Organo-main-group chemistry 1: sulfur 46 Connections Building on: Arriving at: Looking forward to: • Conjugate addition ch10 & ch23 • Sulfur compounds have many • Main group chemistry II: B, Si, and Sn • Nucleophilic substitution at saturated oxidation states ch47 carbon ch17 • Sulfur is nucleophilic and electrophilic • Organometallic chemistry ch48 • Controlling stereochemistry ch16, • Sulfur stabilizes anions and cations • Biological chemistry ch49–ch51 ch33, & ch34 • Sulfur can be removed by reduction or • Polymerization ch52 • Oxidation ch24 oxidation • Aldol reactions ch27 • Sulfoxides can be chiral • Controlling double bond geometry • Thioacetals provide d1 reagents ch31 • Allylic sulfides are useful in synthesis • Rearrangements ch36–ch37 • Epoxides can be made from sulfonium • Radicals and carbenes ch39–ch40 ylids • Sulfur compounds are good at cationic and [2,3]-sigmatropic rearrangements • Selenium compounds resemble sulfur compounds Sulfur: an element of contradictions The first organosulfur compounds in this book were the thiol thiol P dreadful smell of the skunk and the wonderful smell of + If you look in the Oxford English SH SH the truffle, which pigs can detect through a metre of soil dictionary you will see ‘sulphur’. and which is so delightful that truffles cost more than the dreadful smell of the skunk This is a peculiarly British their weight in gold. thiol thiol spelling—neither the French nor the Americans for example have More useful sulfur compounds have included the lep- + SH SH the ‘ph’. It has recently been rosy drug dapsone (Chapter 6), the arthritis drug Feldene decided that chemists the world the dreadful smell of the skunk (Chapter 21), glutathione (Chapter 23), a scavenger of over should use a uniform oxidizing agents that protects most living things against oxidation and contains the natural amino spelling ‘sulfur’. acid cysteine (Chapter 49), and, of course, the famous antibiotics, the penicillins, mentioned in sev- eral chapters. OH O sulfone OO S N N sulfite H N S Me H2NNSO3 Na sulfonamide H O O dapsone—water-soluble ‘pro-drug’ for leprosy Pfizer's piroxicam or Feldene SH thiol H H sulfide O H R N S HO2C NCO2H N O N H NH O O 2 cysteine CO2H glutathione: scavenger of toxic oxidants penicillin family of antibiotics 1250 46 . Organo-main-group chemistry 1: sulfur Important reactions have included sulfur as nucleophile and leaving group in the SN2 reaction (illustrated here; see also Chapter 17), sulfonation of aromatic rings (Chapter 22), formation and reduction of thioacetals (Chapter 24), Lawesson’s reagent for converting carbonyl groups to thiocar- bonyl groups (Chapter 44). R thiolate anion OO OO S R S SN2 PhS O + O PhS sulfonate ester Me Me (para-toluene sulfonate) sulfide sulfonate salt This chapter gathers together the principles behind these examples together with a discussion of what makes organosulfur chemistry special and also introduces new reactions. We have a lot to explain! In Chapter 31 we introduced you to the Julia olefination, a reaction whose first step is the deprotonation of a sulfone. OH PhSO SO Ph 2 2 base SO2Ph 1. RCHO RR H 2. H acidic proton sulfone stabilizes anion Why is this proton easy to remove? This ability to stabilize an adjacent anion is a property shared by all of the most important sulfur-based functional groups. The anions (or better, lithium deriva- tives) will react with a variety of electrophiles and here is a selection: a sulfone reacting with a lactone, a sulfoxide with a ketone, and a sulfide with a silyl chloride. sulfones H H O O O O BuLi Me S S Li + O S Me Me Me OO O O 70% yield OH sulfoxides O OH O BuLi O Ph S S S Li + Ph Me Ph O sulfides BuLi Me3SiCl S S Li S SiMe3 Ph MePh Ph You notice immediately the three main oxidation states of sulfur: S(VI), S(IV), and S(II). You might have expected the S(VI) sulfone and perhaps the S(IV) sulfoxide to stabilize an adjacent anion, but the S(II) sulfide? We will discuss this along with many other unusual features of sulfur chemistry. The interesting aspects are what make sulfur different. The basic facts about sulfur Sulfur in the periodic table Sulfur is a p-block element in group VI (or 16 if you prefer) immediately below oxygen and between (electronegativity) phosphorus and chlorine. It is natural for us to compare sulfur with oxygen but we will, strangely, compare it with carbon as well. CNOF –1 Sulfur is much less electronegative than oxygen; in fact, it Bond strengths, kJ mol (2.5) (3.0) (3.5) (4.0) has the same electronegativity as carbon, so it is no good try- X = C X = H X = F X = S Si P S Cl ing to use the polarization of the C–S bond to explain any- C–X 376 418 452 362 thing! It forms reasonably strong bonds to carbon—strong (1.8) (2.1) (2.5) (3.0) S–X 362 349 384 301 enough for the compounds to be stable but weak enough for Sulfur: an element of contradictions 1251 S S selective cleavage in the presence of the much stronger C–O bonds. It also forms strong bonds to S S itself. Elemental crystalline yellow sulfur consists of S8 molecules—eight-membered rings of sulfur S S S S atoms! crystalline sulfur Because sulfur is in the second row of the periodic table it forms many types of compounds not available to oxygen. Compounds with S–S and S–halogen bonds are quite stable and can be isolated, unlike the unstable and often explosive O–halogen and O–O compounds. Sulfur has d orbitals so it can have oxidation states of 2, 4, or 6 and coordination numbers from 0 to 7. Here is a selection of compounds. Compounds of sulfur Oxidation state S(II) S(IV) S(VI) coordination number 0 1 2 3 4 4 6 7 2– – – example S RS R2SR2S=O SF4 R2SO2 SF6 SF7 Sulfur is a very versatile element As well as this variety of oxidation states, sulfur shows a sometimes surprising versatility in function. Simple S(II) compounds are good nucleophiles as you would expect from the high-energy nonbond- ing lone pairs (3sp3 rather than the 2sp3 of oxygen). A mixture of a thiol (RSH, the sulfur equivalent of an alcohol) and NaOH reacts with an alkyl halide to give the sulfide alone by nucleophilic attack of RS–. O SH O NaOH S + Br OMe OMe Thiols (RSH) are more acidic than alcohols so the first step is a rapid proton exchange between the thiol and hydroxide ion. The thiolate anion then carries out a very efficient SN2 displacement on the alkyl bromide to give the sulfide. Br O SH S O S 2 S NaOH N OMe OMe Notice that the thiolate anion does not attack the carbonyl group. Small basic oxyanions have high charge density and low-energy filled orbitals—they are hard nucleophiles that prefer to attack protons and carbonyl groups. Large, less basic thiolate anions have high-energy filled orbitals and are soft nucleophiles. They prefer to attack saturated carbon atoms. Thiols and thiolates are good soft nucleophiles. •Thiols (RSH) are more acidic than alcohols (ROH) but sulfur compounds are better nucleophiles than oxygen compounds towards saturated carbon atoms (SN2). They are also good soft electrophiles. Sulfenyl chlorides (RSCl) are easily made from disulfides (RS–SR) and sulfuryl chloride (SO2Cl2). This S(VI) chloride has electrophilic chlorine atoms and is attacked by the nucleophilic disulfide to give two molecules of RSCl and gaseous SO2. There’s a lot of sulfur chemistry here! We start with a nucleophilic attack by one sulfur atom of the disulfide. 1252 46 . Organo-main-group chemistry 1: sulfur sulfuryl OO chloride S O O Cl Cl S Cl + SO + Cl Cl 2 R S R S S R S R disulfide sulfonium salt The intermediate contains a tricoordinate sulfur cation or sulfonium salt. The chloride ion now attacks the other sulfur atom of this intermedi- Cl Cl ate and two molecules of RSCl result. Each R S R + S atom of the original disulfide has formed an S R S R S–Cl bond. One sulfur atom was a nucleophile Cl towards chlorine and the other an electrophile. Cl The product of this reaction, the sulfenyl chloride, is also a good soft electrophile towards carbon atoms, particularly towards alkenes. The reaction is very like bromination with a three-membered cyclic sulfonium ion intermediate replacing the bromonium ion of Chapter 20. The reaction is stereo- specific and anti. Cl Cl Cl S SR R SR cyclic sulfonium salt Sulfur at the S(II) oxidation state is both a good nucleophile and a good electrophile. This is also true at higher oxidation states though the compounds become harder electrophiles as the positive charge on sulfur increases. We have already mentioned tosyl (toluene-para-sulfonyl) chloride as an electrophile for alkoxide ions in this chapter and in earlier chapters. At this higher oxidation state it might seem unlikely that sulfur could also be a good nucleophile, but consider the result of reacting TsCl with zinc metal. Zinc provides two electrons and turns the compound into an anion. This anion can also be drawn in two ways. OO O two ways of drawing O S S a sulfinate anion S Cl Zn O O Me Me Me Surprisingly, this anion is also a good soft nucleophile and attacks saturated carbon atoms through the sulfur atom. In this case attack occurs at the less substituted end of an allylic bromide to give an allylic sulfone, which we will use later on.