Chapter 9 Ethers, Thiols, and Sulfides Naming and Physical Properties of Ethers Nomenclature Name ethers as alkanes with an alkoxy substitutent RO- = alkoxy substitutent Choose the smallest part of the ether as the substituent Common names: name the two R groups, followed by “ether” Cyclic Ethers O group is called an “oxa-” substituent: oxacycloalkanes Common names are prevalent

Physical Properties Same molecular formula as Alcohol: CnH2n+2O No Hydrogen Bonding is possible in R—O—R Boiling Points are much lower than alcohols, more like haloalkanes Water solubility much less than alcohols MeOMe and EtOEt have some water solubility Larger ethers are insoluble, very much like alkanes Fairly unreactive, nonpolar solvents for organic reactions Metal Complexation by Crown Ethers Crown Ether is a cyclic polyether: --(CH2CH2O)— Named as: (# of total atoms in ring)-Crown-(# of oxygens) Oxygen lone pair can be donated to M+ to form complexes Allows dissolution of metal salts in organic solvents Size of cavity dictates which metal fits: 18-crown-6 K+ > Rb+ >Na+ etc…

Cryptands and Ionophores Cryptands are topologically complex polyethers Greek kryptos = hidden Even stronger metal binding than crown ethers Nobel prize for crowns/cryptands 1987 Cram, Pederson, Lehn Ionophore = biological polyethers used to transport metal ions

Williamson Ether Synthesis Alkoxides are good nucleophiles and strong bases Reaction with primary, unhindered electrophile gives SN2 Reaction with non-primary or hindered electrophiles gives E2 Cyclic Ethers from Intramolecular Reaction Intermolecular reaction is between 2 separate molecules: A + B C Intramolecular reaction is between parts of same molecule: A C Ring size effects rate: k3 > k5 > k6 > k4 > k7 > k8 Ring strain says k3 slow, Entropy makes k3 fast k4 is slow because ring strain > entropy

Other Ether Syntheses from Alcohols Intramolecular Williamson Ether Synthesis is Stereospecific Like E2 elimination, the leaving group must be anti to nucleophile Gauche leaving group won’t give product Other Ether Syntheses from Alcohols ROH plus Strong Mineral Acid Remember that ROH plus HBr gives RBr because nucleophile is present Protonation by mineral acid gives good leaving group (H2O) but does not give an interfering nucleophile

Reactions of Ethers Only makes symmetric ethers Follows SN2 for primary alcohols, SN1 for 2o and 3o alcohols Useful for making mixed 3o/1o ethers Ether Synthesis through Solvolysis of Haloalkanes or other Electrophiles Solvolysis = nucleophilic substitution by solvent Alcoholysis = solvolysis when solvent = ROH Simple SN1 conditions can give complex ethers by solvolysis Reactions of Ethers Peroxide formation Ethers open to oxygen can form expolosive peroxide compounds Never use old ethers as solvents or reactants; store ethers properly

Reactions of Oxacyclopropanes Cleavage by Strong Acid Reverse of Ether Synthesis by Strong Acid Tertiary Ethers are most reactive to cleavage Secondary Ethers can be cleaved by SN2 or SN1 Reactions of Oxacyclopropanes Nucleophilic Ring Opening Ether Oxygen behaves as an intramolecular leaving group Anionic Nucleophiles can open the oxacyclopropane ring by SN2 attack

Alkoxide usually a poor leaving group (but it doesn’t really leave here) Driving force is opening of the strained 3-membered ring For unsymmetric oxacyclopropanes, the Nu attacks at the least subst. C Regioselectivity = reaction at only one of multiple sites of a molecule B. Alcohols from Oxacyclopropanes LiAlH4 attacks epoxides, but not any other ethers Alkylmetal reagents also react with epoxides only among the ethers

Sulfur Analogues of Alcohols and Ethers Acid Catalyzed Oxacyclopropane Ring Opening Mechanism Regioselective and Stereospecific for Nu- attack at the Most Hindered C Partial C+ forms only on most hindered carbon Not a full carbocation, because we see stereospecific inversion (SN2, not SN1) Now we have tools to add Nu at most (H+, Nu) or least (Nu-) carbon of an epoxide Sulfur Analogues of Alcohols and Ethers Nomenclature R—OH = Alcohol R—SH = Thiol Name as alkanethiol CH3SH = methanethiol Name as a mercapto- substituent HSCH2CH2OH = 2-mercaptoethanol OH > SH priority

R—O—R = Ether R—S—R = Sulfide (common name = thioether) Name like common names for ethers CH3SCH2CH3 = ethyl methyl sulfide (methylthioethane) (CH3)3CSCH3 = t-butyl methyl sulfide H2S = hydrogen sulfide RS– substituent is called alkylthio RS- anion is called alkanethiolate anion: CH3CH2S- = ethanethiolate Properties of Thiols and Sulfides RSH doesn’t Hydrogen bond very well (S is too large to match H) Boiling points are lower than the analogous alcohols RS—H bond is weak, so thiols are more acidic than alcohols Reactivity of Thiols and Sulfides RS- is more nucleophilic than RO- due to larger size Synthesis of thiols and sulfides hydrosulfide

Use hydroxide to deprotonate RSH Formation of Sulfonium Ion = R3S+ as a good leaving group Valence Shell Expansion due to d orbitals is common for S compounds Oxidation of Sulfides Disulfide formation sulfonic acid