alcohols dr. sheppard chem 2412 fall 2014 mcmurry (8 th ed.) sections 10.5-6, 17.2-8, 17.11

ALCOHOLS

Dr. Sheppard

CHEM 2412

Fall 2014

McMurry (8th ed.) sections 10.5-6, 17.2-8, 17.11

Alcohols• Important in synthesis

• Easily converted to or prepared from other functional groups

• Used as solvents • Especially low molecular weight alcohols

• Types of alcohols:

• Phenols and enols have different reactivity from alcohols

Structure of Alcohols• Hybridization of C?• Bond angle around C?• Hybridization of O?

• Classification as primary, secondary, or tertiary:

Spectroscopy of Alcohols: IR• IR absorptions at 1050 cm-1 and 3300-3600 cm-1

Spectroscopy of Alcohols: NMR• Atoms bonded to O are deshielded• 13C-NMR:

• 1H-NMR: singlet at d2.5-5.0

Spectroscopy of Alcohols: MS• M+ usually small or absent• M-18 comes from loss of water• Ex: 1-butanol

Naming Alcohols (Review)• Acyclic alcohols

1. Parent chain is longest chain containing C bonded to –OH

2. Change suffix from “-e” to “-ol”

3. Number from end closest to –OH• Show location of –OH

4. Name/number substituents

• Cyclic alcohols1. Ring is the parent

2. Number ring so –OH is at carbon 1 and other substituents have lowest possible numbers• You do not need to show the location of the –OH

3. Name/number substituents

Naming Alcohols (Review)• Multiple hydroxyl groups

1. Two –OH groups is a diol; 3 is a triol

2. Two adjacent –OH groups is a glycol

3. Name as acyclic alcohols, except keep the “-e” suffix and add “-diol”

4. Indicate numbers for all –OH groups

• Unsaturated alcohols (enol or ynol)1. Parent chain contains carbon bonded to –OH and both carbons of

C=C or C≡C

2. Suffix is “-ol”, infix is “-en-” or “-yn-”

3. Number chain so –OH has the lowest number

4. Show numbers for –OH and the unsaturation

5. Name/number substituents

• Alcohols are polar• Intermolecular forces

• Dipole-dipole and hydrogen bonding

• Boiling points • High; increase with number of carbons; decrease with branching

• Solubility• Low MW soluble in water; decreases as MW increases

Physical Properties of Alcohols

Which molecule in each pair has the higher boiling point?

a)

b)

c)

d)

HO

OH OH

CH3CH2OH CH3CH2CH3

CH3CH2OH CH3CH2CH2OH

OH OH

Acidity/Basicity of Alcohols• Alcohols are weak bases and weak acids• As a base:

• A strong acid is needed to protonate a neutral alcohol

Acidity/Basicity of Alcohols• As an acid:

• A strong base (alkoxide ion) is formed• Methoxide, ethoxide, tert-butoxide, etc.

• Alcohols that are stronger acids yield anions that are more stable or can be more easily solvated

Acidity of Alcohols

• For example, compare CH3O- and (CH3)3CO-

Acidity of Alcohols• Inductive effect:

Acidity of Phenols• More acidic than alcohols

• Phenol pKa = 9.89

• Resonance-stabilized anion

• Electron-withdrawing groups make phenols more acidic• Ex: p-nitrophenol pKa = 7.15

• Electron-donating groups make phenols less acidic• Ex: p-aminophenol pKa = 10.46

Chemistry of Alcohols

I. Preparation of Alcohols

II. Reactions of Alcohols

Preparation of Alcohols• From alkyl halides• SN2 reaction (competes with E2)

R X HO R + XHO

Preparation of Alcohols• From alkenes

1. Acid-catalyzed hydration (Markovnikov, can rearrange)

2. Oxymercuration-reduction (Markovnikov, no rearrangement)

3. Hydroboration-oxidation (anti-Markovnikov, no rearrangement)

Preparation of Alcohols• From alkenes

4. Hydroxylation (yields glycol)

Preparation of Alcohols• From carbonyl compounds

1. Reduction

2. Grignard reaction

Reduction of Carbonyls

• Type of alcohol formed depends on carbonyl

Reduction of Carbonyls• Reducing agent [H] = metal hydride• Hydride (H:-)

• From NaBH4 or LiAlH4

• Mechanism:

• H3O+ as a second step to form alcohol

Reduction of Carbonyls

• Sodium borohydride (NaBH4)• Selectively reduce aldehydes and ketones• Conditions: H2O or aqueous MeOH or EtOH

Reduction of Carbonyls

• Lithium aluminum hydride (LiAlH4 or LAH)• Stronger reducing agent than NaBH4

• Reduces aldehydes and ketones

• Also reduces carboxylic acids and esters (to primary alcohols)

• Conditions: aprotic solvent (ether or THF)• LAH + H2O → H2 (boom!)

Reduction of Carbonyls

Draw the product of this reduction.

O

O O

1. LAH, THF

2. H3O+

Reduction of Carbonyls• In addition to metal hydrides, carbonyls can be reduced

with H2

• This reagent is not mentioned in McMurry!• Catalyst = Raney nickel• Reduce aldehydes and ketones only• Will also reduce double bonds and triple bonds

O

Raney Ni

H2

OH

Summary of Reducing Agents

Functional Group

NaBH4 LiAlH4

H2

Raney NiH2

Pt, Pd, Ni

Aldehyde

Ketone

Carboxylic acid

Ester

C=C, C≡C

What methods can be used to synthesize a primary alcohol?

What starting materials/reagents could be used to synthesize 4-methyl-2-penten-1-ol?

Preparation of Alcohols• From carbonyl compounds

1. Reduction

2. Grignard reaction

The Grignard Reaction• Carbonyl + Grignard reagent → Alcohol

• Carbonyl = aldehyde, ketone, ester, or acid chloride• Grignard reagent = an organometallic reagent (R-Mg-X)• Alcohol = 1°, 2°, or 3° depending on carbonyl

• This is a C-C bond making reaction!

Formation of Grignard Reagent

• R cannot contain acidic hydrogens• Mg oxidized from Mg0 to Mg2+

• Reagents form on metal surface; solvated by ether (Et2O)

• Radical mechanism

(slow)

Reactivity of Grignard Reagent• C-Mg is a polar covalent bond with partial ionic character

• d- makes C nucleophilic (~carbanion)• Will react with d+ of a carbonyl

• Carbon is also basic• Will react with acidic hydrogens

Grignard Reaction Mechanism

1. Nucleophilic Grignard reagent attacks electrophilic carbonyl; new bond formed between R of RMgX and C of C=O

2. Alkoxide ion (a strong base) reacts with acid (usually HCl/H2O or H3O+) to produce alcohol

Grignard Reaction Product• Alcohol produced depends on type of carbonyl reacting• Formaldehyde:

• Aldehyde:

• Ketone:

Grignard with Esters/Acid Chlorides

• Esters and acid chlorides react with TWO equivalents of Grignard reagent1. Ester/acid chloride → ketone

2. Ketone → tertiary alcohol

• Mechanism:

• Product = tertiary alcohol; two alkyl groups are the same

Grignard Reaction Product

Carbonyl Alcohol

Formaldehyde 1°

Aldehyde 2°

Ketone 3°

Ester/acid chloride 3°

Show how the following compound can be synthesized from an acid chloride using the Grignard reaction.

OHCH3

How can 2-phenyl-2-butanol be synthesized using the Grignard reaction?

Grignard Reaction Limitations• Grignard reagents cannot react with or be formed from

any molecule containing an acidic hydrogen• O-H, N-H, S-H, -C≡C-H• RMgX will pick up acidic H and “kill” the reagent

• To allow the reaction to occur even with an -OH present in the starting material, we must “protect” the alcohol

Protection of Alcohols• Three-step process

1. Introduce protecting group

2. Carry out reaction

3. Remove protecting group

• Protecting group is chlorotrimethylsilane (TMS-Cl)• Nitrogen base promotes reaction

• SN2-like reaction is allowed with tertiary Si• Less sterically crowded due to longer bonds

Grignard Reaction with Protecting Groups

Chemistry of Alcohols

I. Preparation of Alcohols

II. Reactions of Alcohols

II. Reactions of Alcohols

A. Oxidation

B. Formation of alkyl halides

C. Formation of tosylates

D. Dehydration

E. Formation of esters

A. Oxidation• Gain of O, loss of H, or both

• Degree of oxidation depends on reagents

Oxidation with PCC• Pyridinium chlorochromate (PCC)• This reagent is not covered in McMurry!• Complex of CrO3 + pyridine + HCl

• Mild oxidizing agent• 1° alcohol → aldehyde• 2° alcohol → ketone• 3° alcohol → no reaction• Solvent = CH2Cl2

N

HO Cr Cl

O

O

OH

PCC

CH2Cl2 H

O

Oxidation with H2CrO4

• Chromic acid• Chromium trioxide or sodium dichromate in aqueous acid

• Stronger oxidizing agent• 1° alcohol → carboxylic acid (aldehyde intermediate)• 2° alcohol → ketone• 3° alcohol → no reaction

Oxidation with KMnO4

• Same results as chromic acid• Less expensive• Better for the environment

B. Formation of Alkyl Halides• Substitution reactions• If alkyl halide is tertiary, reagents are HCl or HBr (aq)• Mechanism = SN1

• Product = racemic mixture (if stereocenter is present)

• Secondary ROH can react, but requires heat and can rearrange

• Evidence of reaction = formation of second layer

Formation of Alkyl Halides• If alkyl halide is primary or secondary, reagents are

thionyl chloride (SOCl2) or phosphorous tribromide (PBr3)

• Milder conditions than HCl or HBr (better option for 2°)

Reaction with SOCl2 or PBr3

• Reaction mechanisms are SN2• Inversion of configuration

C. Formation of Tosylates• Used to convert alcohols into other functional groups• Alcohol reacts with tosyl chloride (TsCl) to make tosylate

• Tosylate ion (TosO- or TsO-) is an excellent leaving group

Formation of Tosylates• Stereochemical configuration of alcohol does not change

when the alcohol forms the tosylate• Reaction occurs at O, not at C

• If tosylate undergoes SN2 reaction, inversion of configuration will occur

Reduction of Tosylates

• Tosylates can be reduced to alkanes with LiAlH4

• Can you think of another method we can use to make an alkane from alcohol?

TsCl

pyridine

LiAlH4

H H H

OH OTs H

D. Dehydration• Formation of alkene• Reaction = E1

• Tertiary alcohols react fastest• Major product = Zaitsev

• Reagents = acid (H3O+, H2SO4 or H3PO4); D (sometimes)• Protonate -OH to create a better leaving group

E. Formation of Esters• Reaction of an alcohol with a carboxylic acid or a

carboxylic acid derivative• We will cover this later in the semester

Synthesis Problem• Propose a synthesis for 3-pentanone from ethanol. You

may use any other organic molecule(s) as a source of carbon atoms.

Draw the major organic products formed in the following reactions, clearly showing all appropriate regio- and stereochemistry.

HO

OH

OH

PBr3

TsCl

pyridine

H2SO4

H3O+

etherO

O

MgBr

excess

OH

SOCl2

OH

OO

1. NaBH4

2. H3O+

OH

OO

1. LiAlH4

2. H3O+

CH2OH

PCC

CH2Cl2

OH

H2SO4

Na2Cr2O7

Reactions of Primary Alcohols• Provide reagents for each reaction

R OH

R OH

O

R' R Cl

R Br

R OTs R Nu

3

4

5

6

1

7

CH2

R H

O

2

Reactions of Secondary Alcohols• Provide reagents for each reaction

R R

OH

R R

O

R R'R R

Cl

R R

Br

R R

OTs

R R

Nu

2

3

4

5

1

6

Reactions of Tertiary Alcohols• Provide reagents for each reaction

R OH

1

2

3

4

R R

R OTs

R R

R Nu

R R

R X

R R

R' R

R