Alcohols, phenols, and ethers

R = alkyl group (substituted or unsubstituted) Structure R-OH alcohol R = alkyl group (substituted or unsubstituted)

Nomenclature of alcohols 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. 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. 5-phenyl-2-hexanol

Nomenclature of alcohols CH3CH=CHCH2CH2OH 3-penten-1-ol 2-phenylethanol trans-3-fluorocyclohexanol

Nomenclature of alcohols 2-hydroxypropanoic acid

Nomenclature of alcohols 3-hexanol?

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

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, C2H5, CH3, 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: The sequence is therefore -OH, -CHO, -CH2OH, -H.

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: R 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).

Step 2 (S) If the direction is counterclockwise, the enantiomer is designated (S). 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).

R or S?

Nomenclature of alcohols 3-bromo-3-chloro-2-methyl-2-propen-1-ol?

E-Z designations (Z)- 3-bromo-3-chloro-2-methyl-2-propen-1-ol use the Cahn-Ingold-Prelog system to assign priorities to the two groups on each carbon of the double bond. 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).

E-Z designations

Sterols - the steroid ring system

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

Solubility of alcohols Low molecular weight alcohols are water soluble:

Spectroscopic properties IR: Unassociated alcohols show a fairly sharp absorption near 3600 cm-1 due to O-H stretching. Associated alcohols (hydrogen bonded) show a broad absorption in the 3300 - 3400 cm-1 range. 1H NMR: Absorption occurs in the range  = 3.5 to 4.5. Coupling is not oberved due to rapid H - H exchange.

Fermentation Fermentation of sugar by yeast gives C2H5OH. Methanol is added to denature it.

Azeotropic mixtures 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? 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 C2H5OH (95%) and H2O (5%) - bp 78.13C H2O (7.5%), C2H5OH (18.5%) and C6H6 (74%) - bp 64.9C

Oxymercuration

Oxymercuration An anti addition via a mercurinium ion: Dissociation: Electrophilic attack: Nucleophilic opening:

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.

Hydroboration H.C. Brown and G. Zweifel, J. Am. Chem. Soc., 83, 2544 (1961)

Hydroboration syn addition no rearrangement no carbocation!

Hydroboration - the mechanism

Hydroboration - the mechanism

Hydroboration - the mechanism

Reduction of carbonyls

Reduction of carbonyls + LiAlH H H 4 O OH H /Ni 2 CH CH CH CH OH CH CH=CHCHO 3 2 2 2 3 CH=CHCHO + NaBH H 4 cinnamaldehyde

Reduction of carbonyls hydride transfer

Reduction of acids 1o alcohol

Reduction of esters

Reactivity of the carbonyl group

Nucleophilic addition

Preparation of alcohols - Grignard synthesis

Grignard synthesis primary alcohol formaldehyde aldehyde secondary alcohol

Grignard synthesis ketone tertiary alcohol primary alcohol ethylene oxide

Planning a Grignard synthesis

Limitations CH4 + Mg(OH)I Any hydrogen bonded to an electronegative element (including an acetylenic hydrogen) is sufficiently acidic to react with a Grignard reagent. CH4 + Mg(OH)I CH3MgI + H2O Grignard reagents react with O2, CO2 and with almost all organic compounds which contain multiply bonded C-O or C-N units.

Reactions of alcohols The reactions of alcohols involve one of two processes: breaking of the O-H bond breaking of the C-O bond

Reactions involving O-H bond breaking R-OH + M RO- + M+ + 1/2 H2

Phenols Ka ~ 10-10

Acidity of phenols

Acidity

Substituent effects + H+ An electron attracting substituent stabilizes the conjugate base. The equilibrium is shifted to the right.

Substituent effects + H+ Electron donating substituents reduce the acidity of phenols.

Substituent effects

Reaction with hydrogen halides

Experimental facts 1. The reaction is acid catalyzed 2. Rearrangements are possible 3. Alcohol reactivity is 3o > 2o > 1o < CH3OH

The mechanism

Reaction of primary alcohols with HX SN2 This reflects nucleophile strength in a protic solvent.

Reactions with phosphorus halides and with thionyl chloride ROH + PX3 RX + H3PO3 Creates a good leaving group from 1o and 2o alcohols.

Tosylates

Why form tosylates? Sulfonate ions are excellent leaving groups:

Dehydration

Dehydration E1 mechanism

Oxidation of primary alcohols C5H5NHCrO3Cl - pyridinium chlorochromate in CH2Cl2 - PCC

Oxidation of secondary alcohols 3-cholestanol 3-cholestanone

Synthesis of alcohols

Synthesis of alcohols

Alcohols in synthesis Problems: carbocations form and rearrangements can occur in the E1 reaction Problems: carbocations form and rearrangements can occur in the SN1 reaction. HX alcohol alkyl halide SN2 reaction - no rearrangements E2 reaction - no rearrangements

Synthesis of 3-methyl-1-butene

Synthesis of 3-methyl-1-butene

Synthesis of 3-methyl-1-butene SN2 E2

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. CH3CH2OCH2CH3 - diethyl ether

Nomenclature of ethers diphenyl ether CH3OCH=CH2 methyl vinyl ether isopropyl phenyl ether 3-methoxyhexane CH3CH2CH2CHCH2CH3 | OCH3

Nomenclature of cyclic ethers Use the prefix oxa- to indicate that an O replaces a CH2 in the ring. oxacyclopropane ethylene oxide oxacyclopentane tetrahydrofuran 1,4-dioxacyclohexane 1,4-dioxane

Williamson synthesis A primary halide is necessary to ensure an SN2 reaction and not an E2 elimination.

Reaction of ethers What is the mechanism?

Epoxides syn addition

Mechanism

Reactions What is the mechanism?

Problems Solomons and Fryhle, 11.26, 11.27, 11.30, 11.33, 11.36, 11.46, 12.11, 12.12, 12.14, 12.16, 12.17, and 12.20