Spectroscopic studies on molecular association: Structures of some o-hydroxylbenzenesulfonanilides and determination of acidity constants

SPECTROCHIMICA ACTA PART A

ELSEVIER

Spectrochimica Acta Part A 51 (1995) 1739 1745

Spectroscopic studies on molecular association: Structures of some o-hydroxylbenzenesulfonanilides and determination of acidity constants Xiaolin Sun a,,, Min Xin a, Zhe Lib ~' Department ~1~Chemistry, Inner Mongolia University, Huhehot 010021, People's Republic qf China h Animal Pharmaceutical Institute of Inner Mongolia, Huhehot 010021, People's Republic of China

Received 24 May 1994, in final form and accepted 21 November 1994

Abstract The molecular association structures of some o-hydroxylbenzenesulfonanilides (HBSAs) are discussed by examining the IR and electronic absorption spectra. The tendencies of HBSA

molecules to associate are totally different and it is shown that steric hindrance is an important factor in preventing HBSA molecules from associating with each other. In addition, acidity constants for some HBSA compounds are determined.

1. Introduction In our previous study [1], we have shown that the o-hydroxylbenzenesulfonanilides (HBSAs) possess potent fasciolicidal activities and the fasciolicidal actions are related to the structures of HBSAs in the membranes of mitochondria. Furthermore, it is also shown by X-ray crystal analysis that the phenolic hydroxyl groups of HBSA can form chelate intramolecular hydrogen bonds with adjacent sulfonyl groups. However, many studies [2,3] have shown that most of the sulfonamides may exist in strong association through intermolecular hydrogen bonds. As part of our structure-activity relationship studies, this paper deals with the molecular association structures of the title compounds in solution by examining IR and electronic absorption spectra. Moreover, in order to investigate acid-dissociation of the phenolic hydroxyl group which is directly related to the fasciolicidal activities of HBSA [4], the effect of hydrogen ion concentration on the spectra are examined and pK~ values of some HBSAs are determined.

2. Experimental The c o m p o u n d s under investigation were synthesized in our laboratory and purified by recrystallization. All the chemicals and solvents used were o f analytical grade. Stock solutions were prepared by dissolving the accurately weighed a m o u n t o f each c o m p o u n d in an appropriate volume o f methanol or ethanol. The solutions used for spectral * Corresponding author. 0584-8539/95/$09.50 © 1995 Elsevier Science B.V. All rights reserved S S D I 0584-8539(95)00248-7

Xiaolin Sun et al./Spectrochimica Acta Part A 5/ (1995) 1739-1745

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measurements were obtained by diluting stock solution with an accurate amount of buffer solution or water. Buffers used (pH ,~2-11) were 0.1 M acetic acid-sodium acetate, 0.I M sodium citrate-sodium hydroxide, and 0.2 M boric acid-sodium hydroxide. The pH values of sample solutions (pH < 2 and pH > 11) were adjusted by 12 N HC1 and 1 N NaOH, respectively, pH values were checked at 25 °C using a pHS-2 acidimeter, accurate to 0.01 units. The ionic strength of the sample solutions were controlled by 1 N KC1 to I = 0.25. The electronic absorption spectra were measured on a Shimadzu U.V.-Vis. recording spectrophotometer UV-265, using 1 cm matched silica cells. Infrared spectra were recorded in the 4000-400 cm z region on a Perkin Elmer FT-IR 1720x spectrophotometer with 0.6 mm NaC1 cells; solvent was anhydrous C C I 4. The structural formulae for the compounds studied are represented in Exhibit 1.

3. Results and discussion

The electronic absorption spectra of compound III with various concentrations of 80% (v/v) methanol aqueous solution are represented in Fig. 1. Examination of Fig. 1 indicates that the electronic spectra of compound III are largely dependent on the concentration. Increasing the compound concentration results in increasing absorbance of both bands at 210 and 230nm, where beyond a certain concentration of the compound (3.0 × l 0 - 4 M) a very broad band is observed. This behaviour can be ascribed to the association of the molecules through intermolecular hydrogen bonding. Another piece of evidence for such behavior is obtained from slightly increasing absorbance values observed for the broad band by increasing compound concentrations above the concenR i = R 2 = R 3 = R 4 = C1

I

CI

OH

cI

R~

~ R 2 . ) ' - " x SO2NH ~ R 3

lI III IV V VI

R4

Ri = RI = Rt= RI= Rz=

H , R2 = R3 = R2 = R4 : H , R 3 = El, R 2 = R 2 = CI, R 3 = R 3 = R 4 = H,

R4 R3= R4R4 = Ri =

Exhibit I.

,i,i ;,,v i

,./il

I

,iEt =0.19

il ,-,ii" I

0,36 0.41 0,44

I

)

r---( --.-t - - -

) I I

',i

it'\ I /

',i \j

I

200

/

f ~ k 300

250

~.

~

350

/nm

Fig. I. S p e c t r a o f c o m p o u n d Ill in 80"/, m e t h a n o l s o l u t i o n at c o n c e n t r a t i o n s o f 3.2 x 10 ~ M 1.5 X ]0 - 4 M (---), 2.0 x 10 - 4 M (' x ' "). a n d 3.0 x 10 - 4 M ( ).

(--),

C! CI H H CI

Xiaolin Sun et al./Spectrochimica Acta Part A 51 (1995) 1739-1745

T a=0.,, , ] °,, .....

q

11.43

I

200

I

I

250

300

1741

,

t-----

3~i0

/nm Fig. 2. S p e c t r a o f c o m p o u n d 1 in 8 0 % m e t h a n o l s o l u t i o n at c o n c e n t r a t i o n s o f 3.2 × 10 - 5 M ( --),2.0× 10 4 M ( - - - ) , a n d 3 . 0 x l 0 - 4 M ( . . . . . ). Table 1 F r e q u e n c i e s i~ (cm

~) o f s o m e c o m p o u n d s in C C L (2 x 1 0 - 3 M ) in the r e g i o n 3 1 0 0 - 3 6 0 0 c m - t

I

I11

IV

i~

Assignment

P

Assignment

P

Assignment

3270s 3346w

O - H - -. O ( i n t r a ) " free N - H

3279w 3300w 3316m 3368s

N +-H • - - ON+-H • • • O N - H • .- O O-H ... O (intra)" free N - H O - H . . • O (inter) b

3240s

O - H . -. O ( i n t r a ) ~ N-H - • • O free N - H

3518w

3373w

Key: s: s t r o n g , m: m e d i u m , w: w e a k . " I n t r a m o l e c u l a r h y d r o g e n b o n d e d O H g r o u p ( O - H • -. O=S). b I n t e r m o l e c u l a r h y d r o g e n b o n d e d O H g r o u p (O H - - . O=S).

tration at which the compound association occurs. In contrast, at the same concentration, the corresponding bands of compound I are not obviously broadened (see Fig. 2), which indicates that the molecular association of compound I through intermolecular hydrogen bonding is much weaker. Some stretching frequencies of compounds I, III and IV are collected in Table 1. The IR spectra of compounds IV and III with various concentrations in the 3600-3100 cm region are represented in Figs. 3 and 4. As shown in Table 1, compounds I, III and IV all show a strong and broad phenolic - O H stretching band at 3270, 3368 and 3240 c m - J respectively in C C 1 4 solution (2 x 1 0 - 3 M ) . This indicates that the intramolecular hydrogen bonds occurring between the phenolic hydroxyl and the sulfonyl group of the compounds still exist in solution. For the compound I, at the experimental concentrations (2 x 10 -3, 4 × 10 -3, and 8 x 10-3M respectively), the two stretching bands (3346 cm ~ for vN,, 3270 c m - ~ for VOH... o) accurately remain constant in both frequencies and shapes except for absorbance increasing simultaneously with the increase in concentration of compound I. This is convincing evidence for compound I existing mainly as associated molecules in solution. We find from Fig. 3 that the molecular association of compound IV through intermolecular hydrogen bonding (S--O- .. H-N) SA(A) 51:lO-K

1742

Xiaolin Sun et al./Spectrochimica Acta Part A 51 (1995) 1739-1745

I

8 =0.007 I ~

)

7:-: j 33.

@?f.r,:.'

R

/!\

-

'

31so

/

'

3:JSO

'

31sO

'

31'50

Cirri -I

Fig. 3. IR spectra of compound IV in C C I 4 solution at concentrations of 2 × 10-~ M ( 4 x l0 -~ M (---), and 8 × l0 -'~ M (. . . . . ). m a y occur to some extent in solution, since with an increase o f concentration o f c o m p o u n d IV the band at 3373 c m - ~ ascribed to the free N H g r o u p is slightly weakened while the band at 3240 c m - J, ascribed to the associated N H group, which will be covered by the band for the intramolecular hydrogen b o n d e d O H group, is slightly strengthened. As shown in Fig. 4, c o m p o u n d III exhibits m a n y bands in the 3 6 0 0 - 3 1 0 0 cm-~ region at the experimental concentrations and these bands are either weakened or strengthened significantly with increasing concentration o f c o m p o u n d III. This indicates that the molecules o f c o m p o u n d III associate strongly with each other in a different m a n n e r in solution, which is also consistent with the results o f the electronic spectra o f c o m p o u n d III described above. Thus, we can conclude that the capabilities for the c o m p o u n d s studied to associate in solution t h r o u g h intermolecular hydrogen bonding interaction are very different from each other and have a sequence: I < IV < I I I . This sequence is consistent with the decrease in the n u m b e r o f substituted halogen atoms on both phenyl rings o f the c o m p o u n d s studied. The steric hindrance is important in preventing the c o m p o u n d s from associating with each other. T |

a = o.oo3i, t ) 0~060 I - - - i

_L

0.0122

....

,

3300,~ ,.,./

//

.,,,

A

3950

\\ 7',..

t

3150

'c m - I 33.50

\'\

\ \ ,,,.. ,-..

,"7

'

\

\I,,

;!

I:J

/

3368 ---~fx, ] / f'~3316~; /

\

'

32'50

',."-..

'

31'50

Fig. 4. IR spectra of compound lll in C C [ 4 solution at concentrations of 2 x l0 -~ M (----), 4 x 10--~ M (---), and 8 x 10-~ M (. . . . . ).

Xiaolin Sun et al./Spectrochimica Acta Part A 51 (1995) 1739-1745

o

/o

ecl- -o 0 0

H

H/

1743

O

0:

-O-

I

.I

H:

H:

-O~

H-

H

O

H

O

H

O-

,,

%o H

~-:--/

"

°Mo

(a)

°H,o

(b)

~-'-/

°...MP

(c)

(d)

Exhibit 2.

O

I / R--S-~ I \ 0

0

R' •

I ÷

R:--S--N

I

R"

/ R'

-O

\

R"

Exhibit 3.

~ I

I~i

Pll !

.IS

!- 2.?S 3' 328

I I O20 I / ~

s. ~ o

s- ILIT T- 4.11]

,

0.25

I-

US

Z"

S.llZ

*.

Io.Ta

S. ntJIS o!,:',,s T" 1211 I1' 13.117

0

1-

J I

,It/nn te,~

g/mann ¢b)

Fig. 5. Electronic spectra of compound I in 40% ethanol-buffer solutions (1.6 × 10 -5 M) with different pH values; (a) pH ~ 1.0-7.0; (b) pH ~ 7.0-14.0.

Through examination of Fig. 4, we can presume four possible association patterns for compound III in solution as shown in Exhibit 2. As shown in Table l, the intramolecular hydrogen bond for compound III (OH - • - O=S, VoH = 3368 c m - 1 ) is much weaker than that of other compounds. To a certain extent, it is possible for compound III to dissociate the intramolecular hydrogen bond into an intermolecular hydrogen bond and form molecular association according to pattern (a). The stretching band ascribed to the intermolecular hydrogen bonded hydroxyl group appears at 3518 cm-~, which has been confirmed by many experiments [5,6]. Like most sulfonamides, compound III may exist in dimeric association (pattern (b)). Two molecules of compound III with intramolecular hydrogen bonding associate stably with each other through two intermolecular hydrogen bonds S - - O . . . H-N), the corresponding stretching band for the associated N H group appearing at 3316 cm -~

Xiaolin Sun et al./Spectrochimica Acta Part A 51 (1995) 1739-1745

1744

Table 2 Values of pK,, determined for compounds studied at 25 °C

No.

pK,,

I I! 111 IV V VI

3.73 4.95 5.10 4.73 4.68 5.03

p~,~ __+0.04 + 0.03 __+0.04 +0.02 4- 0.02 +0.01

10.98 11.10 11.13 15.51 I 1.83 12.78

+ 0.04 + 0.04 + 0.05 +0.06 + 0.03 +0.05

Medium: 40% e t h a n o l - a q u e o u s solution. OH

O-

SO2NH~-

-'"

'

'

SO2NH~ R

O--

+ H+ R'

O~

+H +

SO2N H R

'

R

'

Exhibit 4.

Furthermore, sulfonamides have the resonance forms [7] shown in Exhibit 3. Therefore, molecules of compound III can also be supposed to have structures of patterns (c) and (d). The band at 3300 c m - ~ is attributed to the N H group in the stronger hydrogen bond S - O . . . H - N or S = O . ' . H - N + of pattern (c) and the band at 3279cm-1 to the N H group in the strongest hydrogen bond S - O - • .- H - N + of pattern (d). In this way, we can expect that compound III exists as a large number of free molecules and a limited number of associated molecules of patterns (a) and (b) at a concentration of 2 x 10 -3 M. With an increase of concentration of compound III, the numbers of free molecules and unstable, associated molecules of pattern (a) of compound III continuously decrease, and accordingly the numbers of associated molecules of patterns (b), (c) and (d) increase notably. This is in accordance with the fact that the bands at 3518 cm 1 and 3368 cm -~ are weakened and the bands at 3316cm ', 3 3 0 0 c m - ' and 3279cm ~ are constantly strengthened, In more concentrated solution, the strongest dimeric association of pattern (d) might favor the occurrence of the resonance effect for compound III which results in a large number of carboxamides and a more rapid strengthening of the band at 3279 c m - ' , which needs to be confirmed further. The acidity constants pK~ for the compounds studied were determined by a spectrometric method [8]. The electronic spectra of compound I in 40% (v/v) ethanol-buffer solutions with various pH values are shown in Fig. 5, and the determined values of pK,, for the compounds are listed in Table 2. Examination of Fig. 5 indicates that there are two ionization processes for the compounds studied in solution with pH range of approx. 0 - 1 4 represented as shown in Exhibit 4. From the data of Table 2, it is found that the acid-dissociation of phenolic hydroxyl groups is obviously affected by the substituents on the two phenyl rings of the compounds. This can be well explained by the results of our previous study [l] that the electronic interactions between the two phenyl rings are effectively aided by forming a d - p coordinate bond S ~ N in the compounds studied.

Acknowledgments

This work is supported by National Natural Science Foundation of China and Inner Mongolia's Natural Science Foundation.

Xiaolin Sun et al./Spectrochimica Acta Part A 51 (1995) 1739-1745

1745

References [1] [2] [3] [4] [5] [6] [7] [8]

X. Sun, M. Xin, X. Wang and X. Niu, Chem. Pharm. Bull., 42 (1994) 2002. G. Malewski and R. Konig, Spectrochim. Acta Part A, 20 (1964) 565. R. Konig and G. Malewski, Spectrochim. Acta Part A, 24 (1968) 219. X. Sun, M. Xin, X. Wang and Z. Li, Proc. Third Natl. Symp. on Molecular Mechanics and Design of Drugs, Biejing, 1991, pp. 2-34. F.A. Smith and E.C. Creitz, J. Res. Natl. Bur. Stand., 46 (1951) 145. R.A. Friedel, J. Am. Chem. Soc., 73 (1951) 2881. P. Ruostesuo, Acta Univ. Ouluensis Ser. A. 66 (1978) 53 pp. A. Albert and E.P. Serjeant, The Determination of Ionization Constants, Chapman and Hall, New York. 1984.