© E.V. Blackburn, 2012 Alcohols, phenols, and ethers

© E.V. Blackburn, 2012 Structure R-OH alcohol R = alkyl group (substituted or unsubstituted)

© E.V. Blackburn, 2012 Nomenclature of alcohols The OH group has a higher priority than a multiple C- C bond, a halogen, and an alkyl group in determining the carbon chain numbering. Add the suffix ol to the name of longest, linear, carbon chain which includes the carbon bearing the OH and any double or triple C-C bond. 5-phenyl-2-hexanol

© E.V. Blackburn, 2012 Nomenclature of alcohols 3-penten-1-ol 2-phenylethanol CH 3 CH=CHCH 2 CH 2 OH trans-3-fluorocyclohexanol

© E.V. Blackburn, 2012 Nomenclature of alcohols 2-hydroxypropanoic acid

© E.V. Blackburn, 2012 Nomenclature of alcohols 3-hexanol?

© E.V. Blackburn, 2012 Cahn - Prelog - Ingold rules 1. If the 4 atoms are all different, priority is determined by atomic number. The atom of higher atomic number has the higher priority. Step 1: assign a priority to the 4 atoms or groups of atoms bonded to the stereogenic carbon:

© E.V. Blackburn, 2012 Determination of priority 2. If priority cannot be determined by (1), it is determined by a similar comparison of atoms working out from the stereogenic carbon. In the methyl group, the second atoms are H, H, H whereas in the ethyl group, they are C, H, H. The priority sequence is therefore Cl, C 2 H 5, CH 3, H.

© E.V. Blackburn, 2012 The sequence is therefore -OH, -CHO, -CH 2 OH, -H. Cahn - Prelog - Ingold rules 3. A double or triple bond to an atom, A, is considered as equivalent to two or three single bonds to A:

© E.V. Blackburn, 2012 Step 2 Arrange the molecule so that the group of lowest priority is pointing away from you and observe the arrangement of the remaining groups: If, on going from the group of highest priority to that of second priority and then to the group of third priority, we go in a clockwise direction, the enantiomer is designated (R). R

© E.V. Blackburn, 2012 Thus the complete name for one of the enantiomers of 2- chlorobutane is (S)-2-chlorobutane which is, by chance, the dextrorotatory enantiomer. There is no correlation between (+)/(-) and (R)/(S). Step 2 If the direction is counterclockwise, the enantiomer is designated (S). (S)

© E.V. Blackburn, 2012 R or S?

© E.V. Blackburn, 2012 Nomenclature of alcohols 3-bromo-3-chloro-2-methyl-2-propen-1-ol?

© E.V. Blackburn, 2012 then compare the relative positions of the groups of higher priority on these two carbons. if the two groups are on the same side, the compound has the Z configuration (zusammen, German, together). if the two groups are on opposite sides, the compound has the E configuration (entgegen, German, across). (Z)- 3-bromo-3-chloro-2-methyl-2-propen-1-ol E-Z designations use the Cahn-Ingold-Prelog system to assign priorities to the two groups on each carbon of the double bond.

© E.V. Blackburn, 2012 E-Z designations

© E.V. Blackburn, 2012 Sterols - the steroid ring system

© E.V. Blackburn, 2012 Physical properties of alcohols These differences are due to the OH group which renders a certain polarity to the molecule. The result is an important intermolecular attraction: Alcohols are noticeably less volatile; their melting points are greater and they are more water soluble than the corresponding hydrocarbons having similar molecular weights.

© E.V. Blackburn, 2012 Low molecular weight alcohols are water soluble: Solubility of alcohols

© E.V. Blackburn, 2012 Spectroscopic properties 1 H NMR: Absorption occurs in the range  = 3.5 to 4.5. Coupling is not observed due to rapid H - H exchange. IR: Associated alcohols (hydrogen bonded) show a broad absorption in the cm -1 range.

© E.V. Blackburn, 2012 Fermentation Fermentation of sugar by yeast gives C 2 H 5 OH. Methanol is added to denature it.

© E.V. Blackburn, 2012 Azeotropic mixtures No! An azeotropic mixture forms! An azeotropic mixture is one whose liquid and vapor forms have identical compositions. The mixture cannot be separated by distillation. eg C 2 H 5 OH (95%) and H 2 O (5%) - bp 78.13C H 2 O (7.5%), C 2 H 5 OH (18.5%) and C 6 H 6 (74%) - bp 64.9C The bp of ethanol is 78.3C whereas that of water is 100C (at least on Vancouver’s waterfront!). Can we separate a mixture by distillation?

© E.V. Blackburn, 2012 Oxymercuration

© E.V. Blackburn, 2012 Oxymercuration Dissociation: Electrophilic attack: Nucleophilic opening: An anti addition via a mercurinium ion:

© E.V. Blackburn, 2012 Oxymercuration Why do we observe Markovnikov addition? In the mercurinium ion, the positive charge is shared between the more substituted carbon and the mercury atom. Only a small portion of the charge resides on this carbon but it is sufficient to account for the orientation of the addition but is insufficient to allow a rearrangement to occur.

© E.V. Blackburn, 2012 Hydroboration H.C. Brown and G. Zweifel, J. Am. Chem. Soc., 83, 2544 (1961)

© E.V. Blackburn, 2012 Hydroboration syn addition no rearrangement no carbocation!

© E.V. Blackburn, 2012 Hydroboration - the mechanism

© E.V. Blackburn, 2012 Hydroboration - the mechanism

© E.V. Blackburn, 2012 Hydroboration - the mechanism

© E.V. Blackburn, 2012 Reduction of carbonyls

© E.V. Blackburn, 2012 Reduction of carbonyls

© E.V. Blackburn, 2012 Reduction of carbonyls hydride transfer

© E.V. Blackburn, 2012 Reduction of acids 1 o alcohol

© E.V. Blackburn, 2012 Reduction of esters

© E.V. Blackburn, 2012 Reactivity of the carbonyl group

© E.V. Blackburn, 2012 Nucleophilic addition

© E.V. Blackburn, 2012 Preparation of alcohols - Grignard synthesis

© E.V. Blackburn, 2012 The Grignard reagent

© E.V. Blackburn, 2012 Grignard synthesis formaldehyde primary alcohol aldehydesecondary alcohol

© E.V. Blackburn, 2012 Grignard synthesis ketonetertiary alcohol ethylene oxide primary alcohol

© E.V. Blackburn, 2012 Planning a Grignard synthesis

© E.V. Blackburn, 2012 Limitations Grignard reagents react with O 2, CO 2 and with almost all organic compounds which contain multiply bonded C-O or C-N units. Any hydrogen bonded to an electronegative element (including an acetylenic hydrogen) is sufficiently acidic to react with a Grignard reagent. CH 3 MgI + H 2 O CH 4 + Mg (OH)I

© E.V. Blackburn, 2012 Reactions of alcohols breaking of the O-H bond breaking of the C-O bond The reactions of alcohols involve one of two processes:

© E.V. Blackburn, 2012 Reactions involving O-H bond breaking R-OH + MRO - + M + + 1/2 H 2

© E.V. Blackburn, 2012 Phenols K a ~

© E.V. Blackburn, 2012 Acidity of phenols

© E.V. Blackburn, 2012 Acidity

© E.V. Blackburn, 2012 Substituent effects + H + An electron attracting substituent stabilizes the conjugate base. The equilibrium is shifted to the right.

© E.V. Blackburn, 2012 Substituent effects + H + Electron donating substituents reduce the acidity of phenols.

© E.V. Blackburn, 2012 Substituent effects

© E.V. Blackburn, 2012 Reaction with hydrogen halides

© E.V. Blackburn, 2012 Experimental facts 1. The reaction is acid catalyzed 3. Alcohol reactivity is 3 o > 2 o > 1 o < CH 3 OH 2. Rearrangements are possible

© E.V. Blackburn, 2012 The mechanism

© E.V. Blackburn, 2012 Reaction of primary alcohols with HX SN2SN2 This reflects nucleophile strength in a protic solvent.

© E.V. Blackburn, 2012 Reactions with phosphorus halides and with thionyl chloride Creates a good leaving group from 1 o and 2 o alcohols. ROH + PX 3 RX + H 3 PO 3

© E.V. Blackburn, 2012 Tosylates

© E.V. Blackburn, 2012 Why form tosylates? Sulfonate ions are excellent leaving groups:

© E.V. Blackburn, 2012 Dehydration

© E.V. Blackburn, 2012 Dehydration E1 mechanism

© E.V. Blackburn, 2012 Oxidation of primary alcohols C 5 H 5 NHCrO 3 Cl - pyridinium chlorochromate in CH 2 Cl 2 - PCC

© E.V. Blackburn, 2012 Oxidation of secondary alcohols 3-cholestanol3-cholestanone

© E.V. Blackburn, 2012 Synthesis of alcohols

© E.V. Blackburn, 2012 Synthesis of alcohols

© E.V. Blackburn, 2012 Alcohols in synthesis Problems: carbocations form and rearrangements can occur in the E1 reaction Problems: carbocations form and rearrangements can occur in the S N 1 reaction. alcohol alkyl halide HX S N 2 reaction - no rearrangements E2 reaction - no rearrangements

© E.V. Blackburn, 2012 Synthesis of 3-methyl-1- butene

© E.V. Blackburn, 2012 Synthesis of 3-methyl-1- butene

© E.V. Blackburn, 2012 Synthesis of 3-methyl-1- butene SN2SN2 E2

© E.V. Blackburn, 2012 Ethers Structure: R-O-R, Ar-O-R, or Ar-O-Ar nomenclature Name the two groups bonded to the oxygen and add the word ether. CH 3 CH 2 OCH 2 CH 3 - diethyl ether

© E.V. Blackburn, 2012 diphenyl ether CH 3 OCH=CH 2 isopropyl phenyl ether CH 3 CH 2 CH 2 CHCH 2 CH 3 | OCH 3 3-methoxyhexane Nomenclature of ethers methyl vinyl ether

© E.V. Blackburn, 2012 Nomenclature of cyclic ethers Use the prefix oxa- to indicate that an O replaces a CH 2 in the ring. oxacyclopropane ethylene oxide oxacyclopentane tetrahydrofuran 1,4-dioxacyclohexane 1,4-dioxane

© E.V. Blackburn, 2012 Williamson synthesis A primary halide is necessary to ensure an S N 2 reaction and not an E2 elimination.

© E.V. Blackburn, 2012 Reaction of ethers What is the mechanism?

© E.V. Blackburn, 2012 Epoxides syn addition

© E.V. Blackburn, 2012 Mechanism

© E.V. Blackburn, 2012 Reactions What is the mechanism?

© E.V. Blackburn, 2012