dibromophenyl ring and, in order to produce consistent results, minimizations were carried out with the N(1)-N(2)-C(8)-C(9) torsion an- gles fixed at the values observed in the crystal structures.

Scheme 1 shows the possible isomers/conformers of 11, designated as if there were no delocalization in the side chain. In l l a (R' = H, R2 = CHJ, the two (Z) conformers in Scheme 1 both have lower steric energies (21.7 and 21.8 kcal) than the two ( E ) conformers (23.7 and 27.2 kcal). The steric energies of (Z) conformers 1 and 2 remain simi- lar as R* is changed to phenyl, but the steric energy of (E) conformer 2 increases sharply unless the R 2 c 0 group is ro- tated out of the thiadiazole plane. The similar steric ener- gies of both of the (Z) conformers is an additional argument for a hypervalent S.. .O interaction, whose energy need be no more than a few kilocalories to account for the over- whelming predominance of conformer 1. These results are consistent with quantum chemical calculations that show the

Can

. J. C

hem

. Dow

nloa

ded

from

ww

w.n

rcre

sear

chpr

ess.

com

by

119.

186.

160.

86 o

n 06

/03/

13Fo

r pe

rson

al u

se o

nly.

CAN. J. CHEM. VOL. 71. 1993

FIG. 2. The structure of l l b .

S.. .O interaction in CH,SCH=CHCHO to be equivalent to about 10% of a usual single bond (23).

The minimized "single-ringn structures showno as (2) conformer 1 in Scheme 1 had S.. .O distances =0.2 A longer than observed in the crystal structures. Decreasing the S-0 distance (by changing the angles at C(14), C(15), and C(16)) resulted in increased van der Waals repulsions of several kilocalories. When the MM2 parameter set was changed to allow for an additional bond between S and 0, the mini- mized structures more closely resembled the observed structures. The MM2 calculations reproduced the bond angle changes in bond angles and S.. .O distances that occurred as R' and R' were varied, thus substantiating the proposal that substituent effects in the series l la - l ld are steric rather than electronic in nature.

Calculations for l l d show that the ethyl group is tightly sandwiched between the phenyl and dibromophenyl rings. Rotation of the ethyl group results in severe high-energy strain in the rest of the molecule. Hindered rotation is thus very likely the cause of the complex 'H NMR spectrum for the CH, group in l l d and 12c, as well as for the apparent dis- order of the ethyl group in the crystal structure of l l d . (The large displacement parameters and the uncertainty in the positions suggest disorder; unfortunately the difference map did not clearly reveal a second position for the methyl car- bon C(24).)

NMR spectra and conformations in solution It is interesting to recall that the 'H NMR spectra of com-

pounds such as l l a and l l b , which contain an ortho substi- tuent in the N-aryl group, display the methine proton signal ca. 0.6 ppm upfield from that for analogous compounds containing no such ortho substituent (8). This is compatible with (2) geometry and a conformation in solution in which

the N-aryl group is twisted out of the plane of the thia- diazole ring. This implies that the conformation in solution is similar to the structure in the crystal, and that it is not simply a crystal packing effect that holds the dibromo- phenyl rings nearly perpendicular to the thiadiazole ring plane. Similar shifts have been noted for thioacyl deriva- tives 12, from which (2) geometry and a perpendicular di- bromophenyl ring may also be inferred, as well as for chloromethylene derivatives like 7 . Indeed the close simi- larity in 'H NMR spectra of llb-d and 12a-c, respec- tively, implies similar conformations and thus a significant hypervalent S...S interaction in the thioacylidene series of compounds 12. A hypervalent S.. .Cl interaction may addi- tionally stabilize compounds such as 7.

The 'H NMR spectrum of 2, run at ambient temperature, is also of interest in that the methyl protons appear as a sin- glet (1). This suggests appreciable single bond character for the carbon-carbon "double bond", analogous to the C(14)-C(15) bonds in l la - l ld , with a low barrier to ro- tation. This is borne out by a low-temperature study. The 'H NMR spectrum of 2 (in CD,Cl,) at 183 K shows two dis- tinct singlets at 6 1.85 and 2.23 for the protons of the two methyl groups. As the temperature is raised, the intensities of these two signals decrease and the signals broaden. By 213 K, the two signals have collapsed to a broad hump that continues to sharpen, and by 303 K only one sharp signal is observed for the two methyl groups, at 6 2.04. Lowering of this rotational bamer is thus associated with (electrophilic) acetylation of 1 to give 2 (1). This is relevant to electro- philic substitution in the 1,6,6a-trithiapentalene series where ring opening - rotation - alternative ring closure reactions have been observed during nitrosation (24) and treatment with aryl diazonium ions (25); 1-oxa-6,6a-dithiapentalenes be- have similarly in the latter reaction (25).

Can

. J. C

hem

. Dow

nloa

ded

from

ww

w.n

rcre

sear

chpr

ess.

com

by

119.

186.

160.

86 o

n 06

/03/

13Fo

r pe

rson

al u

se o

nly.

PANDYA I 3T AL.

FIG. 3. Independent molecules (a) A and (b) B in the structure of l l c .

aryl diazonium ions (25); 1-oxa-6,6a-dithiapentalenes be- have similarly in the latter reaction (25).

The 'H NMR spectrum of l l d is interesting in that the signal due to the CH, protons appeared as a multiplet rather than a quartet, suggesting that these protons might be dia- stereotopic with respect to the dibromophenyl ring because of restricted rotation. No simplification was observed when the spectrum was run at 56.5"C, nor was there clear evi- dence of simplification when the CH, triplet was irradiated at ambient temperature. Similar data were obtained from the spectrum run in pyridine-d,,, even at temperatures of 57, 69, and 82°C.

Finally we wish to comment further on the 'H NMR spectra of 15a and 15b. The spectrum of 15a, originally

FIG. 4. The structure of l ld .

measured at 60 MHz, was reported to exhibit the CH, pro- ton signal as a multiplet, suggestive of restricted rotation

about the N-aryl bond (2). We have rerun this spectrum several times (at 80 and 200 MHz in CD,CN, CD3COCD3, and in (CD,),SO) on more modem instruments and can confirm that this signal appears at ambient temperatures as a quartet; typically, the compound shows 6 (CD,CN): 1.38 (t, J 7 Hz, 3H, CH,) and 3.25 (q, J 7 Hz, 2H, CH,), and saturation of the CH, protons causes the quartet to collapse to a singlet. To determine whether N-aryl rotation might become restricted at lower temperatures, we scanned the 'H NMR spectrum (200 MHz) of 15a in CD,COCD, over the temperature range 303-213 K. At 253 K , the CH, quartet shows signs of splitting as a result of differentiation of A and B protons as an AB system. This becomes clearer as the temperature is lowered, and from the spectrum at 233 K we calculate JAB 7.3 Hz. By 213 K the methylene proton signal is a multiplet (ABX, system). By this temperature, inter- conversion of enantiomeric conformers through N-aryl ro- tation has become very slow.

We have also noted that the CH, signal in the 'H NMR spectrum (80 MHz) of 15b in CD,CN at ambient tempera- tures is a slightly broadened singlet (8). However, the spec- trum at 200 MHz of this salt in (CD,),SO (with perchloric acid added to suppress dissociation to the methine base) shows the methylene protons clearly discriminated as an AB system with signals at 6: 4.13 (d, J 18 Hz, 1H) and 4.76 (d, J 18 Hz, 1H). Evidently there is restricted N-aryl rotation in 15b under these.conditions.

Can

. J. C

hem

. Dow

nloa

ded

from

ww

w.n

rcre

sear

chpr

ess.

com

by

119.

186.

160.

86 o

n 06

/03/

13Fo

r pe

rson

al u

se o

nly.

570 CAN. J . CHEM. VOL. 71. 1993

TABLE 6. Selected bond distances (A), bond angles ( O ) , and torsion angles (")

lln rnol. A l l a mol. B l l b l l c mol. A l lc mol. B l ld

( Z ) Conformer 1 ( Z ) Conformer 2 ( E ) Conformer 1 ( E ) Conformer 2

SCHEME 1

Acknowledgements

W e are grateful to the Natural Sciences and Engineering Research Council of Canada for financial support of this work.

1. P. D. Callaghan, A. J. Elliott, S. S. Gandhi, M. S. Gibson, H. Mastalerz, and D. J. Vukov. J. Chem. Soc. Perkin Trans. 1, 2948 (1981).

2. H. Mastalerz and M. S. Gibson. J. Chem. Soc. Perkin Trans. 1, 245 (1983).

3. G. H. Alt. J. Org. Chem. 33, 2858 (1968). 4. G. V. Boyd and S. R. Dando. J. Chem. Soc. C, 2314 (1971);

1397 (1970). 5. H. Mastalerz and M. S. Gibson. J. Chem. Soc. Perkin Trans.

1, 2952 (1981). 6. H. Mastalerz, T. Mohammad, and M. S. Gibson. Can. J.

Chem. 65, 2713 (1987). 7. L. G. S. Brooker, G. H. Keyes, H. H. Sprague, R. H. van

Dyke, E. van Lare, G. van Zandt, and F. L. White. J. Am. Chem. Soc. 73, 5326 (1951).

8. T. Mohammad and M. S. Gibson. Phosphorus, Sulfur, Sili- con, 70, 243 (1992).

9. International tables for X-ray crystallography. Vol. IV. Kynoch Press, Birmingham. 1968.

10. G. Sheldrick. SHELX76 program for crystal structure deter- mination. University of Cambridge. 1976.

1 1. ORTEP 11. Report ORNL-5 138. Oak Ridge National Labo- ratory, Tenn. 1976.

12. U. Burkert and N. L. Allinger. Molecular mechanics. ACS Monograph 177, American Chemical Society, Washington, D. C. 1982.

13. A. Z. Khan and J. Sandstrorn. J. Chem. Soc. Perkin Trans. 1, 2085 (1988).

14. (a) G. Fukata, C. O'Brien, and R. A. M. O'Ferrall. J. Chem. Soc. Perkin Trans. 2, 792 (1979); (b) N. Lozac'h. Adv. Heterocycl. Chern. 13, 161 (1971); A. Kucsman and I. Kapovits. Studies in organic chemistry. Vol. 19. Organic sulfur

Can

. J. C

hem

. Dow

nloa

ded

from

ww

w.n

rcre

sear

chpr

ess.

com

by

119.

186.

160.

86 o

n 06

/03/

13Fo

r pe

rson

al u

se o

nly.

chemistry. Edited by F. Bernardi, I. G. Csizmadia, and A. Mangini. Elsevier, Amsterdam. 1985. Chap. 4 .

15. F. H. Allen, 0. Kennard, D. G. Watson, L. Brammer, A. G. Orpen, and R. Taylor. J. Chem. Soc. Perkin Trans. 2 , S1 (1987).

16. R. E. Rosenfield, R . Parthasarathy, and J . D. Dunitz. J. Am. Chem. Soc. 99, 4860 (1977).

17. C. Cohenaddad, M. S. Lehmann, P. Becker, L. Parkanyi, and A. Kalman. J . Chem. Soc. Perkin Trans. 2, 191 (1984).

18. H. B. Burgi and J. D. Dunitz. Acc. Chem. Res. 16, 153 (1983).

19. F. H. Allen, 0 . Kennard, and R. Taylor. Acc. Chem. Res. 16, 146 (1983).

PANDYA ET AL. 57 1

20. N. Padmaja, S. Ramakumar, and M. A. Viswamitra. Acta Crystallogr. Sect. A: Found. Crystallogr. A46, 725 (1990).

21. V. Sona and N. Gautham. Acta Crystallogr. Sect. B: Struct. Sci. B48, 11 1 (1992).

22. J . A. R. P. Sarma and G. Desiraju. Acc. Chem. Res. 19, 222 (1986).

23. J . G . Angyan, R. A. Poirier, A. Kucsman, and I. G. Csizmadia. J . Am. Chem. Soc. 109, 2237 (1987).

24. R. M. Christie, A. S. Ingram, D. H. Reid, and R. G. Webster. J . Chem. Soc. Perkin Trans. 1, 722 (1974), and references cited therein.

25. R. M. Christie and D. H. Reid. J. Chem. Soc. Perkin Trans. 1, 880 (1976).

Can

. J. C

hem

. Dow

nloa

ded

from

ww

w.n

rcre

sear

chpr

ess.

com

by

119.

186.

160.

86 o

n 06

/03/

13Fo

r pe

rson

al u

se o

nly.