Characterization and stability of cyclic disulfides and cyclic dimeric bis(disulfides)

Tehzhcdron

OO40-4020/89 S3.00+.00 Q 1989 PergamonRessplc

Vol. 45, No. 1, pp. 91 to 102, 1989

Print&in GnatBritain.

CHARACTERIZATION

AND STABILITY

OF CYCLIC

DISULFIDES

AND CYCLIC

DIMERIC

BIS(DISU~IDES)

JANETTE

HOUK AND GEORGE

M. W~~ITESIDES*

Departments of Chemistry Harvard University Cambridge, Massachusetts 02138 and Massachusetts Institute of Technology 02139 Cambridge, Massachusetts

(Received in USA 12 May 1988) This paper describes the preparation of cyclic Abstract. bis(disulfide) dimers derived from m-2-butene-l,&dithiol and &-1,2-cyclohexane dithiol and the cyclic tris(disulfide) dimer of 1,3,5-triS(mercaptOmethyl)benzen8 by high dilution oxidation of the thiols with iodine. The stability toward ring-opening polymerization of thaee three new cyclic disulfides and of nine previously reported cyclic disulfides was tested by heating the None disulfide with a catalytic amount of sodium methanethiolate. of the cyclic bisfdisulfides) were stable with respect to polymerization under these conditions. The results of these experiments, together with literature reports concerning the stability of similar disulfides, indicate that few simple alkyl disulfides are thermodynamically stable in cyclic form.

Introduction As part

of a study

the disulfides interchange products

formed

reactions,1'3

obtained

(eq 1).

structure

using

interested

dithiols

and oligomeric

species

between

of thiols

we have been

from organic

bis(disulfides), containing

of the relation

by oxidation

in the distribution

among monomeric

and high molecular

The question

and properties

of

thiol-disulfide

disulfides,

weight

of central

of cyclic

disulfide-

mechanistic

interest

in

(1)

R'SH this work

concerns

bisidisulfide): bis(disulfide) to specify

structural

favor cyclic

factors

required what

at thermodynamic

ric disulfides

seems

the

in particular,

classes

on oxidation, bis(disulfides)

to be a consistently

bis(disulfide)

relative

to favor

structures

equilibrium? that

generate

formation

Although monomeric

disulfides

the structural

has proved

to be difficult.

unfavorable

enthalpy

probably

R favor

it is straightforward

identifying

to polymer,

of the cyclic

for the group

or polyme-

features

The major

of formation

originating

required

to

problem

of the cyclic

in CSSC

angle

strain. We and others related

discrete

conditions,

reported

the formation

of cyclic

and tetrakis(disulfides)

but the question

or thermodynamic describes

have

tris-

products

the preparation

of whether

has not been of several

these

bis-

bis(disulfides)

a number

substances

systematically

cyclic

91

under

represent

addressed.

and

of kinetic This paper

and tris(disulfides)

under

92

J. HOUK and G. M. WHITESIDES

kinetic

conditions,

respect

to polymer

reviews

the literature

in three

ways.

and establishes relevant

First,

examination

is helpful

especially

under

helpful

difficult

and their

whether

to distinguish

oligomeric

disulfides

ease with

which

convert

to polymers science:

obtained

unambiguously

makes

of cyclic

cross-linking

disulfide

bonds

formation

possible.8

A number

of weakly

cyclic

can be reduced

Crystal

structures

potentially

are available

Third,

have

the

species

useful

polymers

and disulfides

in

been

also makes

reversible

cyclic

1-14 provide

for compounds

are also

The ease with which

and higher

Compounds

of linear

products.

disulfide-containing

in polymers.6r7

to thiols

is

it is often

and from the self-

Thiols

bis(disulfides)

in the literature:

formation

polysulfide

of a,o-dithiols4

disulfides.5

even at low

information

dimeric

cyclic

forms.

bis(disulfides)

dithiols;

bis(disulfides)

reagents

of cyclic

between

of cyclic

weight

disulfide

This

is useful

of the cyclic

are formed,

reducing

weight

High molecular

important

compounds

and

information

of the pure

with

collects

stability

polymeric

conditions.

and formation

from the oxidation

reported

these

the low molecular

polymer

polymerization

derived

are unstable also

This

the relative properties

equilibrating

in studies

compounds

The paper

to this subject.

of the spectral

in verifying

concentrations,

systems.

it establishes

bis- and tris(disulfides) Second,

that these

in concentrated

polymer

disulfides

examples

are

(Figure

l,g 3,1° 7,11

8,12

1).

10,l"

ll,l" and 14.16 A variety

of substituted

reported.l3,14 melting

The parent

range.13

solid with prepared

Tetrathiocin

a sharp

melting

by Musker

dithiols.lO

several

a general

dimer16

been prepared and spectral

analogs in carbon

pyridine

with

by oxidation

sodium

sulfide

of dithiols

with

iodine

study

we have

high

5,16 6,20

used

similar

DMSO gave dilution 10,l"

been

with

described

by

7, 8, and five dithiols

with

NBS and

of 2,6-bis(bromomethyl)byproduct.18

Oxidation

techniques

generated

the cyclic

12,6 and 14.16

to prepare

of

Oxidation

13 in 95% yield.lg

ll,l"

techniques

of

by oxidation

of 7 have

have prepared

9 as a minor

with

using

2,13 3,1° 4,15

for cyclization

from the dithiol

The reaction

gave

tetrafluoro-1,4-benzenedithiol

colorless

of 4,6-dimethyl-

of the corresponding

tetrachloride.

an ill-defined

as a stable

procedure

properties

Chan et al.ll

2, have been

with

3, 10, and 11 have been

and tetramer16

have

pyridine

current

Compounds

The preparation

methylated

solid

4 has been described

et al. using

groups.11*12t17

disulfides

is a yellow

point.15

Both the cyclic

1,3_benzenedithiol iodine.

dibenzo[l,2,5,6]tetrathiocins,

compound

In the

cyclic

disulfides

from dithiols.

Results

and Discussion

Synthesis prepared iodine

under

products (< 25%). probably A similar

and Characterization

new cyclic

bis(disulfides)

high-dilution

(Table

I).

reflects high

tetrafluoro-1,4_benzenedithiol sparingly toluene).

soluble

in organic

The solid

does

reactions

of this compound

with

not melt,

(up to 10 mg/mL

but slowly

as it forms.

of 2,3,5,6-

13.1g

Compound

in benzene

polymerizes

poor

15 (68%)

from solution

in the oxidation

with

to kinetic

are typically

forming

DMSO to compound

solvents

We have

by oxidation

leading

in the reaction

(95%) was obtained

Dimers.

dithiols

a procedure

for high dilution

high yield

precipitation

yield

of several

conditions,

Yields

The unexpected

of Bis(disulfide)

15 is

or

to a brittle

Cyclic his(disulfide) dimers

s-s

c

s-s

Pigi.lra

1.

Structures of several cyclic disulffdas.

prwiausly

3

report&

J. HOUK and G. M. WHITESKDPA

94 Table I.

Physical Properties of Cyclic ais(disulfides).

structure

w.p. mj

Yield

FOX7Wll2l

15

C18ft18S6

&-k

S-d--S-

16

10%

87-Y

C&ZS4

178-81

15%

a;;;r>

yellow-orange for

solid

when

chemical weight

ionization

heated

of

value

450

that

was

is

for

singlet

peaks,

above

for

aromatic

for

the

proton

at

from the

in position simplicity

of

interchange

the

cyclophane21 show

and

melting

'C.

proton

peaks

conformers

that

10%

yield.

formed,

and

this

showed

the

desired 17 shows

17 and solution

of

the

species,

both

interchange.l

was

40.38

5.27

54.31

40.64

5.12

54.24

Found:

49.39

6.64

43.99

Required:

49.27

6.89

43.84

Found:

49.71

7.14

43.15

Requited:

49.27

6.89

43.84

behavior

a parent

peaks in the

in the

do

impact

(Rast

method),

weight

15 consists at not

6 =

of of

3.3,

differ

two one

substantially

unoxidized

trithiol. unhindered of

a

442

and

is largely geometry

nor

A molecular

ion.

molecular of

is observed

electron

the

The

cyclophane

2,11,20-trithia[3.3.3](1,3,5)-

not

may

account

a molecular

weight

parent

ion from

bis(disulfide)

a large

polymeric

Found: Required:

occurring

(16) precipitate for of

peak the

the 250

parent

products dithiol used

in this

ion

dimer peak

obtained differ

low

236).

substantially to

The

study

in related

a yellow

The

from

studies

one

NMR

paste The

of

from

mass NMR

and

of

16

dithiol. which

spectrum spectra

a concentrated

another.

dimeric of

point mass

The

proton

proton

oxidation

differentiate

it was

corresponding

sublimed.

= 312.

iodine

oxidation

as

Melting

yield.

the

on

solution

(theory

gave

routinely and

obtained

from

of

17 was

at R/S by

was

at &)/e = 236.

spectrum

of g&-1,2-cyclohexanedithiol

cyclic

spectroscopy

did

significantly

Oxidation

of

dimer

solubility

a small

differ

45.08

flexibility.

The

indicated

not

4.25

%S

4,11,24-trioxo-2,13,22-trithia[4.4.4](1,3,5)cyclophane22

in only

spectrum

50.67

depression

1,2,7,8-Tetrathiacyclododeca-4,10-diene

did

Required:

Neither

there

differing

cyclophanes,

conformational

depression

45.08

spectrum

These

suggests

4.39

the

protons

S = 6.5.

BH

50.59

15 gave

with

NMR

%C Found:

Similar

point

agreement

corresponding

analogous

of

benzylic

spectrum

between The

bridges.

from

The

dimer.

one

130

(2, R = R).13

satisfactory

the

C12H20S4

spectrometry

obtained

in

required

the

mass

=1ZH20S4

110-15 (poly.)

dibenzo[l,2,5,6]tetrathiocin

also

.MLnalp+iS

NMR polymeric

thiol-disulfide

of

95

Cyclicbis(disulfide)dimers

Polymerization

of 17 occurs

The 1~ WWR of a sample showed

peaks

due to both

Oxidation manner

dithiol

4.

are quite

of Cyclic

disulfide

acid

disulfide

stable

above

ring

A conflicting

fonn.26

nine-

A study

disulfides dithiane

study

dithiacycloheptane

in purities polymerizes

for five years

in neat

prepared

differing

conditions.

a very

to remain

cyclic

unpolymerized

disulfides

under

was to make

a temperature

ii)

polymerizes

iii) compounds

such as g&-1,2-

cases

formed.

this procedure;

these

indistinguishable

polymerized

to a solid

The general

disulfides

to cyclize

for compounds

under

we have

properties

of

of polymerization

by exposing

stable

and

methanethiolate.

the melting the liquid

point cyclic

Bis(disulfides) liquids

cooled

from polymeric

range

has been

disulfides

cyclic

procedure

the disulfide,

at 70 OC, but melted

A melting

form of 1,2-ethanedithiol

cyclic

dithiols

physical

was determined

sodium

WWR spectra

of neat

conditions

Thermodynamically

above

In most

'C.

benzene)13;

data

summarizes

containing

(w:w) added

as polymer

to >150

in a few

products.

conditions.

slightly

noted.

solidified

i)

(t+ = 12 h)20;

is added,

II presents

regarding

of base.

up two tubes

ca. l-2%

include:

at 25 'C, but that

a catalyst

The table

to polymerization

these

pure, after

such as dibenzo-1,2,5,6_tetrathiocin,

of the corresponding

of polymeric

amount

while

(which polymerizes

for 21 months

Table

and information

Stability catalytic

may

l-Oxa-4,5of a

if the stabilities

the tendency

characteristics

and 1,2-

reports

at 27 'C2*),

in 16 h in refluxing

form when

and examined.

disulfides

monomeric

and l-oxa-4,5-dithiacycloheptane.26r28t2g

to determine

with

equilibrating

raised

ring cyclic

such as 3,3-dimethyl-1,2-

heated,

as stable

in neat

We wished correlated

when

(the WW doubles

dithiacyclohex-4-ene27

that in neat

or in the presence

was reported

on standing,

polymerize

that polymerize

during

form,

3-hydroxy-1,2-dithiolane

reported

reports

indefinitely

and N-phenyl-4-oxo-5-aza-1,2_dithiacyclohexane

upon heating

changes

These

= 1.9 kcal/mol

of individual

that polymerize

a substance

with

of 5-15-membered

the six-

in neat

at room temperature.2g

of stability

that

both

stable

of disulfides

are stable

the

occurs

o,w-dithiols,

series

rings

of

and purity.

If, however,

to be quite

of the disulfides.

of the same disulfide

intact

state.30

R-alkyl

to polymerization.27

dry sample

compounds

due to

The stability

its structure

3,3,5,5-tetramethyl-1,2-dithiocyclopentane

(AH polymerization

days),31

is complicated

polymerization

are reported

on the same

catalyst26

dithiolane,25e27

upon

point,

of C5-Cl2

compounds

only

differences

compounds

of 17.

from the same

Polymerization.

in the solid

its melting

of the properties

reports

Reports

toward

and eleven-membered

to be stable

standing

point

out in a similar to that

derived

of the dimer

form is dependent

For the disulfides

only seven-,

reflect

Disulfides

is relatively

and seven-membered form.25

similar

disulfide

The spectrum

in neat

is heated

readily.24

is heated.

its melting

was carried

of 4 is very

and polymeric

distinct.

above

and polymer.23

spectrum

of.4

as the dimer

of two diastereomers.

Stability

Lipoic

The mass

WWR spectra

the existence

a cyclic

dimer

state

that had been heated

of a-1,2-cyclohexanedithiol

to give

The proton

in the solid

of dimer

for these

one with The tubes

were

material.

became

again

solids

that

opaque

or

showed

if the temperature

by several

to

liquids

Bis(disulfide)

of 150 to 154 'C for a linear reported

and one

heated

and any

4 and 17 remained

to sticky

remain

experiments

no base

of the disulfide disulfide

to a

disulfides

lH

3 was

polymeric

investigators.32

J. HOUK and G. M. WHITESIDES

96

Stability of Cyclic Disulfides to Polymerization When Melted in the Presence of NaSCH,.

Table II.

m.p. (OC)

structure

mpd

TiEI& (mi")

Behavior es e Liquid Helt with NaSxe

140

>4ao

no

change (by %i NMR)

6

Oil B&h Temp (OC)

Ring size

18

130-2

19

56-a

70

>4ao

no change (by %I NMR)

6

20

32-3

70

Z-480

no change (by 1H NMR)

6

21

liquid

70

>iao

turns to a sticky, cloudy white solid

7

22

viscous liquid

70

Cl5

solidifies to a cloudy white solid

a

3

62-4

70

Cl5

solidifies to I yellow solid; remelts if the temp is increased to >160 "C

a

4

178-181

la5

<15

remains a liquid at elevated temp. complete polymerization has occurred (by 'S NW

a

17

110-115 (POlY.)

ias

Cl5

16

84-87

90

<5

turns to I yellow insoluble liquid

12

173-176

iao

<5

turns to a yellow insoluble liquid

14

15

___

___

__

does not melt: polymerizes to a yellow iascloble solid when heated to >130 % with no base added

14

12

150-153

iao

<5

turns to a yellow insoluble solid

la

7

a

&a"gth of time for which the compound remains in monomeric for" when melted in the presenca of NaSCH3.

The This

the

peak

formed

under

It

against

also

be

solution

equilibrated

is also

carried of

which

the

against

not

out

in the

dimer 2 mM

slowly

ppm,

are

it

the

C2

peak

when

mercaptoethanol.

to

appear

assigned

the

of

ppm. aromatic

NaSHe.

determine

if 7

generates

in the

spectra

(MEox).

when

the

the

an of

oligomeric

1,3-bis(mercaptomethyl)benzene

direction;

disappears

6.35

of

interchange

not

2-mercaptoethanol opposite

at

presence

is possible

does

therefore

peak

position

in the

thiol-disulfide

This

observed

oxidized

at

7 is melted 6.35

in which

species.

species,

equilibrated can

of

at

a characteristic

protons

when

peak

conditions

structures.

mM

shielded

disappears

mixture

equilibrated

7 exhibits

of

to

characteristic

equilibrium the

spectrum

corresponds The

ring.12 Using is

1~ NMR

peak

The 6.35

disulfide

is

equilibration ppm is

peak

in a 1

97

Cyclicbis(disulfide)dimers

Conclusions We conclude

that

thermodynamically concentrated

the only class

stable

solutions

with

of compounds

catalyst

for thiol-disulfide

drawn

These

studies

disulfides

formed

under

we have

membered

cyclic

polymer

in more

are also useful

found

disulfides dilute

balance

18, 19, and 20). of a

disappears

reinforce

cyclic

with

solutions

in

conclusions

disulfide-

for these

stable

six-,

and eight-

with

respect

not yet carried We observe

dilute

by a factor

in addition,

to

out a

polymerisolutions

disulfides

of dilution

or to other

interchange

in concentrated

of cyclic

(10 mW) more

(precipitation)

We have

of the

of compounds,

seven-,

stable

substances.

solutions

may,

m

of polymer)

in AG due to entropy There

the identity and mixtures

In thiol-disulfide of five-,

(-10 mW).l

precipitation

RTAS = 5.5 kcal/mol. changes

compounds,

and bis(disulfides)

at concentrations

The change

in establishing

with

a number

in energies

(usually

sulfides)

phase

is

in the absence

stability

results

concerning

conditions.

that

(-10 M), and apparently

103.

but this These

potentials

for comparison

equilibrating

studies,

zation

of redox

kineticallv

that

or as

systems.l12

cyclic

detailed

catalyst.

disulfides

in the melt

(e.g. compounds

stable

interchange,

of an effective

from studies

containing

are relatively

cyclic

to polymer

is the 1,2-dithianes

A number

the presence

of simple

respect

and bis(diof approximately

is readily

estimated

be contributions

to be

to AG due to

processes.

Kxperimental General. atmosphere Organic

All reactions

of nitrogen

Chemicals.

Deuterated

from Aldrich

Chemical

or distilled

under

from disodium determined uncorrected. Elemental

Mass

before

Inc.,

of Cyclic

were

chemicals thiols

use.

using

by Spang

Atlanta,

a Kratos

addition

adjusted excess

so that

in ethanol

period.

recrystallized cooling powder.

The white

and washed

with

by dissolving

the solution

it begins

@S-benzene)

6 6.5

for ClSHISS6

funnels,

mixture

spectrometer.

Eagle

Harbor,

MI or

remained that

simultaneously, stirred

slightly formed

via

ethanol

(600 mL)

and iodine

yellow

were

from a small

was collected

The product

by

was

at room temperature

and slowly

0.68 g (68%) of 15 as a fine white

to an insoluble

Compound

1,3,5-

(400 mL) and iodine

of thiol

(3 x 30 mL).

to polymerize

= 442).

added

to rapidly

it in benzene

(s, 3 Ii), 3.3

(15).

in ethanol

of addition

precipitate

ethanol

polymerizes

in hot benzene.

300 QC), but

calcd

(400 mL) were

to 0 'C to give

The compound

is dissolved

were

are

GA.

The rates

the reaction

of iodine.

filtration

MS-50

Laboratories,

(1 g, 4.7 mmol)

rate dropping

over a three-hour

weights points

Disulfides

Tris(mercaptomethyl)benzenel (1.76 g, 6.93 mmol)

obtained

recrystallized

(THF) was distilled

Melting

2,3,12,13,22,23-hexathia[4.4.4](1,3,5)cyclophane

constant

were

Rast molecular

solvent.

an

from Columbia

were

Tetrahydrofuran

before

obtained

out under

and other

as the solid

performed

carried

was obtained

available

use.

dianion

spectra were

Microlab,

Preparations

solvents

benzophenone

were

1,2-Dithiane

Commercially

nitrogen

analyses

Atlantic

Co.

benzophenone

using

and measurements

or argon.

15 does

yellow-orange

not melt

to an orange

solid

(s, 6H); Rast mol wt33

when

solid

heated

at ~130 450 + 20

if it

(up to

'C: 1~ WMR (mol wt

and G. M. WHITEBIDES

J. Houx

98

1,2,7,8-tetratbiacyclcdcdeca-4,10-diene 15.

a-2-butene-1,4-dithioll

solid:

mp 84-87

'C; 'H NMR

(CDC13)

Wt33 = 250 + 20

(mol wt calcd

(rel intensity)

236

6 5.6

(14), 119

34 mg

similar

dithioll mol)

(5 g, 0.34 mol)

in chloroform

(450 mL) were

funnels,

g, 0.068 mol)

in chloroform

bisulfite

reactions

to destroy

200 mL),

dried

a sticky

yellow

paste

0.05-0.1

torr)

to give

191.5-192

(MgSOq),

afforded

oc);

(m, 3H), 1.7 38.1,

36.4,

sity)

294

excess

M

0.1

of iodine

and the solvent (5 g).

4 as fine white (CDCL3)

6 3.5

1.1-1.5

(m, EH);

35.2,

26.7,

26.6,

(45), 178

(m, lH), 3.0

26.1; mass (87), 146

dimeric

species

(m, 2H), 1.55

was sublimed:

spectrum

(m, 2H),

1.3

(m, 2H);

(CDC13) 13c NMR

pressure

(130-145

2.3

(m, 2H),

2.1

54.2,

(rel inten-

(21), 81

remained

from

mp

57.4,

(70 eV), R/S

(CDC13)

"C at

(m, 2H),

6 58.5,

(19), 113

6 2.9

(3 x

to give

'C (lit.15

(m, 2H),

polymer

1~ NMR

The

Recrystallization

(CDC13)

(4), 114

m-1,2-cyclohexanedithiol-disulfide

of

of the

sublimed

mp 178-181

13C NMR

(6.8

amount

remained.

at reduced

solid.

needles:

lH NMR

A small

(2 x 200 mL) and water

(1.4 g) was

0.3 g (21%) of a white

(m, 4H),

(9), 292

removed

The paste

that

acid

addition

of triethylamine

at the completion

hydrochloric

a

(8.55 g, 0.34

via constant

solution

to the solution

the slight with

simultaneously,

stirred

using

Trans-1,2-cyclohexane

(750 mL) over a 3-h period.

was added

was washed

of 15.

(450 mL) and iodine

added

to a rapidly

solution

hot hexanes

(28),

(4) was prepared

for the synthesis

rate dropping

sodium

(70 eV), ~/q/e

(lo), 103

(94), 84 (29).

to that

in chloroform

spectrum

(46), 117

m-dodecahydro-dibenzo[l.2.5.6]tetrathiocin procedure

to

(dd, 4H): Rast mol

= 236); mass

(ll), 118

in analogy

(10%) of 16 as a white

(m, ZH), 3.3

for C8Hl2S4

(l), 150

87 (25), 86 (24), 85

(16) was prepared

(0.32 g) gave

(100).

behind 2.3

when

the

(m, ZH),

1.7

6 53.4-53.1,

31.8-31.4,

24.6-24.4. m-dodecahydro-dibenzo[l.2.5.6]tetratbiccin .g&-1,2-cyclohexanedithioll (125-135

'C at 0.50-0.1

110 oc; lH NMR (CDC13)

(CDC13)

6 62.1,

intensity)

292

44.8,

in 15% yield torr)

6 3.6 30.0,

(22), 178

afforded

the product

(t, lH), 3.5 29.1,

was sublimed:

13C NMR

spectrum (20), 113

(CDC13)

6 55.7-55.3,

lH NMR

oxidation Olmstead

of 1,2_ethanedithiol and Musker,lO

polymer (CDC13)

30.9-29.8,

1,2,5,6-Tetrathiacyclocctane

Recrystallization

nodules:

mp 173-176

'C (lit.17

'C (lit.lO mp 62-64

oxidation Marvel,6

of 1,4_benzenedithiol mp 149-153

solid:

in 41% yield

by iodine

of Goodrow,

in analogy as small

in 25% yield

to

white

by iodine

of Wong

and

"C).

a general

from a-1,2procedure cyclic

56.5-57.5

"C).

for the

iodine

monomeric

from 3:l hexane/methanol

OC (lit. mp35

the

(m, 8H):

"C).

to the procedure

to the corresponding

Recrystallization mp 56-58

when

1.2-2.0

"C).

(12) was prepared

using

(m, 2H),

7 in 63% yield

(19) was prepared

of a,o-dithiols

disulfides.34 white

gave

OC (lit.6 mp 150-153

m-2,3_dithiadecalin

(100).

behind

(7) was prepared

according

bis(mercaptomethyl)cyclohexanel oxidation

170-171

(70 eV), sl/e (rel (9), 81

to the procedure

from hot benzene

Para-tri(phenylenedisulfide)

mp 10513C NMR

23.9-22.8.

2,3,12,13-Tetrathia[4.4]metacyclophane 15.

6 3.3

solid:

(m, 8H);

remained

(3) was prepared according

mp 62-64

1.2-1.9

(5), 114

m-1,2-cyclohexanedithiol-disulfide species

as a white

(t, lH),

from

Sublimation

to 15.

24.1; mass

(49), 146

dimeric

(17) was prepared

in analogy

provided

19 as a

Cyclic bis(disulfide) dimers 1,2-Dithiaoycloheptane

was prepared

(21)

88% yield using the same procedure distillation

(quintet,

as a colorless

liquid:

4H), 1.7 (quintet,

1,2_Dithiacyclooctane distillation product

(quintet,

procedure

viscous

disulfide

in 72%

of 19.

Kugelrohr

lit.27 bp 65.5 'C at 2 torr) afforded lII NMR

the

(CDC13) 6 2.6 (t, 4H), 1.7

of Cyclic

In a typical

(15-20 mg) were weighed

sodium methanethiolate

relative

summarized

in Table

Acknowledgments. Grant

in methanol

noted.

This work was supported

analyses

(20 pL, ca. l-2% w:w of

disulfide).

Results

of cyclic

To one of the tubes The tubes were heated

of these

experiments

are

II.

34411.

GM

and Bis(disulfides)

two samples

into 1-mL test tubes.

to cyclic

in an oil bath and any changes

Disulfides

experiment,

was added 0.2 M sodium methanethiolate

spectral

from 1,6-hexane-dithiol

as in the synthesis

liquid:

of the Stability

Polymerization.

Health,

(t, 4H), 2.0

4H), 1.4 (m, 4H).

Determination toward

(CDC13) 6 2.8

2H).

(60-64 'C at 1 torr,

as a colorless

in

Kugelrohr

of 19.

lit.36 bp 55-60 'C at 1.7 torr) afforded lI-INMR

(22) was prepared

yield using the same general

from 1,5-pentane-dithiol

as in the synthesis

(45-50 'C at 0.5 torr,

the product

99

by the National

We thank Jerome

and Judith

Wolfe

Institutes

Lewis and Keith Chenault

for her help in preparing

of

for mass

this paper.

Notes and References 1.

Houk, J.; Whitesides,

2.

Szajewski, 2026.

Whitesides,

1977, Q,

Proteins:

Shaked,

Biol.

2011-

R.P. J. Ora. Chem.

Z.: Ssajewski,

M.A.K.

L

R.P.; Whitesides,

4156-4166. interchange:

New York,

Academic:

J.E.; Szajewski,

G.M.; Houk. J.; Patterson,

of the SulfhvdrYl

Pergamon:

GrOUD;

Molec.

Whitesides,

of thiol-disulfide

Biochemistrv SH

Lilburn,

1980, 2,

6825-6836.

G.M. J. Am. Chem. Sot, 1980, m,

1983, 48, 112-115.

G.M. Biochemistry Reviews

G.M.;

332-38.

Ora. Chem. 3.

G.M. J. Am. Chem. Sot. 1987, m,

R.P.; Whitesides,

GrOUD 1973.

New York,

Jocelyn,

1972.

1978, 11, 231-297.

Friedman,

M. The Chemistrv

in Amino Acids.

PeDtides.

P.C. Biochemistrv

Creighton,

and

and of the

T.E. Proa. Bioohvs.

Hupe, D.J.: Wu, D. J. Ora. Chem.

1980,

45, 3100-3103. 4.

Marvel,

5.

Davis,

C.S.: Olson,

Tobolsky, 606.

1956, u, Wong, u, 7.

A-V.:

Davis,

198, 1953. 6.

L.E. J. Am. Chem. Sot. 1957, B,

F.O.; Fettes,

Leonard,

F.O.

3089-3091.

E.M. J. Am. Chem. Sot. 1948, 70, 2611-2612. F.:

Roeser,

(to Reconstruction

Bertoszi,

E.R.; Davis,

G.P. J. Polvm. Finance

Sci. 1948, 2, 604-

Corn.),

F.O.; Fettes,

U.S. Patent

E.M. J. Polvm.

2 657 Sci.

17-27.

D. T.-M.;

Marvel,

C.S. J. Polvm.

Sci.. Part A: Polvm.

Chem.

1976,

1637-1644.

Stern, m

M.; Fridkin,

1.; Warshawsky,

A. J. Polvm.

Sci..

Part A: Polvm.

1982, 2Q, 1469-1487.

8.

Hansen,

J.N. Anal.

9.

Gafner,

G.; Admiraal,

Biochem.

10.

X-Ray

structures:

Tetrahedron

1981, m,

3, Goodrow,

Lett.

1982, 2,

3231-3234.

W.K. Phosn h o rus Sulfur

M.H.; Musker,

W.K.;

Commun.

Olmstead,

1986, a,

1969, m,

M.H.: Olmstead,

M.M.; Musker, Struct.

146-151.

L.J. Acta Crvstallocr.

10, Goodrow,

M.H.;

1983, se, 299-302.

M.M. Acta Crvstalloar..

255-256.

2114-2119.

M.M.; Musker,

W.K.

Olmstead,

11, Goodrow,

Sect. C: Crvst.

J. HOUK and G. M. WHITESIDES

100 11.

Dixon, K.R.; Mitchell, Beveridge,

R.H. Can. J. CQ8&

K.A.: Bushnell,

1983, a,

G.W.; Mitchell,

1598-1602.

R.H. Can. J. Chem.

1983, 61,

1603-1607. 12.

Chan, T.-L.: CNSt.

Siu, T.-W.; 13.

Poon, C.-D.; Mak, T.C.W. A ct a C

StNCm

1986, Q,

897-900.

Tam, T.-F.;

Chan, T.-L. J. Ora. Chem, 1976, Q,

Field, L; Stevens,

W.D.;

Lippert,

Wong,

P.-C.;

1289-91.

E.L., Jr. J. Ora. Chem.

1961, a,

4782-4783. 14.

We are most dithiols.

interested

in disulfides

We have carried

tetrathiacyclooctane references

fragment

for compounds

elsewhere

from oxidation

or lead tetraacetate: xz, 2331-2337. dithiolate: 1691.

from the oxidation search

using CAS-Online.

found in the search,

in this article,

(263-11-6)

formed

out a substructure

follow.

dithiol

M.I.H.,

B.: Klar, G. Liebias

dimethyl[c,g]-[1,2,5,6]tetrathiocin with

lead tetraacetate

Weston,

A.F. Btrahedron

polarographic

and elemental

1978, a,

75-83.

(66086-40-6)

sulfur:

Cragg,

2,8(or

of the

R.H.;

2,9)-

from

dithiol:

Przegalinski,

el.

2,3,8,9-Tetramethyldibenzo[c,g][l,2,5,6]-tetrathiocin

from thermolysis

of the corresponding

Nakhdjavan,

bis(dithiolate):

tellurium

(IV)

B.: Klar, G. w

1977,

2,3,8,9-Tetramethoxydibenzo[c,g][l,2,5,6]tetrathiocin

1683-1691. (99323-86-l)

from electrochemical

K.W.; Klar, G.; Knittel, l,S(or

774-781.

fi J. Biul

or 2,9-

from oxidation

(69452-96-6)

of the corresponding

A.; Matysik,

1984,

1977, 1683-

(66086-39-3)

Lett. 1973, 2, 655-656.

oxidation

M.: Persona,

superoxide

tellurium

Ann. Chem.

(72760-56-6)

Diethyldibenzo[c,g][l,2,5,6]tetrathiocin,

with

Aust. J. Chem.

of the corresponding

2,8-Dimethyl[c,g]-[1,2,5,6]tetrathiocin

dithiol

and

Dibenzo[c,g][1,2,5,6]tetrathiocin

Crank, G.: Makin,

Nakhdjavan,

CAS numbers

Names,

but not mentioned

of the corresponding

From thermolysis

of 1,2-

for the 1,2,5,6-

oxidation

of the dithiol:

D. 2. Naturforsch..

1,10)-Dinitro-3,10(or

dibenzo[c,g][1,2,5,6]tetrathiocin

Stender,

B: Chem. Sci. 1985, &Q,

3,8)-bis-trifluoromethyl-

(75083-33-g)

and N,N,N',N'-

tetramethyl-2,?-dinitro-4,?-bis(trifluoromethyl)dibenzo[c,g][l,2,5,6]tetrathiocin benzotrithioles Warkentin,

(75083-34-o)

from carbamothiolates

J.D. J. Ora. Chem.

1980, e,

synthesis

Lakshmikantham,

tetrakis(tri-fluoromethyl) corresponding Nouv. J. Chim,

(82766-68-5)

P.; Hansen,

Lebedev, m,

A.V.;

231-237.

Zaikin,

polysulfides: V.G.; Mikaya,

of arsenic

P.; Weedon,

compounds

of tetrathiooxalate:

(87495-58-7)

Chem.

(91574-83-3)

by the corresponding

W.R.: McBride,

45-60.

1,2,5,6-Tetrathiocin-3,8-dimethanesulfonic

B.C.; Reglinski,

1,2,5,6-

from pyrolysis

E.A.; Kuz'min,

A.I. J. Oraanomet.

Cullen,

A.C.

3,4,7,8-

1982, 22, 223-224. Chernyshev,

3,4,7,8-

of the

N.; de Mayo,

1,2,5,6-Tetrathiocin-3,8-dimethanol

in the reduction

Bott, S.G.; Atwood,

from methylation

P. 2. Chem.

in the

1,2,5,6_Tetrathiocin,

1,2,5,6_Tetrathiocin,

Tetrathiocin-3,8-diylbis(trimethyl)silane of silicon-containing

prepared

by photolysis

Jacobsen,

1978, 2, 331-342.

of

K.;

dithioguinone:

Cava, M.P.;

(651-38-7)

dithiocarbonyl:

tetrakis(methylthio) Jeroschewski,

M.S.;

1874-1877.

1987, 2,

Rasheed,

1,4,7,10-Tetra-

(107474-48-6)

of the corresponding

M.V.: Raasch,

J.L. J. Ora. Chem.

in the preparation

4806-7.

aminodibeczo[c,g][l,2,5,6]tetrathiocin attempted

reported

and OH- or SH-:

J. J. Inora.

O.V.;

1985, formed

dithiol:

Biochem.

1984, 21,

acid, disodium

Salt

Cyclic bis(disulfide) dimers (28599-39-5) thiurams: above

formed

by reaction

Lysenko,

compound,

101

of the corresponding

N.M. Zh. Obshch.

Kl&&

dithiol

1974, 4p,

with

157-161.

The

2,2'-[1,2,5,6-Tetrathiocin-3,8-diylbis(methyl-

eneoxy)]diethanesulfonic

acid,

disodium

salt

(28599-40-B),

and 2,2'-

[1,2,5,6-Tetrathiocin-3,8-diylbis(methylenethio)]-diethanesulfonic (28599-41-9):

Prepared

by reaction

oxidation

of the corresponding

V.E. mr.

Khim.

derivatives, J.A.

Can. J. Chem.

1981, 2,

synthesis:

1101-1104.

[c,g][l,2,5,6]tetra-thiocin,

dithioguinone:

1978, 2, 331-342.

Wawzonek,

3582.

Phthalimide,

(14672-95-8) V.A.;

by reaction

and

N.; de Mayo,

reactions P.; Weedon,

1,8-dimethyl-2,7-di-3-pyridylof sulfur

S.; Hansen,

on the corresponding

G.R. J. Ore.

Chem.

1966, a,

3580-

N,N'-(1,2,5,6-tetrathiocin-3,8-diyldimethylene)di-

prepared

Morgun,

68644-44-O)

lH,BH-[1,2,5,6]-

Tetrathiocino[3,4-b:8,7_b']dipyrrole,

pyrrolidine:

and 8

Gl&ki,

of in photochemical

Jacobsen,

of 4-methyl-camphor

formed

J.T.;

1,4:7,10-Dimethanodibenzo-

formation

A.C.

(13405-06-6),

Petrun'kin,

1,2,3,4,7,8,9,10-octahydro-

(la,4a,7fi,lO,T)- (68682-33-7),

J. Chim.

and by

(78780-17-3)

Wrdbel,

1,4,7,10,13,13,14,14-octamethyl-(la,4a,7a,lOa)-

Nouv.

acid

NaCN

V.N.;

Cassipourine

181-183.

stereospecific

with

Fedoseeva,

dithiols:

Zh. 1970, x,

total

of trisulfides

M.I.

from the corresponding

Ukr.

Khim.

dithiol:

Zh. 1966, x,

Portnyagina, Pregn-5-en-ZO-

1081-1084.

3-(acetyloxy)-16,17-[[(38,168)-3-(acetyloxy)-20-oxopregn-5-ene-

one,

16,17-diyl]bis(dithio)]-(3,9,16,9)-

(63108-86-l),

Kamernitskii,

Ustynyuk,

Ser.

Khim,

A.V.;

1976, a,

b'ldiguinoxaline Elokhina,

Turuta,

2078-2080.

(93232-12-3)

V.N.;

Bannikova,

A.M.;

O.B. Khim.

steroids:

Izv. Akad.

Nauk.

SSSR.

[1,2,5,6]Tetrathiocino[3,4-b:7.8prepared

Nakhmanovich,

transformed

T.K.

A.S.;

Geterotsikl.

from the corresponding

Karnaukhova, Soedin.

R.V.;

1984, 20,

dithiol:

Kalikhman,

I.D.:

1062-1065.

[1,2,5,6JTetra-thiocino[3,4-c:7,8-c']diisothiazole-3,8-dicarbonitrile (66232-81-3)

and many

T.; Simmons,

H.E.;

See also U.S.

Patents

Nemours

and Co.

15.

Feher,

F.; Degen,

16.

Ronsisvalle, s,

344-348.

Sato,

compounds:

Chem.

S.A.;

1980, 45,

and 4066656;1978

B. Ancrew. Chem.

Fukanaga,

5122-5130.

to E.I.

du Pont de

Int. Ed. 1967, 6, 703.

F.: Pappalardo,

Pahor,

N.B.:

Calligaris,

S. Gazz.

Chim.

Ital.

T.; Wakabayashi,

Vladuchick,

O.W. J. Oro.

4210716;1980

G.; Bottino,

Pappalardo, 17.

related

Webster,

S. Qra.

Mac n. Re son.

M.; Randaccio,

I -I110

1980

1980,

L.; Bottino,

F.;

227-231.

M.; Iiata, K.; Kainosho,

M. Tetrahedron

1971, 27,

2737-2755. 18.

Galuszko,

19.

Raasch,

K. Rocz.

20.

Gronowitz,

S.; Lidert,

Gronowitz,

S. Chem.

M.S.

21.

Boekelheide,

22.

Vogtle,

Chem.

J. Oro.

1975, 49,

Chem.

Z. Chem.

Scrinta

V.; Hollins,

F.; Lichtenthaler,

1597-1602.

1979, 44,

2629-2632.

Scrinta

1980, x,

1980, u,

97-101.

Lidert,

Z.;

102-107.

R-A. J. Am. Chem. R.G. Anoew.

Chem.

Sot.

1973, s,

Int. Ed.

3201-3208.

1972, 11,

535-

536. 23.

We have

noted

that a-1,2-cyclohexanedithiol-bis(disulfide)

polymerizes

more

observation

is not conclusive

inherently slight

less

impurity

readily

stable.

than

This

the corresponding evidence result

in the cis compound.

dimer

trans-dimer.

that the former

This

compound

may be due to the presence The purity

of cyclic

is of some

monomeric

102

J. HOCK

disulfides species 24.

Reed,

has been

found

to polymerize:

L.J.

New York, hm e.

1956,

to greatly

see ref.

In Oraanic 1961; Vol.

and G. M. WHITESIDES

Sulfur

affect

COIQQQB&;

1, pp 443-452.

Kharasch,

Thomas,

Schotte.

L. &rki v. Kem . 1956, 9, 309-317.

26.

Affleck,

J.G.;

27.

Schoberl,

28.

Dainton, sot.

29.

30.

Fettes,

Dougherty,

G. J. Ora. Chem.

A.; Griifje, H. Liebias

1957, s, E.M.

of these

N., Ed.;

R.C.;

Reed,

Pergamon:

L.J. J. Am

6148-6149.

x,

25.

F.S.;

the tendency

26 and 29.

Davies,

J-A.;

Ann.

Manning,

1950, 15, 865-868.

Chem.

1958,

P.P.;

Zahir,

614,

66-83.

S.A. Trans.

Faraday

813-820. In Oraanic

New York,

1961, Vol.

Barltrop,

J.A.:

Sulfur

Comvounds;

Kharasch,

N., Ed.:

Pergamon:

1, p. 267.

Hayes,

P.M.:

Calvin,

M. J. Am. Chem.

Sot.

1954, 76,

4348-4367. 31.

Cragg,

32.

Goodrow,

R.H.;

3231-3234 33.

Pasto, Hall:

Weston,

M.H.;

Husker,

and references

cited

therein.

D.J.;

Goodrow,

35.

Bass,

36.

Field,

Lett.

M.W.;

Johnson,

Englewood

34.

A.F. Tetrahedron

Olmstead,

M.H.;

S.W.;

C.R. ;

Cliffs, Husker,

Evans,

L.; Barbee,

W.K.

W.K.

655-656.

ete

New Jersey,

S.A.,

1973,

Tetrahedron

Svnthesis

R.B. J. Ora.

i ati n; Prentice-

1969: pp. 74-75. 1981,

Jr. J. Or a . Chem. Chem.

457-459. 1980, 45, 710-715.

1969, 34,

1982, 23,

36-41.