Chapter 9: More Reactions of Alcohols

deprotonation of ROH yields

RO- (alkoxide)

• requires a base much stronger than RO-

  • the reaction will go in one direction to form RO-, since the conjugate acid to the strong base is very weak, thus equilibrium is favored to the right

  • strong bases include LDA, butyllithium, and KOH

alkali metals

deprotonate alcohols (strong nucleophiles and strong bases causes reduction)

• works by reduction of H+ to form H-H (H2 gas)

  • water yields hydroxide (OH-) and H2

  • alcohols yield alkoxide (RO-) and H2

reactivity of alcohols with alkali metals tracks with

sterics

• ROH reactivity: H > CH3 > 1° > 2° > 3°, where H is most reactive and 3° is least reactive

alcohols as bases

ROH + H+ yields ROH2+ (oxonium)

• this turns a very bad leaving group (-OH from ROH) to a very good leaving group (H2O from ROH2+)

  • H2O is a very weak base and is stable on its own, thus it is a good leaving group

1° alcohols can undergo 

substitution reactions with H-X

• where X is Br or I

• mechanism: the OH of ROH attacks the H atom of H-X to become protonated to ROH2+, then the X- atom attacks the electrophilic C atom, and the OH2+ group is cleaved to form the substitution product

• HCl does not work well for substitution, since Cl- is not sufficiently nucleophilic to attack the electrophilic C atom

2° and 3° ROH can undergo 

SN1/E1 under acidic conditions due to carbocation stability of the more hindered substrate

• mechanism: the O of the OH group attacks the H atom of H-X, forming the OH2+ group, and the bond between the electrophilic C atom and OH2+ is broken to form the carbocation, then the X- atom attacks the carbocation to form the substitution product

E1 is favored with

high temperature and a strong acid with a weakly nucleophilic conjugate base

• mechanism: the OH group attacks the H atom of the strong acid to form OH2+ (the strong acid has a weakly nucleophilic conjugate base through resonance forms), then the bond between that and the electrophilic C atom is broken to form the carbocation, then H2O attacks an adjacent H atom and the e- are pushed to form the alkene double bond

substitution with HBr forms

2 molecules (RBr, H2O) from 2 starting materials (ROH, HBr)

elimination with H2SO4 forms

3 molecules (alkene, H3O+, -OSO3H) from 2 starting materials (ROH, H2SO4)

high temperature favors

E1 due to entropic considerations

• at high temperature, a favorable entropy dominates to make the overall free energy of the reaction favorable and negative, thus more disorder favors E1

carbocation rearrangements occur

quickly before the reaction proceeds to form a more stable carbocation

• shifts occur from the same stability or more stable carbon type in the carbocation

1,2 hydride shift

the H moves with the lone pair of e- (H-) from one C atom to the adjacent C atom to form a new carbocation of similar or greater stability

orbital picture of the 1,2 hydride shift

at the transition state, the partial positive sp2 carbon and partial positive sp3 carbon transfer the H atom between them, to reorient the H atom to form a new carbocation

the driving force for carbocation rearrangements is the

formation of the more stable carbocation

• this forms faster since less energy is required to form it as it is more stable

intramolecular rearrangements are

much faster than intermolecular rearrangements

• intramolecular forces are faster than intermolecular forcesc

carbocations of a similar stability give

product mixtures

only mechanisms involving

carbocation intermediates can have rearrangements

• ex. solvolysis can have carbocation rearrangements

1,2 alkyl shift

the alkyl group moves with its bonding e- to an adjacent C atom to form a similar or more stable carbocation

1° alcohols can rearrange by a

concerted alkyl shift

• mechanism: the OH group attacks the H atom on H-X and becomes protonated to form the good leaving group OH2+, and the e- from the alkyl group attack the electrophilic C atom and the leaving group bond is broken to form the stable carbocation and alkyl shift, and the positive C atom is then attacked by X- to form the substitution product

esters

• organic ester: R-C=O-OR’ (carboxylic ester)

  • esterification: ROH + H+

• inorganic esters: R-O=S=O-OR’ (sulfonate ester), RO-P-(OH)2 (phosphite ester)

  • ROH can be converted to RX via inorganic esters

PBr3/PI3 inorganic ester

mechanism: the OH nucleophile attacks the P and one Br atom is expelled from the inorganic ester to form the OH bonded with the PBr2/PI2, and the expelled Br-/I- atom attacks the electrophilic C atom, and the good leaving group is then expelled to form the substituted product (RBr, RI) with no rearrangements

• the minor byproduct of the inorganic ester can react two more times in an Sn2 reaction with 1° and 2° ROH

SOCl2 inorganic ester

mechanism: the OH nucleophile attacks the S and one Cl atom is expelled from the inorganic ester to form the OH bonded with the S=O-Cl, and the expelled Cl- atom attacks the electrophilic C atom, and the good leaving group is then expelled to form the substituted product (RCl) with no rearrangements

• the base can then attack the H atom of the minor byproduct, and the e- from that H-O bond are pushed between the S and O atom to form a double bond, and the Cl atom is expelled to form HB+, Cl-, and O=S=O

inorganic ester intermediates react like

R-X

• via Sn1 reactions with the formation of a carbocation

synthesis of sulfonate esters from ROH

when treated with a base, the OH group can attack the S atom and the Cl atom is expelled from the sulfonyl chloride, and then the Cl- atom reattacks the H atom, and the e- from the O-H bond are pushed onto the O atom to form the sulfonate inorganic ester (good leaving group)

ethers

R-O-R’ (O is bonded to two C atoms)

nomenclature of ethers

• alkoxy substituent for alkanes

• cyclic ethers have “oxa-” prefix

  • heteroatom is O, which replaces C or H

physical properties of ethers

• no H bond donor

  • lower boiling point than ROH (no hydrogen bonding)

  • less water soluble

• relatively unreactive

• common solvents for a variety of organic reactions

synthesis of ethers

SN2 reaction of RO-, RX

• the O- atom acts as the nucleophile to attack the electrophilic C atom of R-X, and the X atom leaving group is expelled to form the ether ROR

for ether synthesis, the

SN2 vs. E2 preferences must be considered

• with 1° substrates, SN2 occurs with RO- as a strong base

• with 2° or 3° substrates, E2 occurs with RO- as a strong base

Sn2 with alkoxide and R-X in the same molecule (cyclic ether)

oxacyclopropane (epoxide)

• mechanism: -OH deprotonates the OH group in the molecule to form O-, which then attacks the electrophilic C atom attached to the X atom which is then expelled, and this forms the cyclic ether through an intramolecular Sn2 reaction

  • faster than linear reaction

the size of the ring formed impacts the

rate of the reaction

• K3 > K5 > K6 > K4 > K7 > K8

  • Kn = the rate of forming an n-membered ring

competing factors for ring formation of cyclic ethers

• entropic: disorder, favors smaller rings due to energy dispersal (less free rotation of the bonds, thus they do not intervene when forming the ring)

• enthalpic: stability, favors more stable rings (6, 5 membered rings, since there is more strain in smaller rings due to bond angle and torsional strain)

intramolecular Sn2 reactions are

stereospecific

• there must be an anti relationship between the leaving group and nucleophile for Sn2 attack to occur, which goes with inversion through backside attack

ethers from alcohols and mineral acids

mechanism: OH is protonated by attacking the H of the acid, which forms the good leaving group OH2+, and the same alcohol then attacks the C atom and expels the leaving group OH2+ to form the ether, and is then deprotonated by H2O

• these reactions are effective for making symmetrical ethers with mineral acids and alcohols

reaction of 1° + 1° ROH requires

high temperature, but too high temperatures make E1 dominate

2° ROH react by

Sn1 via the formation of a carbocation

most attempts to unsymmetrical ethers give

mixtures, based on the starting alcohols and mineral acid

3° ROH are

selective for mixed ethers

• the favored nucleophile (ROH) will be the less sterically hindered one to attack the carbocation

reactions of ethers

• oxidations in air: ethers can react with O2 to form peroxides in which the two O atoms have been inserted between the two C atoms, which are very explosive

• cleavage with HBr and HI

  • mechanism: the O atom of the ether attacks the H atom of H-X, and the X- atom then attacks the electrophilic C atom as the good leaving group with the protonated O atom has been formed, which then forms the substituted product of R-X and ROH via Sn2

  • selectivity in unsymmetrical ethers: the X- atom will attack the less sterically hindered C atom to form the product

reactions of oxacyclopropanes

ring opening by nucleophiles

• mechanism: the nucleophile will attack the C atom adjacent to the O atom, and once the ring has been opened and the nucleophile has been added, the O- atom is protonated

• the driving force for ring opening is the release of torsional and bond angle strain to form the linear product

regioselectivity in unsymmetrical substrates

strong nucleophiles and other reagents such as hydrides and organometallics will attack the less sterically hindered side of the oxacycloalkane, thus they are regioselective

Sn2 ring opening is 

stereospecific, and goes with inversion

• ring opening is thus regioselective and stereospecific, and the stereocenter inverts from ring opening

ring opening by acids

mechanism: the O atom attacks the H atom of the acid to become protonated, and the acid then attacks the more sterically hindered side of the oxacycloalkane, and is then deprotonated once the product is formed

ring opening by acids involves an

inversion of stereochemistry and regioselectivity is switched

• the transition state involves the bond breaking between the partial positive O atom and the partial positive C atom that is more sterically hindered, and the acid attacking the C atom

• not quite Sn1, but there is carbocation character in the transition state, since the buildup of the partial positive charge is better stabilized on a more sterically hindered (3°) C atom and this is more attracted by the partial negative nucleophile

thiols, thioethers

thiols (RSH) are great nucleophiles and stronger acids than ROH

• good for Sn2 to form a thioether

• less hydrogen bonding and lower boiling point than ROH, therefore they are more acidic and polarizable

neutral thiols and thioethers are also

good nucleophiles

• the sulfonium ion can be produced, where S is the nucleophile that attacks the electrophilic C atom to form sulfonium

sulfonium ions are

excellent nucleophiles

• mechanism: the strong base -OH attacks the C atom attached to sulfonium, and the e- are pushed onto S to form the thioether