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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