Download - ALCOHOLS Dr. Sheppard CHEM 2412 Fall 2014 McMurry (8 th ed.) sections 10.5-6, 17.2-8, 17.11
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ALCOHOLS
Dr. Sheppard
CHEM 2412
Fall 2014
McMurry (8th ed.) sections 10.5-6, 17.2-8, 17.11
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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
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Structure of Alcohols• Hybridization of C?• Bond angle around C?• Hybridization of O?
• Classification as primary, secondary, or tertiary:
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Spectroscopy of Alcohols: IR• IR absorptions at 1050 cm-1 and 3300-3600 cm-1
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Spectroscopy of Alcohols: NMR• Atoms bonded to O are deshielded• 13C-NMR:
• 1H-NMR: singlet at d2.5-5.0
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Spectroscopy of Alcohols: MS• M+ usually small or absent• M-18 comes from loss of water• Ex: 1-butanol
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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
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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
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• 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
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Which molecule in each pair has the higher boiling point?
a)
b)
c)
d)
HO
OH OH
CH3CH2OH CH3CH2CH3
CH3CH2OH CH3CH2CH2OH
OH OH
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Acidity/Basicity of Alcohols• Alcohols are weak bases and weak acids• As a base:
• A strong acid is needed to protonate a neutral alcohol
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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
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Acidity of Alcohols
• For example, compare CH3O- and (CH3)3CO-
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Acidity of Alcohols• Inductive effect:
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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
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Chemistry of Alcohols
I. Preparation of Alcohols
II. Reactions of Alcohols
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Preparation of Alcohols• From alkyl halides• SN2 reaction (competes with E2)
R X HO R + XHO
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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)
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Preparation of Alcohols• From alkenes
4. Hydroxylation (yields glycol)
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Preparation of Alcohols• From carbonyl compounds
1. Reduction
2. Grignard reaction
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Reduction of Carbonyls
• Type of alcohol formed depends on carbonyl
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Reduction of Carbonyls• Reducing agent [H] = metal hydride• Hydride (H:-)
• From NaBH4 or LiAlH4
• Mechanism:
• H3O+ as a second step to form alcohol
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Reduction of Carbonyls
• Sodium borohydride (NaBH4)• Selectively reduce aldehydes and ketones• Conditions: H2O or aqueous MeOH or EtOH
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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!)
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Reduction of Carbonyls
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Draw the product of this reduction.
O
O O
1. LAH, THF
2. H3O+
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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
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Summary of Reducing Agents
Functional Group
NaBH4 LiAlH4
H2
Raney NiH2
Pt, Pd, Ni
Aldehyde
Ketone
Carboxylic acid
Ester
C=C, C≡C
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What methods can be used to synthesize a primary alcohol?
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What starting materials/reagents could be used to synthesize 4-methyl-2-penten-1-ol?
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Preparation of Alcohols• From carbonyl compounds
1. Reduction
2. Grignard reaction
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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!
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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)
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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
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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
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Grignard Reaction Product• Alcohol produced depends on type of carbonyl reacting• Formaldehyde:
• Aldehyde:
• Ketone:
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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
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Grignard Reaction Product
Carbonyl Alcohol
Formaldehyde 1°
Aldehyde 2°
Ketone 3°
Ester/acid chloride 3°
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Show how the following compound can be synthesized from an acid chloride using the Grignard reaction.
OHCH3
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How can 2-phenyl-2-butanol be synthesized using the Grignard reaction?
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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
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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
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Grignard Reaction with Protecting Groups
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Chemistry of Alcohols
I. Preparation of Alcohols
II. Reactions of Alcohols
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II. Reactions of Alcohols
A. Oxidation
B. Formation of alkyl halides
C. Formation of tosylates
D. Dehydration
E. Formation of esters
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A. Oxidation• Gain of O, loss of H, or both
• Degree of oxidation depends on reagents
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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
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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
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Oxidation with KMnO4
• Same results as chromic acid• Less expensive• Better for the environment
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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
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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°)
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Reaction with SOCl2 or PBr3
• Reaction mechanisms are SN2• Inversion of configuration
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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
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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
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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
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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
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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
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Synthesis Problem• Propose a synthesis for 3-pentanone from ethanol. You
may use any other organic molecule(s) as a source of carbon atoms.
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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
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OH
SOCl2
OH
OO
1. NaBH4
2. H3O+
OH
OO
1. LiAlH4
2. H3O+
CH2OH
PCC
CH2Cl2
OH
H2SO4
Na2Cr2O7
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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
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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
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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