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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