Topic 19: Sulfur Chemistry

Read:Gordon W. Whitham Organosulfur Chemistry. Oxford Science.

Professor David L. Van VrankenChemistry 201: Organic Reaction Mechanisms I

H3CSCH2

O

+

H

R H

..-

H3C SH3C

X

Cl

: SCH2

O

O

Nu..SR

Cl..

Nomenclature

NaOS

ONa

OO

sodium sulfateNaO

SONa

O

sodium sulfite

HOS

ONa

O

sodium bisulfiteNaO

SS

OO

sodium thiosulfate

MeS

OH

OO

sulfonic acidMe

SOH

O

sulfinic acid

..Me

SOH

sulfenic acid

....

unstable

MeS

Me

OO

sulfoneMe

SMe

O

sulfoxide

..

MeS

Mesulfide

....

commoninorganicsulfurreagents

commonsulfurfunctionalgroups

Na+

..

..-:

Sulfoxides and Sulfones

■ The 3p orbitals are too large to overlap effectively with 2p orbitals on oxygen or carbon. There is little pi character in the S-O bonds of dimethylsulfoxide and dimethylsulfone.It is common to draw S=O bonds in organosulfur compounds, particularly for sulfones, which look odd with a +2 charge on sulfur. The best depiction should place a single bond between oxygen and sulfur and a negative charge on the oxygens.

Clark, T.; Murray, J.; Lane, P.; Politzer, P.J. Mol. Model. 2008, 14, 689.

■ Ignore the positive charge on sulfur. A sulfoxide is nothing like a carbocation; the LUMO resembles σs-c*.

OSH3C

H3C..

OSH3C

H3CO

SH3CH3C

....

dimethyl sulfide dimethyl sulfoxide dimethyl sulfone

O -SH3C

H3C..

O -SH3C

H3CO -+

+2 bestdepiction

easiest to draw

CH3

SH3C -O

..+

most of the positive chargeis on Hs

Nu..

The LUMOis high in energyand anti to S-C bonds

CSH3C

O -

..+

H HH

-B δ+ δ+

δ+:

HF/6-31G(d)

973O O

>99<1

SS

991

SSO O

7822

SSO O

7030

O O

Is "S=O" just like C=O?

■ The fact that there is very little pi character in the S-O bonds of sulfoxides and sulfones should suggest that there will be very little pi character between sulfur and carbon. While enones, ethers, and thioethers want to be conjugated, sulfoxides and sulfones do not.

Bakos, V. Coll. Czech. Chem. Comm. 1978, 43, 2619.

Sulfur L.P. as Nucleophiles: Oxidation of Sulfur

■ Sulfur lone pairs on thioethers (RSR) are more nucleophilic than sulfur lone pairs on sulfoxides (RSOR). That means you can stop oxidation of sulfides at sulfoxides without over-oxidizing to sulfones.

■ Thioether oxidation is faster than epoxidation

Yeo, S.-K.; Motoo, S.; Kanematsu, K.JOC 1994, 59, 1621.

MeMe

S RCO3HMeMe

O

S RCO3HMeMe

O

O

S..

faster slower

sulfide sulfoxide sulfone

1 equiv.

....

OO

HO

R

S SO O2 equiv.

m-CPBA

0 °C, 20 min84%

Sulfur L.P. as a Nucleophile: Sulfonium and Sulfonium Ions

■ Formation of sulfonium ions

■ Sulfoxide l.p. aren’t as nucleophilic. Note the higher temperature.

sulfoniumion

sulfoxoniumion

S

Br

S+

-Br

acetone23 °CPh Ph

::

SPh

Br: S

Ph

Ph+ S

+etc+

O

SH3CH3C

IH3C

O

SH3CH3C

CH3

:

+

I-

DMSO80 °C, 24 h

Anion Stabilization By Sulfur Groups

■ Anion stabilization

G. Boche p. 353 “The Chemistry of sulphur-containing functional groups“ Eds. S. Patai; Z. Rappoport. Wiley, 1993.

■ Dithiane anions can be used as “acyl anion” equivalents.

Wilson, S. R.; et al. JACS 1980, 102, 3577.

■ The corresponding 5-membered dithiolane anions can’t be made efficiently.

O OS

20 35pKa

Li+ Li+OSH3C

H2C-

OSH3C

H2C-

OSH3C

H2C-

45 35 31pKa'

.. .. ..

S S

R H

S S

R LipKa

R = H 31R = Me 38

S SR R'

SH SH+

Bu Li IR'

R R'

O

R Li

O

can't bemade

H2O

I

R'

HgX2

SN2

SS

R

Li

Anion Stabilization By Sulfur Groups

■ C=S isn’t highly polarized. With two phenyl substituents on the thioketone the nucleophile adds to sulfur, not carbon, to generate a carbanion.

Beak, P. J. Am. Chem. Soc. 1972, 94, 597

S

PhPh

S

PhPh

n-BuHS

PhPh

n-Bu

Li

LiBu

workup

Reaction of Sulfoxide Oxygens

■ Sulfoxide S=O is much more basic than a ketone C=O

Scorrano, G.Acc. Chem. Res. 1973, 6, 132

■ Contrast the nucleophilicity of sulfur and oxygen in a sulfoxide. The oxygen has a lot of negative charge and reacts more rapidly than sulfur with “hard” electropositive electrophiles. The HOMO is larger on sulfur. “Soft” electrophiles with low-lying LUMOs and little positive charge react fastest on sulfur.

MeMe

O

S ..

pKa -7.2

OH+ O

OEt

H+

-6.5

OS

H+

-1.8

~100,000xmore basicthan C=O

MeMe

O

S .... H A+ charge

LUMO

,O

Cl

H3C I

, SiMe3XNa+,

Reaction of Sulfoxide Oxygens

■ Pummerer reaction

Pummerer Review: Org. React. 1991, 40, 157. Johnson, C. R. TL 1967, 52, 5299.

■ The elimination step is often depicted as a concerted E2 process.There is no mechanistic evidence, but I would accept it.

B

SPh

O

..

O

O

O+

R SPh

OAc

..+

pyridine

R SPh

..+

H

SPh

OAc

-+

AcO-

:

:

:

H

R SPh

OAc

..+..-

pKa < 18ylide

B

R SPh

OAc

..+

:H

Substitution of Sulfur Substituents: Attack at Sulfonyl Groups

■ Contrast the electrophilicity and mechanisms for substitution

■ SLOW attack at RSO2X sulfur:that’s why tosylate and mesylate are good L.G. for SN2.

sulfenyl chloride sulfinyl chloride sulfonyl chloride

FunctionalGroup

Reactivity

SubstitutionMechanism

(also two-stepfor PhSO2Cl)

■ Note the peculiar reactivityof sulfuryl chloride ( SO2Cl2) which is not at all like thionyl chloride (SOCl2).

OSPh

Cl

OSPh

ClO

SPhCl

> >

R S

Nu

Clconcerted SN2

..

.. ..

vs....

..R S

Nu

Cl..

.. OR S

O -Nu

Cl..

sulfuraneintermediate

addition-elimination

..

OS

Ar

OO Nu Nu

SLOW

ClSCl

O O Nu SO O.. Cl NuCl-

:

:

Substitution of Sulfur Substituents: Attack at Sulfonyl Groups

■ Contrast the differing mechanisms for sulfonylation under the two most typical conditions: TsCl/pyridine vs. MsCl/Et3N

King, J. F. Acc. Chem. Res. 1975, 8, 10.Gordon, I. M.; Maskill, H.; Fuasse, M.-F. Chem. Soc. Rev. 1989, 18, 123.

SAr

Cl O

OROH..

Cl

SArOO -

OHR +

SAr O

OO

R

ROH SCH2

ClO

OS

CH2

O

O

HOR..MsO-R

sulfene

TsClpyridine

MsClEt3N

HR3N:

SCH2

ORO

O

H +

..-

Substitution of Sulfur Substituents: Fast Attack at Divalent Sulfur

■ Phosphines also rapidly attack disulfides through SN2 reactions. Note the difference in names: cystine disulfide vs cysteine thiol

Whitesides, G. M.; Lilburn, J. E.; Szajewski, R. P. JOC 1977, 332Overman, L. E.; Matzinger, D.; O'Connor, E. M.; Overman, J.D. JACS 1974, 96, 608.Bachrach, S. M.; Gailbreath, B. D. JOC 2001, 66, 2005.

■ Disulfides exchange very rapidly through SN2 under physiological conditions.

SHHO

S -HO

ArS SAr SHO S

Ar + -SArfast

pKa 9.6..

S S

Cystine

Cystine

R3P: S -S

Cystine

CysteineR3P+

H2O

R3P=O

Substitution of Sulfur Substituents: Fast Attack at Divalent Sulfur

■ Sulfenylating reagents lead to episulfonium ion intermediates. Heat reverses the reaction.RSOCl and RSO2Cl don’t react with alkenes.

Hopkins, P.; Fuchs, P. JOC 1978, 43, 1208

■ Sulfenic acids are unstable and react with each other. Note that SN2 reactions at divalent sulfur are so fast that you don’t even need a good leaving group.

SR

OH

SR

O

SRS

R

OH: + H2O

SPh

ClSPh+

..

episulfonium ion anti addn

Cl-

SPh

Cl..PhS-Cl

Substitution of Sulfur Substituents: Exchange via Sulfuranes

■ Think of SF4 as a model for all S(IV) sulfurane intermediates; it’s trigonal bipyramidal. Sulfuranes undergo substitution through a dissociative SN1 substitution mechanism via sulfonium intermediates.

SF4 = F SF

F

F

:gas

Ph SPh

OC(CF3)2Ph

:=

OC(CF3)2Ph

Martin'ssulfurane

ClX

+

..Cl-

H3C SH3C

Cl

Cl

:H3CSH3C

Cl

:H3C

SH3C :..

sulfonium

Elimination from Sulfonium Ylides

■ The Corey-Kim oxidation is not a common procedure, but it helps one to understand more common oxidation recipes like the Swern oxidation.

JACS 1972, 94, 7586.TL 1974, 287.

CH3S

H3CClN

O

O

H3CS

H3CCl+ N

O

O-78 °CCH2Cl2

ROH

H3CS

CH2

O+

H

H3CS

CH2

O

+

H..

H3CS

H3CN+

O

O

Cl-

-

..

..

:-

Nu..

HB:

CH3S

H3C

O

retro-ene

ylide

Swern Oxidation: Mild Access to Chlorosulfonium

■ The Swern oxidation generates the same type of chlorosulfonium intermediate used as the Corey-Kim oxidation, but starts from readily available DMSO.

Tidwell, T. T. Org. React. 1990, 39, 297-572Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651

chlorosulfoniumion

CH3S

CH3

OO

Cl O

CH3SCH3

OO

Cl O

Cl-

+

Cl

. :

H3CS

CH3

OO

Cl

ClO

+:

H3CS

CH3

ClRCH2OH

Et3N+

-78 °CCH2Cl2

..

-CO2-CO

X--

+

.

..

..

H3CS

CH2

O+

H

R H

H3CS

CH2

O

+

H

R H

..-

HB:

CH3S

H3C

O H

R

retro-ene

ylide

Sulfonium Ylides Make Epoxides

■ Sulfoxonium ions and sulfonium ions are easily deprotonated.

■ Sulfonium ylides react with aldehydes and ketones to give epoxides.

Rosenberger, M.; et al.Helv. Chim. Acta 1980, 63, 1665.

SH3C CH2

H3C

O

SH3CH3C

CH2 ..+

-

..

-..

• more neg. charge• more reactive

pKa 18CH3S

CH3H3C+

..

O

SH3CH3C

CH3

+pKa <18Cl

SCH3H3C

+..

pKa 18.2(AcO)

sulfoxonium ylide sulfonium ylide

S CH3H2CCH3

..

+-O

DMSO0-25 °C, 2 h

.. -O SMe2 O+

+ SMe2

..

Sulfoxonium Ylides

■ Sulfoxonium ylides add reversibly to the C=O of enones. Eventually, you get 1,4 addition to form cyclopropanes.

Todoroki, Y.; et al. Tetrahedron 1996, 52, 8081.

OS CH3

CH3

+

-

DMSO80 °C, 2 h

O

O O

-O SMe2

O

+

O -

SMe2

O

+

slow

O

+

:

O O O O

..reallyslow

:

OSMeMe ..

O

H

H H

drospirenone O

O