Victor Grignard (1871-1935)
To construct C-C bond, need C+ and C:-
How then do we prepare carbanion? C:-
Nobel Prize Chemistry 1912
http://nobelprize.org/chemistry/laureates/1912/grignard-bio.html
GRIGNARD REAGENTS
Limitations of alkynyl anions for C-C bond formation:
a) only proceed with 1o alkyl halides;
b) product must have alkyne functionality
RMgX
12.6 Prep of Alcohols – Grignard Reagents
• Grignard reagents react like LAH, and will attack the carbonyl
group of a ketone or an aldehyde
• The key difference – Grignard reaction give a new C-C bond!
Klein, Organic Chemistry 3e
Synthesis with Grignard Reagents
Synthesis with Grignard Reagents
Synthesis with Grignard Reagents
Mechanism of the Addition of a
Grignard Reagent
• Grignard reagents act as nucleophilic carbon anions (carbanions,
:R) in adding to a carbonyl group
• The intermediate alkoxide is then protonated to produce the alcohol
12.6 Prep of Alcohols – Grignard Reagents
• Because the Grignard is both a strong base and a strong
nucleophile, care must be taken to protect it from exposure to water
or alcohols
• Anhydrous ethers are usually used as solvents for Grignard reactions
• Consider the reaction below.
• The alcohol can act as an acid, so a Grignard reagents and alcohols are
incompatible
• The alcohol can be protected to prevent it from reacting
Klein, Organic Chemistry
3e
12.7 Protection of Alcohols
• A three-step process is required to achieve the desired overall
synthesis: (1) protect alcohol (2) perform Grignard reaction, then
(3) deprotect
Klein, Organic Chemistry 3e
12.7 Protection of Alcohols
• One such protecting group is trimethylsilyl (TMS)
• The TMS protection step requires the presence of a base to
neutralize the HCl byproduct
Klein, Organic Chemistry 3e
12.7 Protection of Alcohols
• Evidence suggests that substitution at the Si atom occurs by an SN2
mechanism
• Because Si is much larger than C, it is more open to backside
attack
Klein, Organic Chemistry 3e
12.7 Protection of Alcohols
• The TMS group can later be removed with H3O+ or F-
• TBAF is often used to supply fluoride ions
Klein, Organic Chemistry 3e
12.7 Protection of Alcohols
• The overall process is shown below:
Klein, Organic Chemistry 3e
Preparation of R-X from R-OH
1. Addition of H-X to 3o Alcohols
2. Use of SOCl2 or PBr3 for 1o and 2o Alcohols (SN2)
3. Conversion of –OH to –OTs, then SN2 with KI
Issue: Since the –OH of alcohol is a very poor leaving group it can be lost: 1) by protonating
with strong acid so that H2O is the LG; 2) conjugating –O to S or P, so that the LG with have a
O-P or O-S LG
Preparation of R-X from 3o R-OH
• Step 1: Protonation of alcohol
• Step 2: Loss of water to afford 3o carbocation
• Step 3: SN1 reaction of halide with carbocation
1° and 2° alcohols are resistant to acid catalyzed dehydration
For alcohols, H2O (CB of H3O+) must be LG, therefore in first step protonate -OH of alcohol :
Preparation of R-X from R-OH
• Thionyl chloride (SOCl2) converts alcohols (1o and 2o) into alkyl chlorides
• Phosphorus tribromide (PBr3) converts alcohols (1o and 2o) into alkyl bromides
1° and 2o alcohols react with SOCl2 or PBr3 by an SN2 mechanism
Preparation of R-X from R-OH
Stereochemistry: Inversion by SN2 Mechanism
Question: Reaction of trans-3-tert butyl-1-cyclohexanol with SOCl2 provides a product in
which the halogen is axial.
T or F
Conversion of Alcohols into Tosylates
•
•
•
Reaction with p-toluenesulfonyl chloride (tosyl chloride, p-TsCl) in pyridine yields alkyl
tosylates, R-OTs
Formation of the tosylate does not involve the C–O bond so configuration at a chirality
center is maintained
Alkyl tosylates react like alkyl halides
Good Leaving Groups are the conjugate bases of strong acids
Tosylate anion is excellent LG by comparison with sulfuric acid
12.9 Reactions of Alcohols
• Recall the –OH group can be converted into a good leaving group,
such as a tosyl group
• The tosylate can then undergo
SN2 substitution to obtain an
alkl halide
Klein, Organic Chemistry 3e
Preparation of R-X from R-OTs
Iodide by SN2 on Tosylate
Stereochemistry: Inversion by SN2 Mechanism
Preparation of R-X from R-OTs
Stereochemistry: Inversion by SN2 Mechanism
Step 1: Conversion of –OH to tosylate (retention of C-O stereochemistry)
Step 2: Backside displacement of tosylate LG with I-
OXIDATION/REDUCTION
Oxidation [O]- gain of O or loss of H2
Reduction [H]- gain of H2 or loss of O
[O] indicates an generalized oxidation step
Pyridinium Chlorochromate (PCC) - oxidizes 1o and 2o alcohols, but
stops 1o at aldehyde!!!
12.10 Oxidation of Alcohols
• Oxidation of the alcohol with chromic acid involves (1) formation
of a chromate ester, and (2) elimination to form the p bond
Klein, Organic Chemistry 3e
Jones Reagent
Jones Reagent (CrO3 or Na2Cr2O7 + H2SO4 + acetone) –
oxidizes 1o alcohols to carboxylic acids and 2o alcohols to ketones
[O]
[O]
[O]
12.10 Oxidation of Alcohols
• Predict the product for the following reaction
2˚ alcohol
aldehyde
1˚ alcohol
ketone
carboxylic
acid
carboxylic
acid
Klein, Organic Chemistry 3e
ConcepTest
ConcepTest
ConcepTest
ConcepTest
OXIDATION
Oxidation [O]- gain of O or loss of H2
Reduction [H]- gain of H2 or loss of O
Key: Attach a species to oxygen which has a higher affinity for electrons, e.g., highly oxidized
metals, halogens, etc.
Oxidations
TFAA or
Swern Oxidation
Mild for primary alcohol to aldehyde and secondary to ketone
Without epimerization of adjacent chiral center
Intermediate in Swern believed to be same as Corey-Kim oxidant from DMS/Cl2
Oxidations
Dess-Martin Periodinane (DMP
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Dess-Martin periodane oxidation (DMP) – yields analogous results as the Swern
oxidation.
DMP oxidation is believed to proceed through a periodane intermediate:
Acid-Catalyzed Dehydration
•
•
•
•
•
Relies upon ionization of 3° or 2° R-OH to carbocation under acidic conditions
3° alcohols are readily dehydrated with acid, 2°require severe conditions
Primary alcohols require very harsh conditions – impractical
Reactivity is the result of the nature of the carbocation intermediate
Alcohol hydroxyl group can leave if first protonated (since –OH is poor LG)
Mechanism of E1 Dehydration (Loss of H2O)
Step 1: Protonation of alcohol
Step 2: Loss of water to afford carbocation intermediate
Step 3: Removal of adjacent H+ with concomitant formation of pi bond
REGIOSELECTIVITY
A reaction is said to be regioselective if it might produce two or more
structural isomers but in fact yields one of them preferentially.
Zaitsev’s Rule - in the elimination of H-X from an alkyl halide, the
more highly substituted alkene predominates
Hoffman Elimination – a big, bulky base (e.g., KOtBu) abstracts the most sterically accessible
H-atom leading to the less substituted alkene
REGIOSELECTIVITY
Acid catalyzed dehydration of an alcohol, wherein the –OH is first
protonated so that H-O-H can act as a leaving group (LG), normally
proceeds well only upon 3o alcohols and also with little or no
regioselectivity.
Elimination of an alcohol involves:
a) Conversion of alcohol to tosylate LG;
b) Regioselective base-catalyzed elimination of –OTs
SYNTHESIS TOOLBOX
CHANGING THE POSITION OF A LEAVING GROUP
SYNTHESIS TOOLBOX
CHANGING THE POSITION OF A p-BOND
HBr
hv
HBr
t-BuOK
NaOEt
SYNTHESIS TOOLBOX
CHANGING THE POSITION OF A LEAVING GROUP
Concept
Synthesis
ConcepTest
CHANGING THE POSITION OF A LEAVING GROUP
Suggest an efficient synthesis for the following transformation.
Convert –OH to -OTs
Zaitsev
Anti-Markovnikov
Hydration