Electrochemical and spectroscopic study of the addition of several nucleophiles to 1,2,5-thiadiazole 1,1-dioxide derivatives

JOURNAL OF PHYSICAL ORGANIC CHEMISTRY

J. Phys. Org. Chem. 2000; 13: 272–282

Electrochemical and spectroscopic study of the addition of

several nucleophiles to 1,2,5-thiadiazole 1,1-dioxide

derivatives

Silvia Luc õÂ a Aimone, Jos eÂ Alberto Caram, Mar õÂ a Virginia Mir õÂ ®co and Enrique Julio Vasini*

Instituto de Investigaciones Fisicoqu õÂ micas Te oÂ ricas y Aplicadas (INIFTA), Facultad de Ciencias Exactas, Departamento de Qu õÂ mica,

Universidad Nacional de La Plata, Casilla de Correo 16, Sucursal 4, (1900) La Plata, Argentina

Received 3 November 1999; revised 29 December 1999; accepted 4 January 2000

ABSTRACT: The nucleophilic addition reactions of several alcohols and 1-propanethiol to a C

,4-disubstituted derivatives of 1,2,5-thiadiazole 1,1-dioxide were studied in acetonitrile solution. The substrates used

were 3,4-diphenyl (1a), 3-methyl-4-phenyl (1b), phenanthro[9,10-c] (1c) and acenaphtho[1,2-c]-1,2,5-thiadiazole

,1-dioxide (1d), 3,4-diphenyl-1,2,5-thiadiazoline 1,1-dioxide (2a) and 4-ethoxy-5-methyl-3,4-diphenyl-1,2,5-

=N double bond of

3

1

thiadiazoline 1,1-dioxide (2b). Spectroscopically (UV–VIS) and electrochemically (cyclic voltammetry) measured

equilibrium constants at 25.0°C are presented and discussed for the reaction of 1a and 1b with alcohols (methanol, n-

propanol, n-butanol, isobutanol, 2-propanol, sec-butanol, tert-butanol, ethylene glycol, allyl alcohol and 2-

phenylethanol). A reaction of 1-propanethiol with 1c was observed, but the alcohols did not react with 1c, 1d or the

thiadiazolines (2a, 2b). The effect of the solvent on the equilibrium constant of the 1a–ethanol system was measured

using, besides acetonitrile, propylene carbonate, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl

sulfoxide and tert-butanol. The results were correlated with an empirical H-bond acceptor solvent parameter.

1

13

Previously unreported spectroscopic (UV–VIS, IR, H and C NMR) data for some of the compounds studied are

also provided. Copyright  2000 John Wiley & Sons, Ltd.

KEYWORDS: 1,2,5-thiadiazoles; organic electrochemistry; nucleophilic addition; structure; reactivity

INTRODUCTION

reversibly to 3,4-diphenyl- (1a; Scheme 1) or to 3-

methyl-4-phenyl-1,2,5-thiadiazole 1,1-dioxide (1b) in a

1:1 molar ratio to give the corresponding 1,2,5-thiadiazo-

line 1,1-dioxides [4-ethoxy- 3,4-diphenyl (2a.EtOH) and

4-ethoxy-4-methyl-3-phenyl (2b.EtOH)].

Several derivatives including the thiadiazole ring have

received considerable attention owing to their actual or

potential applications in pharmacology and biology. A

large number of bioactive molecules include this moiety.

An important recent example is the discovery of 1,2,5-

thiadiazole derivatives that are potent and speciﬁc

inhibitors of HIV-1 inverse transcriptase. Regarding

speciﬁcally the 1,1-dioxide derivatives of 1,2,5-thiadia-

zole, antagonists of the H2 receptors of histamine,

These studies were extended in this work to other

1,2,5-thiadiazole 1,1-dioxide derivatives [1a, 1b, phe-

nanthro[9,10-c]- (1c) and acenaphtho[1,2-c]-1,2,5-thia-

diazole 1,1-dioxide (1d), 3,4-diphenyl- (2a) and 4-

ethoxy-5-methyl-3,4-diphenyl-1,2,5-thiadiazoline 1,1-di-

oxide (2b)] and to several nucleophiles (alcohols of

different structural characteristics and propanethiol).

Depending on the nucleophile–substrate combination, it

was found that the addition reaction either did not take

place, reached an equilibrium or was complete. The

magnitude of the equilibrium constants, K[T,N]

(T = thiadiazole derivative; N = nucleophile), the ab-

sence of reaction or its practical irreversibility were

correlated with both nucleophile and substrate structure.

The nucleophiles used were methanol (MeOH),

ethanol (EtOH), n-propanol (n-PrOH), n-butanol (n-

BuOH), isobutanol (i-BuOH), 2-propanol (i-PrOH), sec-

butanol (s-BuOH), tert-butanol (t-BuOH), ethylene

1

2

–6

7

–9

antihypertensive drugs

and central nervous system

1

0

depressors were developed. In addition, some b-

1

12

lactamic antibiotics, quinazolinic cardiac stimulants,

anti-parasitical nitroimidazoles

derivatives of 1,2,5-thiadiazoline 1,1-dioxides.

As a part of our electrochemical work on thiadiazoles,

we have recently reported

1

3,14

15

and pesticides are

1

6–18

that ethanol (EtOH) adds

*

Correspondence to: E. J. Vasini, INIFTA, Universidad Nacional de

La Plata, C.C. 16, Suc. 4, (1900) La Plata, Argentina.

E-mail: vasini@inifta.unlp.edu.ar

Contract/grant sponsor: Consefo Nacional de Investigaciones Cient ı´ -

ﬁcas y T e´ cnicas (CONICET).

Contract/grant sponsor: Comisi o´ n de Investigaciones Cient ´ı ﬁcas de la

Provincia de Buenos Aires.

glycol [ET(OH) ], allyl alcohol (allyiOH), 2-phenyletha-

2

Contract/grant sponsor: Universidad Nacional de La Plata.

nol (2PhEtOH) and 1-propanethiol (PrSH).

Copyright  2000 John Wiley & Sons, Ltd.

J. Phys. Org. Chem. 2000; 13: 272–282

ADDITION OF NUCLEOPHILES TO 1,2,5-THIADIAZOLE 1,1-DIOXIDE DERIVATIVES

273

Scheme 1

Acetonitrile (ACN) was used as the solvent in most

experiments. The equilibrium constant of the addition

reaction of EtOH to 1a was also studied in other solvents

Results). Crude samples of the 2a.ROH and 2b.ROH

thiadiazoline compounds were isolated for all ROH,

except t-BuOH, through evaporation of the solvent at

reduced pressure (1–10 Torr) and room temperature from

solutions of 1a or 1b in pure ROH.

(K[1a,EtOH,solvent]). Several aprotic solvents besides

ACN were employed: propylene carbonate (PC), N,N-

dimethylformamide (DMF), N,N-dimethylacetamide

(

DMA) and dimethyl sulfoxide (DMSO). The protic but

Solvents and nucleophilic reactants. Standard meth-

20–22

non-reactive (see Results) solvent t-BuOH was also used.

The K[T,N] values measured by either spectroscopic

or voltammetric methods were in good agreement. The

voltammetrically measured K[T,N] depends on the

reaction mechanism at the interface, proposed according

to the experimentally observed electrochemical behavior.

In contrast, spectroscopic absorbances are proportional to

actual concentrations. Thus, the agreement reinforces the

adequacy of the voltammetric mechanism.

ods.

were used for the puriﬁcation of commercial

solvents, which were dried with molecular sieves and

stored under a dry nitrogen atmosphere. Their water

content was measured by Karl Fischer titration. As

described below, the solutions of 1b in ACN solvent are

affected by the presence of water, even at very low

concentrations. To observe this inﬂuence, two procedures

were used to dry ACN: procedure i consisted in

distillation over CaH under a dry N atmosphere and

2

procedure ii consisted in further drying the distilled ACN

through passage over activated 4A molecular sieves.

ACN containing 350 ppm of water was obtained by

means of procedure i, while procedure ii reduced the

water content to 50 ppm.

EXPERIMENTAL

Synthesis and puri®cation procedures

Thiadiazole derivatives. Compounds 1a, 1b, 1c, 1d and

2

a were synthesized, puriﬁed and characterized accord-

Spectroscopic properties

1

9

ing to standard methods and 2b was synthesized

according to the reported technique. The puriﬁcation

3

1a. The UV spectra in several aprotic solvents and the

1

3

procedure for 1b was slightly modiﬁed by the addition of

dry triﬂuoroacetic acid to the recrystalization solvent.

Only after this change could the relatively low (29%)

yields reported in the literature be achieved. The acid

medium prevents a dimerization reaction of 1b (see

C NMR in deuterated tetrahydrofuran have already

16

been described.

3

� 1

1b. UV: e_m_a_x= 6.09 Â 10 l mol cm at 312 nm in dry

1

ACN solution. H NMR (ꢀ, TMS) in ACN-d solution:

3

Copyright  2000 John Wiley & Sons, Ltd.

J. Phys. Org. Chem. 2000; 13: 272–282

2

74

S. L. AIMONE ET AL.

phenyl multiplet (7.52–7.96 ppm), CH₃singlet

spectrum was ﬁnally obtained. The relative decrease

(increase) in absorbance of the T (T.ROH) band was

larger the higher the molar ROH concentration. The

equilibrium constant (K[T,ROH]) was calculated using a

1

3

(

2.67 ppm).

C NMR (same solution): 170.5 ppm

N—), four signals

34.0–127.7 ppm (phenyl ring) and 18.3 ppm (CH₃).

(

Ph—C N—), 167.5 ppm (CH —C

=

3

1

16

Benesi–Hildebrand-type equation:

1

c. UV (ACN or EtOH solvent): several absorption bands

4

centered

at

220 nm

(e = 4.77 Â 10 ),

264 nm

ROHT

1

ROH

TÁROH

0

4

3

4

"

ꢀ1

(

e = 3.86 Â 10 ), 344 nm (e = 1.39 Â 10 ) and 454 nm

ꢁ1

TÁROH

ꢁ1

A

KT; ROH"

� 1

TÁROH

(e = 1.40 Â 10 l mol cm ).

ꢁ

1

where ꢁ and "

are the wavelength of maximum

1

TÁROH

1

d. UV (ACN or EtOH solvent): several absorption

absorption and the corresponding molar absorptivity of

4

bands centered at 229 nm (e = 6.27 Â 10 ), 265 nm

T.ROH, and

4

3

(

e = 2.48 Â 10 ), 318 nm (e = 7.38 Â 10 ) and 333 nm

� 1 � 1

3

(e = 6.80 Â 10 l mol cm ).

ꢁ

2

A

ꢁ

1

ꢁ1

exp

ꢁ1

T

exp

Compounds 1a and 1b in solutions of reactive alcohols

A

A � " Â

ꢀ2

TÁROH

ꢁ₂

T

are in the form of their ROH addition products:

"

thiadiazolines 2a.ROH and 2b.ROH (Scheme 1). The

1

3

16

C NMR spectrum of 2a.EtOH has been published .

is the absorbance of T.ROH at ꢁ , corrected for the

1

ꢁ

2

UV data (ꢁ_m_a_xand e_m_a_x) for several 2a.ROH and 2b.ROH

absorbance of T at the same wavelength (ꢁ and " are

2

T

are given in Table 3.

The H NMR spectrum of 2b.MeOH (in MeOH-d₄

solution) presents a multiplet at 7.46–8.33 ppm (phenyl)

the wavelength of maximum absorption and the corre-

sponding molar absorptivity of T). Under our experi-

mental conditions, the nucleophile concentration

remained virtually constant ([ROH] = [ROH] ) because

1

3

and a singlet at 1.80 ppm (—C—CH ). The C NMR

3

t

0

spectrum (same solvent) presents signals at 178.7 (Ph—

the initial concentration of ROH was always much higher

C), 98.4 (CH —C—OMe) and ca 130 ppm (Ph). The

than [T]₀.

3

23

methyl carbon resonance was observed at 26.5 ppm.

IR (KBr pellets): 2a.ROH and 2b.ROH obtained from

the evaporation at room temperature and reduced

pressure of solutions of 1a or 1b in ROH presented, in

addition to IR absorptions from the RO groups and the

phenyl substituent(s), sharp N–H stretching bands at ca

According to the criteria proposed by Person to

minimize errors, the equilibrium constants were mea-

sured for conditions under which the equilibrium

concentration ratio, [T]/[T.ROH], ranged between 0.1

and 10. The coherency of the experimental points was

24

tested according to the method of Rose and Drago.

�

1

3300, 1560 (C

=N), 1050 (C–N), 1315 and 1175 cm

Cyclic voltammetric (CV) experiments were per-

formed in a conventional undivided gas-tight glass cell

with dry nitrogen gas inlet and outlet. The working

electrode was a 3 mm diameter vitreous carbon disk

(>SO₂).

2

Experimental measurements

encapsulated in Teﬂon, the counter-electrode was a 2 cm

Pt foil and an Ag (0.1 M, ACN)/Ag reference electrode

UV spectral measurements were made with a Cary 3 or a

Zeiss PMQ3 spectrophotometer equipped with thermo-

stated cell holders. Teﬂon-stoppered quartz cells of 1 cm

optical pathlength were used. Molar absorptivities (e)

reported are accurate to Æ2.5%.

(to which all potentials reported are referred) was used.

The supporting electrolyte was 0.25 M NaClO . An LYP-

4

M2 potentiostat, a three-module LYP sweep generator

and a Houston Omnigraphic 2000 pen recorder were

used.

1

13

H and C NMR spectra were measured with a Bruker

The voltammetric behavior of 1a and 1b in ROH–

ACN mixed solvent solutions was similar to that

2

4

00 MHz instrument and IR spectra with a Shimadzu IR-

35 spectrophotometer.

1

7,18

reported for the 1a–EtOH–ACN system:

before

The reaction of the thiadiazole substrates with

the addition of ROH, the ACN solution of thiadiazole

nucleophiles was followed by the UV spectral changes

that took place when a stock solution of one of the

substrates (which will be designated generically as T) in

ACN was added to a mixed ACN–nucleophile (usually

ROH) solution: the UV absorption band of T gradually

decreased in intensity and an absorption band (corre-

sponding to the thiadiazoline addition product, T.ROH)

appeared and increased in intensity. Isosbestic points

were observed during these changes (usually ca 240 and

(T) showed two reversible voltammetric signals corre-

�

Á

�

Á

2�

sponding to the T/T (peak I) and the T /T (peak

II) couples [see Fig. 2(1a), curve 1]. The addition of

ROH produced no immediate changes, but the voltam-

mograms started to change with time at a rate that

increased with the amount of ROH added. The second

cathodic peak decreased in current intensity and

disappeared from the ﬁnal equilibrium voltammograms

for all experimental ROH concentrations used. The

current intensity of the ﬁrst cathodic peak also decreased

and reached a ﬁnal equilibrium intensity that depended

290 nm). The rate of change of the absorbance was faster

the higher the alcohol concentration and an equilibrium

Copyright  2000 John Wiley & Sons, Ltd.

J. Phys. Org. Chem. 2000; 13: 272–282

ADDITION OF NUCLEOPHILES TO 1,2,5-THIADIAZOLE 1,1-DIOXIDE DERIVATIVES

275

Figure 1. UV±visible spectra of the 1a±s-BuOH±ACN system at different times (t) after addition of a solution of s-BuOH in ACN

�

5

to solution of 1a in ACN. Analytical concentrations: [1a] = 2.35 Â 10 M, [s-BuOH] = 12.83 M. T = 25.0°C. Full lines

correspond to the spectrum of 1a in the pure solvents indicated. Dotted lines correspond to spectra at t = 7.5,29,49,69 and

1

20 h after s-BuOH addition. The direction of absorbance change with increasing time is indicated by the arrows

inversely on the ROH concentration. Two cathodic

peaks [IIIc and IVc; see Fig. 2(1a), curve 2] appeared at

lower potentials.

RESULTS

Spectroscopic (UV) and electrochemical (CV) be-

havior of the reacting substrate±nucleophile

systems. Comments on the kinetic behavior

1

7

According to the proposed

quantities of T and T.ROH are consumed at peak Ic

provided that peak IIc has already disappeared), and the

mechanism, equal

(

cathodic peaks (IIIc and IVc) are related to the

electroreduction of the remaining T.ROH. A function

The nucleophilic addition reaction

[

Eqn. (3)] of the relative intensity of these peaks and the

T Á ROH

T ROH T Á ROH; KT; ROH

ꢀ4

voltage sweep rate (v) can be used to calculate the

equilibrium constant:

TROH

h

i

can be monitored (see Experimental section) by the

changes as a function of time in the UV spectra (Fig. 1) or

in the cyclic voltammograms (Fig. 2) of the T–ROH–

solvent systems.

iꢀIIIc iꢀIc

2

1=2

v

2v

KT; ROHROH

ꢀ3

iꢀIc

1=2

v

The equilibrium constants measured for all reacting

systems by both methods are given in Table 3 and will be

commented on below. Some comments on the effect of

the residual (50–350 ppm, see Experimental section)

The preparation of solutions, the CV experiments and

other manipulations were carried out in a glove-box

under a dry nitrogen atmosphere.

Copyright  2000 John Wiley & Sons, Ltd.

J. Phys. Org. Chem. 2000; 13: 272–282

2

76

S. L. AIMONE ET AL.

Figure 2. Cyclic voltammograms of 1a and 1b in ACN and EtOH solvents and equilibrium voltammograms in several ROH±ACN

�

1

.

solvent mixtures. Supporting electrolyte, 0.25 M NaClO , vitreous carbon disk working electrode. Part (1a): scan rate = 0.1V s

4

Curve 1, [1a] = 1.51 mM, ACN solvent; curve 2 (dotted line), [1a] = 3.16 mM, EtOH solvent; curve 3, [1a] = 4.2 mM in 1.49 M n-

butanol in ACN; curve 4, [1a] = 4.2 mM in 2.20 M ethylene glycol in ACN; curve 5, [1a] = 4.2 mM in 2.66 M allyl alcohol in ACN.

�

1

Part (1b): scan rate = 0.2V s . Curve 1, [1b] = 1.06 mM, ACN solvent; curve 2 (dotted line), [1b] = 5.05 mM, EtOH solvent; curve

, [1b] = 3.70 mM in 2.19 M isobutanol in ACN; curve 4, [1b] = 3.73 mM in 4.74 M ethylene glycol in ACN; curve 5,

1b] = 3.65 mM in 2.03 M n-propanol in ACN

3

[

water content of the solvent and nucleophilic reactants

may be useful here.

Water addition to, for example, 1a (which is the ﬁrst

step in the hydrolysis reaction ) must be very similar to

25

EtOH addition. The resulting thiadiazoline (2a.HOH),

1

6

Residual water and reaction kinetics. Detailed

absorbance vs time measurements were made in many

experiments to investigate the kinetics of the reaction.

The evolution of all reacting systems ﬁtted a pseudo-ﬁrst-

has a UV absorption spectrum similar to that of

2a.EtOH. Hence the observed rate corresponds to the

sum of both water and EtOH addition reactions. The

results imply that H O adds much faster than EtOH and

2

order law, but the calculated rate constants (k

depended strongly on the water content of the solvent

)

that the water (or EtOH) addition reaction is not

catalyzed by acids. Beyond a certain minimum and up

to the maximum experimentally employed, the molar

ratio [TFA]/[1a] did not affect the measured kobs (Table

1, fourth and ﬁfth rows). This was also found to apply to

1b (Table 2).

obs

1

6

(Table 1). A comparison of the ﬁrst row of Table 1 with

the last three rows shows that a water content of 350 ppm

results in a k_o_b_svalue which is ca 40 times higher than the

minimum obtained by decreasing the water content or the

water activity by protonation (TFA addition) or com-

plexation with acid cations (addition of Li ).

Residual water and equilibrium constants. The

K[T,ROH] values are not measurably affected by residual

water, e.g. the values of K[1a,EtOH] and K[1b,EtOH],

that were calculated when the kinetic runs included in

Tables 1 and 2 reached equilibrium, agreed within the

experimental error. This is reasonable since the ROH to

Table 1. Pseudo-®rst-order rate constant, k_o_b_s_,, for the

addition of EtOH to 1a in ACN solution for different ACN

puri®cation procedures

a

H O content of

ACN (ppm)

2

�

1

[TFA]/[1a] [LiCIO ](M)

k_o_b_s(h )

4

Table 2. Pseudo-®rst-order rate constants for addition

reaction of EtOH to 1b in ACN solution for different dry

TFA concentrations

3

50 (i)

0 (ii)

50 (i)

0 (ii)

—

3.02

100

—

0.107

7.8 Æ 0.2

2.48 Æ 0.04

0.99 Æ 0.01

0.20 Æ 0.01

0.19 Æ 0.01

0.20 Æ 0.01

a

5

3

5

4

� 1

[1b] (M Â 10 )

[TFA]/[1b]

k_o_b_s(h )

3

50 (i)

1

.559

.547

0.802

11.26

123.3

130.6

0.117 Æ 0.007

0.119 Æ 0.007

0.118 Æ 0.003

0.116 Æ 0.007

a

� 5

[

EtOH] = 6.50 M; [1a] = 8.94 Â 10 M; T = 25.0°C. The water con-

tent of ACN (Karl Fischer titration) was measured after the following

pretreatments: i = fractional distillation over CaH , N atmosphere;

ii = fractional distillation over CaH in an N atmosphere, followed by

1.313

2

a

2

[EtOH] = 2.67 M; T = 25.0°C. ACN puriﬁcation procedure:

ii (Table 1).

˚

drying with 4 A molecular sieves.

Copyright  2000 John Wiley & Sons, Ltd.

J. Phys. Org. Chem. 2000; 13: 272–282

ADDITION OF NUCLEOPHILES TO 1,2,5-THIADIAZOLE 1,1-DIOXIDE DERIVATIVES

277

Table 3. Spectrophotometrically (UV) and voltammetrically (CV) measured equilibrium constants K[T, ROH] [reaction (4)],

ꢁ

grav

Á

a

Benesi±Hildebrand [Eqn. (1)] and gravimetric extinction coef®cients (e

and e

) for the addition products (T ROH)

BH

�

1

ꢁ

3

ꢁ

3

K[T,ROH] (l mol

UV

)

e

Â 10

e

Â 10

BH

grav

�

1

� 1

T

ROH

MeOH

(l mol cm

)

(l mol cm

)

CV

1a

16.2 Æ 0.2

16.8 Æ 0.3

15.5 Æ 0.1

14.1 Æ 0.6

16.5 Æ 0.1

17.1 Æ 0.1

19.4 Æ 0.1

22.2 Æ 2.8

—

15.6 Æ 0.5

16.4 Æ 0.8

—

15.1 Æ 0.4

16.8 Æ 0.4

17.5 Æ 0.3

16.0 Æ 0.3

15.9 Æ 0.3

—

3.6 Æ 0.1

3.3 Æ 0.2

3.6 Æ 0.5

3.7 Æ 0.8

3.5 Æ 0.6

2.8 Æ 0.1

—

EtOH

3.2 Æ 0.2

—

a

EtOH

n-PrOH

n-BuOH

i-BuOH

i-PrOH

s-BuOH

AllylOH

3.0 Æ 0.1

3.4 Æ .02

2.3 Æ .1

0.26 Æ 0.01

0.27 Æ 0.02

0.22 Æ 0.02

0.93 Æ 0.01

2.5 Æ 0.1

1.37 Æ .02

0.21 Æ 0.04

—

2PhEtOH

—

ET(OH)₂

—

1b

EtOH

—

14.7 Æ 0.2

1.7 Æ 0.2_a

1.4 Æ 0.1

1.5 Æ .1

EtOH

14.8 Æ 0.2

15.9 Æ 0.4

16.7 Æ 0.5

15.7 Æ 0.5

24.0 Æ 3.3

14.7 Æ 2.7

—

a

n-PrOH

n-BuOH

i-BuOH

i-PrOH

s-BuOH

ET(OH)₂

14.5 Æ 0.3

14.1 Æ 0.2

—

1.6 Æ 0.2

1.7 Æ .1

a

1.6 Æ 0.1

2.1 Æ .1

a

1.4 Æ 0.1

2.1 Æ .1

a

14.0 Æ 0.3

0.09 Æ 0.02

0.12 Æ 0.03

—

0.25 Æ 0.02

0.22 Æ 0.01

0.75 Æ 0.01

—

ꢁ

= 268 mn for 1a and 265 nm for 1b [see Eqn. (2)]. Indicated errors are least-squares standard deviations.

a

Measurements made with the addition of TFA (see text).

5

6

water molar concentration ratio is so high (ca 10 –10 )

that the interconversion reaction (5) should be shifted

completely to the right:

puriﬁed and thoroughly dried solvent (procedure ii,

Experimental section) remained unchanged for several

hours, the intensity of the UV absorption band of 1b at

3

12 nm decreased slowly in nominally dry ACN

T Á HOH ROH T Á ROH HOH

ꢀ5

(procedure i, Experimental section). The rate of decrease

was faster when a small amount of water was added to the

ACN solvent. The decrease in the absorbance of the

312 nm band was accompanied by the appearance and

increase of two new bands at ca 255 and 385 nm. Two

isosbestic points at ca 282 and 350 nm were observed and

the solution acquired a light yellow color. However, when

fresh solutions of 1b in dry ACN (procedure i), in which

only the 312 nm band was observed in the UV spectrum,

were analyzed by thin-layer chromatography (TLC), two

spots were found. Apparently the silica of the TLC layer,

the residual water present in the solvent or the water

incorporated during the chromatographic run catalyzed

the process of the development of the yellow color.

Stable UV spectra and a ‘single spot’ (the one

The measurement of equilibrium constants for the

addition of water to thiadiazoles is complicated by the

2

5

subsequent hydrolysis reaction which prevents the

attainment of a stable equilibrium. However, an estima-

tion of its value could be obtained using the voltammetric

method in the 1a–H O–DMSO system, in which the

2

slowest hydrolysis rate was observed. Water concentra-

tions in the range 0.1–0.2 M were used (i.e. 1800–

3

600 ppm). The K[1a,HOH] value obtained (28 Æ 2

�

1

l mol ) was about three times K[1a,EtOH] in DMSO

solution (Table 4).

In the case of 1b, the water content and activity were

reduced to a minimum to avoid the above-mentioned

dimerization reaction. Therefore, most spectroscopic

equilibrium measurements were made in the presence

Table 4. K[1a,EtOH] measured in several solvents at 25.0°C

and empirical H-bond acceptor solvent parameters

of added TFA (typically with a [TFA]/[1b] molar ratio

0

a

of ca 0.8), but control experiments in very dry EtOH–

ACN mixtures, without the addition of TFA, conﬁrmed

that the K[1b,EtOH] values did not change appreciably in

the presence of TFA (Table 3). The addition of acid was

not necessary in equilibrium voltammetric measurements

owing to the presence of the supporting electrolyte, as

commented upon below.

�

1

Solvent

b

DN

K[1a,EtOH] (l mol )

ACN

PC

DMF

DMA

DMSO

t-BuOH

0.31

0.40

0.69

0.76

1.01

14.1

15.1

26.6

27.8

29.8

20.0

3.2 Æ 0.2

3.9 Æ 0.1

12.9 Æ 0.2

14.5 Æ 0.4

9.0 Æ 0.7

14.8 Æ 0.7

Residual water in ACN solutions of 1b. It was

observed that, although ACN solutions of 1b in freshly

a

Least-squares ﬁtting gives pK = � 1.36 b with a regression coefﬁcient

r = 0.997.

Copyright  2000 John Wiley & Sons, Ltd.

J. Phys. Org. Chem. 2000; 13: 272–282

2

78

S. L. AIMONE ET AL.

corresponding to the larger R value) TLC runs were

the eventual existence of double-addition products.

Furthermore, no decreasing trend in the K values with

increase in ROH concentration, which could suggest a

contribution from double addition, was ever observed.

f

obtained upon addition of dry TFA to solutions of 1b in

nominally dry ACN. Preliminary experiments indicated

that dimerization of 1b takes place in neutral or basic,

nominally dry, ACN solutions and on the chromato-

graphic plate. The added acid drastically decreases the

reactivity of residual water (the acid cation of the

supporting electrolyte has a similar effect, as mentioned

below in the section on electrochemical measurements).

The dimerization reaction of 1b will be discussed

elsewhere.

Voltammetry in ROH±ACN solvent mixtures.

Voltammetric evaluation of equilibrium constants

The electrochemical properties of 1a and 1b in ROH–

ACN mixed solvent solutions were studied using CV as

described in the Experimental section and exempliﬁed in

Fig. 2.

UV Spectrophotometric evaluation of equilibrium

constants

The relation between the intensity of the voltammetric

peaks and the equilibrium constant depends on the

mechanism of the electrochemical and the homogeneous

reactions at each peak. The mechanism found for the 1a–

Reaction (4) was followed spectroscopically, as de-

scribed in the Experimental section, through the

measurement of spectral changes such as those shown

in Fig. 1.

This method was used for solutions of the thiadiazole

substrates at 25.0°C in ROH solvents and in mixed

ROH–ACN solvents. Spectral changes similar to those

described above were observed for 1a and 1b in all ROH

and ROH–ACN solvent mixtures employed, with the

exception of t-BuOH, with which the substrates did not

react, as evidenced by an unchanged UV spectrum over a

17

EtOH–ACN system was also operative for the systems

studied here, as was concluded from the very similar

voltammetric responses. The voltammetric method,

which can be used with UV-absorbing solvents or

nucleophiles, is further supported by the agreement

(Table 3) between the spectrophotometrically and the

voltammetrically measured equilibrium constants.

The voltammetric K[T,ROH] values given in Table 3

were obtained from the linear plots of the right-hand side

of Eqn. (3) vs [ROH] for different T–ROH–ACN

systems. The errors reported are least-squares standard

deviations of these plots.

1

year period at 25.0°C. Similarly, no change in the

spectra was observed during a period of several months

for solutions of 1c, 1d, 2a or 2b in any of the ROH or

ROH–ACN solvents.

It must be mentioned that no yellowing or decomposi-

tion was observed during the voltammetric measurement

of the 1b–ROH–ACN systems. The relatively high

The application of a Benesi–Hildebrand-type treat-

ment [Eqns (1) and (2)], with ꢁ = 268 nm for 2a.ROH

concentration of Na from the supporting electrolyte

1

and 265 nm for 2b.ROH, and ꢁ = 328 nm for 1a and

was probably sufﬁcient to decrease the activity of the

residual water, thus inhibiting the decomposition reac-

tion.

2

312 nm for 1b, gave a good linear dependence with least-

squares correlation coefﬁcients better than 0.998 (4–9

values).

It can be recalled that thiadiazolidine compounds are

electroinactive under the present experimental condi-

The Benesi–Hildebrand-calculated equilibrium con-

stants and molar absorptivities (e_B_H) were compared with

the molar absorptivities (e_g_r_a_v) calculated assuming that,

in pure ROH solvents, the substrates were completely

converted to the thiadiazolines (2a.ROH or 2b.ROH).

The differences between e_B_Hand e_g_r_a_v(Table 3) are only

signiﬁcant (e_g_r_a_vbeing smaller) for the systems with

smaller equilibrium constants, i.e. when the assumption

made in measuring e_g_r_a_vwas not correct.

16

tions. Here the practical absence of double addition

could be deduced with the same argument as used above

for the UV spectral measurements.

1

13

H and C NMR and IR characterization of the

addition compounds

The linearity of the Benesi–Hildebrand plots indicated

a 1:1 reaction of 1a or 1b with all reactive alcohols, since

monoaddition was one of the premises used to deduce

Eqn. (1).

The characteristics of the spectra in ROH solvents (see

Experimental section) are in agreement with the

postulated addition reaction of alcohols to one of the

C=N double bonds of the heterocycle. The downﬁeld

13

It must also be mentioned that the eventual double

addition products would be saturated (thiadiazolidine)

compounds. These have UV absorption maxima in the

same region as the thiadiazolines, but their molar

shift in the C NMR resonance of the methyl carbon of

Á

2b MeOH (26.5 ppm) with respect to the corresponding

methyl signal of 1b (18.3 ppm) indicated, according to

26

known additivity rules, that the methoxy substituent

had added to the heterocyclic carbon atom bearing the

methyl substituent, since the addition to the ‘phenyl’

heterocyclic carbon would result in an upﬁeld shift. This

16

absorptivities are one order of magnitude smaller.

Hence the experimental dispersion of the UV-measured

equilibrium constant places an upper limit of ca 10% on

Copyright  2000 John Wiley & Sons, Ltd.

J. Phys. Org. Chem. 2000; 13: 272–282

ADDITION OF NUCLEOPHILES TO 1,2,5-THIADIAZOLE 1,1-DIOXIDE DERIVATIVES

279

18

conﬁrms our indirect electrochemical results

theoretical calculations.

and

2

7

The IR spectrum of the solid residues obtained from

the evaporation at room temperature and reduced

pressure of solutions of 1a or 1b in all ROH (except t-

BuOH) presented bands that closely resembled those of

the corresponding thiadiazolines 2a or 2b (for instance,

2

b shows bands at 1590, 1560, 1490, 1450, 1325, 1170

�

1

and 1045 cm ). The sharpness of the band at ca

�

1

3300 cm and its persistence under prolonged vacuum

at room temperature indicated that it was an N–H band,

and did not originate from residual alcohol in the solid.

Further vacuum drying of the compounds at higher

temperature (60°C) for several days gave solids with an

IR spectrum identical with that of the initial thiadiazole

compound (1a or 1b). As t-BuOH does not react, only 1a

or 1b was recovered from room temperature and reduced

pressure evaporation of solutions of 1a or 1b in t-BuOH.

Figure 3. Cyclic voltammograms of the 1c±PrSH±ACN

�

1

system. [1c] = 2.95 mM; [PrSH] = 0.859 M; v = 0.2V s

.

Dotted line, after solution preparation; solid line, 30 days

(

after solution preparation

In¯uence of the solvent in the 1a±EtOH equili-

brium

ACN solution was similar to those of the reactive 1a–

ROH systems. The time sequence and the magnitude of

the changes in the current intensity of the voltammetric

peaks were nearly identical, although the peaks identiﬁed

as IIIc and IVc appeared at somewhat higher potentials

(ca � 1.45 and � 1.75 V, respectively) than those of the

1a–ROH systems.

The inﬂuence of the solvent in the voltammetric behavior

of 1a was analyzed in PC, DMF, DMA and DMSO, in

addition to ACN. The effect of the solvent on the

nucleophilic addition reaction [Eqn. (4)] was evaluated in

mixtures of these solvents with EtOH at 25.0°C. Since t-

BuOH does not react, it was also used as a test solvent.

The behavior of the 1a–EtOH–t-BuOH system was

investigated using the UV spectrophotometric method,

because t-BuOH is not an adequate electrochemical

solvent.

It was found that a 0.17 M concentration of PrSH was

sufﬁcient to drive the equilibrium position so far to the

right that the reaction could be considered complete. At

those low nucleophile concentrations, the equilibration

time was more than 3 months. After that period, the

intensity of peak Ic was too small to measure an

equilibrium constant accurately, but it could be estimated

For the 1a–solvent systems, two one-electron voltam-

metrically reversible couples, similar to those shown for

the initial voltammogram in Fig. 2, were observed in all

the solvents investigated. The potential of peak Ic did not

change appreciably with the change of solvent, whereas

that of peak IIc shifted to lower potentials with an

increase in the donor number (DN) of the solvent. The

effect is undoubtedly caused by the decrease in the Lewis

acidity of the supporting electrolyte cation in more basic

�

1

as larger than 300 l mol .

The voltammetric response of 1c in ACN solution in

the presence of added PrSH differed from that of 1a under

the same conditions: the two couples of the 1c–ACN

�

� .

2�

system (E [1c/1c ] = � 0.58 V; E [1c /1c ] = � 0.73

p

V) were observed in freshly prepared 1c–PrSH–ACN

solutions (Fig. 3, dotted line). A slow decrease in the

current intensity of the second couple and an increase in

the ﬁrst were observed during a few days. The

voltammogram shown in Fig. 3 (full line) was ﬁnally

obtained: the ﬁrst couple has doubled its current intensity

and shows reversible behavior, the second couple has

practically disappeared and no further cathodic peaks

(corresponding to IIIc and IVc) have developed. An

anodic peak at 0.44 V also observed.

1

7

solvents.

The values of K[1a,EtOH] in different solvents are

given in Table 4. As expected, they correlate well with

the empirical hydrogen bond acceptor b parameter of the

2

8

solvent (least-squares ﬁt: pK = � 1.36b, r = 0.997, six

points).

As detailed above an equilibrium constant for the

addition of water to 1a was voltammetrically estimated

A solid was obtained by evaporation (at room

temperature and reduced pressure) of the solvent from

solutions that presented the above-described voltam-

metric behavior. The IR spectrum (KBr pellet) of the

solid had, besides absorptions corresponding to 1c, other

bands that were similar in position and intensity to those

using the 1a–H O system in DMSO solution.

2

Voltammetric study of the PrSH addition to

thiadiazoles in ACN

29

of the recently synthesized thiadiazoline of 1c (1cH₂;

The voltammetric behavior of the 1a–PrSH system in

Scheme 2): a low-intensity doublet at 1635 and

J. Phys. Org. Chem. 2000; 13: 272–282

2

80

S. L. AIMONE ET AL.

experimental techniques employed. This decrease in

reactivity after the ﬁrst addition has also been observed

recently and used to obtain selectively monoaddition

products from the reaction of 1a with Grignard

30

reagents. This behavior was qualiﬁed as ‘an interesting

feature’, without further comments on its cause.

According to our structural studies of these mol-

27

ecules, the mutual steric hindrance of the 1a phenyl

substituents causes them to rotate out of coplanarity with

the heterocyclic plane (to a phenyl–heterocycle dihedral

angle of ca 43°). We have also shown that the interaction

between the methyl and the phenyl substituents in 1b has

similar steric effects. The phenyl–heterocycle dihedral

angle in 1b is ca 41°. Thus, the resonance interaction

between the C

=N bond(s) and the phenyl ring(s) can

only take place to a small extent.

Upon monoaddition, the heterocyclic carbon atom of

2

1

a that had bonded to the nucleophile changes from sp to

3

sp hybridization, and the corresponding phenyl sub-

stituent is displaced out of the crowded region over the

C—C bond of the heterocycle. This frees the phenyl

substituent on the other heterocyclic carbon to rotate to

coplanarity and full delocalization interaction of its p-

Scheme 2

system with the corresponding C

=

N double bond can

�

1

1610 cm

which corresponds to 9,10-disubstituted

take place. This remaining Ph—C=N— group turns into

a typical (coplanar and comparatively less reactive)

aromatic imine. The addition of a nucleophile to the

�

1

phenanthrenes (1640 and 1608 cm in 1cH ) and an

intense band at 1280 cm (1cH : 1275 cm ) assigned

2

�

1

� 1

2

‘

methyl side’ of a 1b molecule has similar effects.

This thiadiazoline geometry has been conﬁrmed by x-

to the C–N stretching in the

C=C—N group. IR

�

1

31

bands at 3300 (NH), 2920 (CH aliphatic) and 1370 cm

ray monocrystalline diffraction studies of 2a and 2b.

(

CH ) were also observed. The anodic peak at 0.44 V is

The measured phenyl–heterocycle dihedral angles for the

3

2

9

3

2

3

also observed in the voltammogram of 1cH₂.

sp and the sp sides of these molecules were 89.23° (sp ;

3

2

Hence the product of the addition of PrSH to 1c

1c.PrSH; Scheme 2) might reasonably be considered an

2a), 96.58° (sp ; 2b), 7.6° (sp ; 2a) and 10.7° (sp ; 2b).

(

N-propylthio derivative. As discussed in the case of 1cH₂,

the N,N-addition compound is stabilized by the resonance

energy of a phenanthrene hydrocarbon ring that would

Equilibrium constant values. Dependence on the

structure of nucleophile and substrate

not be available had PrSH added to a C=N double bond.

Compound 1c.PrSH, as 1cH , was unstable and could not

be isolated. It reverted easily to 1c during puriﬁcation

treatments.

The experimentally measured K[1a,ROH] and

K[1b,ROH] for all saturated, linear-chain, primary

alcohols (Table 3) average 3.4 Æ 0.2 and 1.7 Æ 0.2,

respectively. Thus, as in the case of ROH addition to

the carbonyl group, there is no measurable steric effect

caused by the length of the hydrocarbon chain.

2

32

DISCUSSION

Monoaddition

The sites for the nucleophilic attack are, of course,

different in 1a and 1b molecules [Ph—C(C)

=N— or

CH —C(C) N—, respectively), but in both cases the

=

3

Reactive alcohols add to thiadiazoles 1a and 1b in a 1:1

molar ratio. Although the molecules present two similar

reaction involves the breaking and formation of similar

bonds and similar structural changes. The experimental

fact that K[1a,ROH] ꢁ 2K[1b,ROH] for sterically un-

hindered alcohols might indicate that the different

reaction sites are of secondary importance and that the

factor of 2 in the K values is statistically determined: 1a

provides two possibilities for the bonding of a ROH

(or identical, in the case of 1a) sites for the addition

reaction, the addition of one molecule of nucleophile

seems to decrease the reactivity of the remaining reaction

site of the substrate. No reaction with ROH nucleophiles

or PrSH was observed with thiadiazolines, such as the 2a

33

and 2b, that have only one C

=N bond in the heterocycle

molecule whereas 1b has only one.

ring.

A steric effect due to differences in the reaction sites of

Monoaddition is independently supported by all

the substrates can be observed when the K values for

J. Phys. Org. Chem. 2000; 13: 272–282

ADDITION OF NUCLEOPHILES TO 1,2,5-THIADIAZOLE 1,1-DIOXIDE DERIVATIVES

281

with EtOH and the solvent hydrogen bond acceptor

parameter b is in agreement with the characteristics of

reaction (4).

Acknowledgements

This work was ﬁnancially supported by the Consejo

Nacional de Investigaciones Cient ı´ ﬁcas Y T e´ cnicas

(CONICET), the Comisi o´ n de Investigaciones Cientiﬁcas

de la Provincia de Buenos Aires (CIC Pcia. Bs. As.) and

the Universidad Nacional de La Plata (UNLP), Facultad

de Ciencias Exactas, Departamento de Qu ´ı mica and

Facultad de Ingenier ´ı a, Departamento de Ingenier ´ı a

Qu ´ı mica. M.V.M and J.A.C. are researchers of CON-

ICET and UNLP and S.L.A. and E.J.V. are researchers of

CIC Pcia. Bs. As and UNLP. The authors acknowledge

Professor Dr E. G. Gros (UMyMFOR, Universidad de

Buenos Aires, CONICET) for analytical and spectro-

scopic measurements and Professor O. Piro (Departa-

mento de Fisica, Facultad de Ciencias Exactas UNLP) for

x-ray difraction measurements.

Figure 4. Optimized geometry (PM3 semiempirical method)

Á

for the adduct of ethylene glycol and 1a [1a ET(OH) ]. The

2

Ê

length of the hydrogen bond (dotted line) is 1.84 A

linear-chain nucleophiles are compared with those

corresponding to b-branched ROH nucleophiles (Table

3

). K[1a,b-branched ROH] is ca 30% smaller than the 3.4

�

1

l mol

value of K[1a,linear-chain ROH] (K[1a,i-

�

1

BuOH] ꢁ K[1a,2PhEtOH] ꢁ 2.4 l mol ), while K[1b,i-

�

1

BuOH] ꢁ 1.7 l mol ꢁ K[1b, linear-chain ROH].

Steric hindrance caused by the structure of the

nucleophile must be the dominant effect for secondary

and tertiary alcohols. The equilibrium constants for the

addition of i-PrOH or s-BuOH are of comparable

magnitude for both substrates, but ca 10 times smaller

than the ‘linear-chain ROH’ value. No reaction was

observed between either substrate and t-BuOH.

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Article Doi

Electrochemical and spectroscopic study of the addition of several nucleophiles to 1,2,5-thiadiazole 1,1-dioxide derivatives

DOI: 10.1002/1099-1395(200005)13:5<272::AID-POC241>3.0.CO;2-Y

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