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Home , Sulfenyl chloride, Thioketone

Professor David L. Van Vranken Chemistry 201: Organic Reaction Mechanisms I

Topic 19: Sulfur Chemistry

R H X Nu.. R O H O H3C : S ..S S .. H3C S Cl H C + CH O CH2 3 - 2 Cl

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

O O O . S S. NaO ONa NaO ONa sodium sulfate sodium sulfite common inorganic O O O sulfur .. S - Na+ S reagents NaO S: HO ONa sodium thiosulfate sodium bisulfite

O O O ...... S S S Me OH Me OH Me OH unstable sulfinic acid common sulfur O O O functional ...... groups S S S Me Me Me Me Me Me and

■ 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 , 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.

dimethyl sulfide dimethyl sulfoxide dimethyl sulfone

.. O O easiest S . S . S H3C . H3C . H3C O to draw H3C H3C H3C Clark, T.; Murray, J.; Lane, P.; Politzer, P. J. Mol. Model. 2008, 14, 689. O - O - +2 best S .. S H3C + H3C O - depiction H3C H3C

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

+ -B: δ δ+ The LUMO H + most of the HF/6-31G(d) CH H Hδ is high in energy 3 C positive + and anti S.. . charge H3C S. to S-C bonds H3C + is on Hs -O O - .. Nu 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 3 97 pi character between sulfur and O O carbon. While enones, , and thioethers want to be conjugated, sulfoxides and sulfones do not. <1 >99 S S 1 99 O O S S 22 78 O O O O S S 30 70

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.

R O O O H 1 equiv. O O .. RCO3H RCO3H S . Me S.. Me S Me . O Me faster Me slower Me

sulfide sulfoxide sulfone ■ Thioether oxidation is faster than epoxidation

2 equiv. O O S m-CPBA S Yeo, S.-K.; Motoo, S.; Kanematsu, K. 84% JOC 1994, 59, 1621. 0 °C, 20 min Sulfur L.P. as a Nucleophile: Sulfonium and Sulfonium Ions

■ Formation of sulfonium ions

Br

-Br: Br S: S S Ph + etc + :S + S acetone Ph + Ph Ph Ph 23 °C sulfonium ion

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

O O S: I- H3C H C I S 3 H3C CH3 H3C DMSO H C + 80 °C, 24 h 3 sulfoxonium ion Anion Stabilization By Sulfur Groups

■ Anion stabilization O Li+ O Li+ H C S H C S H C S O O 3 3 3 O H2C.. H2C.. H2C.. S - - -

pKa 20 35 pKa' 45 35 31

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.

I

R Li R' R R' can't be + made O O SH SH

H2O HgX2 pK R H Li I a Bu Li R R' R R' R = H 31 S S S S S S R = Me 38 SN2

R ■ The corresponding 5-membered dithiolane anions can’t be made efficiently. S S Wilson, S. R.; et al. JACS 1980, 102, 3577. Li Anion Stabilization By Sulfur Groups

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

Bu n-Bu n-Bu workup Li S S S H Ph Ph Ph Ph Ph Ph Li

Beak, P. J. Am. Chem. Soc. 1972, 94, 597 Reaction of Sulfoxide Oxygens

■ 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.

O + + charge Na, H A Scorrano, G. .. , , X SiMe O Cl 3 Acc. Chem. Res. 1973, 6, 132 .. Me S LUMO Me H3C I

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

H H H O +O +O +O ~100,000x

.. more basic S Me S OEt than C=O Me pKa -7.2 -6.5 -1.8 Reaction of Sulfoxide Oxygens

■ Pummerer reaction

- O: O O + + S S .. Ph O Ph OAc

Ac Ac - O O AcO: + + + .. R S.. R S.. R S Ph .. Ph Ph - H H B: ylide

pKa < 18

■ The elimination step is often depicted as a concerted E2 process. Ac There is no mechanistic evidence, but I would accept it. O R +S .. Ph H Pummerer Review: Org. React. 1991, 40, 157. B: Johnson, C. R. TL 1967, 52, 5299. Substitution of Sulfur Substituents: Attack at Sulfonyl Groups

■ Contrast the electrophilicity and mechanisms for substitution

sulfinyl chloride sulfonyl chloride .. O O

Functional

.. S > S .. > S Group Ph Ph Ph O Reactivity Cl Cl Cl

concerted SN2 addition-elimination Cl Cl Cl Substitution ...... (also two-step S R S S vs for PhSO2Cl) Mechanism R .. R .O. - .. .. O Nu Nu Nu sulfurane intermediate

■ SLOW attack at RSO2X sulfur: O O :Nu Nu S that’s why tosylate and mesylate are Ar O good L.G. for S 2. N SLOW ■ Note the peculiar reactivity O O :Nu O O S Cl- S.. Cl Nu of ( SO2Cl2) which Cl Cl is not at all like thionyl chloride (SOCl2). 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

Cl Cl O O Ar O TsCl S Ar S O - S O pyridine ROH.. Ar O O O R + H R

H HOR.. + MsCl O Cl O O OR Et3N ROH S S S MsO-R O CH2 O CH2 O CH.. 2 - H sulfene R3N:

King, J. F. Acc. Chem. Res. 1975, 8, 10. Gordon, I. M.; Maskill, H.; Fuasse, M.-F. Chem. Soc. Rev. 1989, 18, 123. Substitution of Sulfur Substituents: Fast Attack at Divalent Sulfur

■ exchange very rapidly through SN2 under physiological conditions.

pKa 9.6 .. ArS SAr SH S - S Ar HO HO HO S + -SAr fast

■ Phosphines also rapidly attack disulfides through SN2 reactions. Note th e difference in names: cystine vs cysteine

Cystine Cystine

R3P: S S S -S R3P+ Cystine Cysteine H2O

R3P=O

Whitesides, G. M.; Lilburn, J. E.; Szajewski, R. P. JOC 1977, 332 Overman, 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. Substitution of Sulfur Substituents: Fast Attack at Divalent Sulfur

■ 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.

OH O R S: S R + H2O R S R S OH

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

.. Cl- Ph PhS-Cl Cl ..S Cl SPh + SPh episulfonium ion anti addn

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

F OC(CF3)2Ph F Martin's SF4 = S: = Ph S: gas F sulfurane Ph F OC(CF3)2Ph

Cl-.. H C Cl 3 : H3C S H C H C 3 : 3 S: H3C S .. + H3C Cl Cl Cl sulfonium X 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.

ylide

O Nu.. O .. ROH H3C - O H O H .. : N Cl S +S Cl N + S S .. H C CH H C CH H C + CH 3 3 H3C -78 °C 3 2 3 - 2 O O CH Cl H 2 2 retro- B: ene O Cl- H3C O +S N H3C S O H3C CH3

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

chlorosulfonium ylide ion RCH OH R H R H - Cl 2 Et N O: O Cl X- 3 O H O H + + +S + .. S.. O .. -78 °C S S H3C CH3 H3C CH3 H3C CH2 H3C + CH2 Cl CH Cl - 2 2 H retro- B: -CO2 ene -CO R O H Cl O Cl O S O O O O H3C CH3 + CH3 ..S CH3 : S CH CH3 .. 3 Cl Cl-

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

■ Sulfoxonium ions and sulfonium ions are easily deprotonated.

(AcO) O pK <18 pKa 18.2 CH3 pKa 18 Cl a + + + S S S H3C .. .. CH3 H3C CH3 H3C CH3 H3C O .. • more neg. charge S + S • more reactive H3C H C CH.. 2 3 CH.. 2 H3C - H3C - sulfoxonium ylide sulfonium ylide

■ Sulfonium ylides react with and to give epoxides.

.. + O - S .. CH -O SMe2 O H2C.. 3 + CH3 Rosenberger, M.; et al. DMSO Helv. Chim. Acta 1980, 63, 1665. 0-25 °C, 2 h + SMe2 Sulfoxonium Ylides

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

O O + O S .. CH3 -O SMe2 really : + - CH3 slow

DMSO O O 80 °C, 2 h

slow

:O - O O O + O drospirenone O SMe 2 S + Me .. Me O O O O H H H O

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