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Chapter Two
Polar Reaction Under Basic Conditions
a. Substitution and Elimination at C(sp3)-X σ bonds
b. Addition of Nuclephiles to Electrophilic π bonds
c. Substitution at C(sp2)-X σ bonds
d. Base-promoted Rearrangements
Nuclephility and Basicity
SN 2
Nu-
Good nuclephiles and good bases
Unhindered RO-, R2N-, R3N, RC≡C-, Cl-
SN 1
R-
Good nuclephiles and poor bases
Br-, I-, R2S, RS-, R3P, malonate anion, R2CuLi
B-
E2
E1
Poor nuclephiles and good bases (bulky)
t-BuO-, i-Pr2NLi(LDA), R3N, (TMS)2NK, i-Pr2NEt, t-BuLi
TMS: Trimethylsilane
SN2, E2: basic condition
SN1, E1: acidic condition
Substitution by the SN2 Mechanisms
R
S
a. Back attack
SP2 C and 3o C can’t undergo SN2
b. Sterospecific
c. Only 1o and 2o C(sp3) undergo SN2
SNAr
How to retent the configuration?
S
S
Solvent: Polar Aprotic
DMSO, DMF, Acetone, THF, MeCN, EA…
Polar solvent can stabilize the intermediate.
Aprotic solvent can avoid H+ react with Nu-.
Loss Configurational Purity by Nuclephilic Substitution
The leaving group is α or β to a carbonyl group.
Substituted group is good nuclephile, also good leaving group.
Elimination by the E2 Mechanisms
β hydrogen, Good base, 3o C
Stereochemistry of E2
Newman projection
Sawhore projection
Please draw the structure of product.
b.
a.
E2
c.
E2
d.
Syn Elimination
If the base were part to the substrate, the acidic hydrogen be removed in an intramolecular
reaction(syn elimination).
Hofmann Elimination
Syn elimination
major
E1cb and 1,3-Elimination
E1cb: β hydrogen is particularly acidic(carbonyl) and leaving group is poor(-OH, -OR)
hemiacetal
1,3-Elimination(decarboxylation)
CH2COOH
carbonyl
Substitution by the Elimination-Addition Reaction
Nu: -OMe
E+: carbonyl group, Br
No SN2 due to the steric hindrance.
Leaving group: Br, β hydrogen
Elimination-Addition Reaction
better electrophile than carbonyl group(steric)
Please draw the reasonable mechanisms
of this reaction
Exercises
Please draw the mechanisms of following reaction
a.
e.
CO2
b.
c.
CO2
d.
α-Elimination: Generation of Carbene
Defination: A carbene is a divalent carbon species link to two adjacent groups by covalent
bonds, possessing two nonbonded electrons and six valence electrons.
Preparation of carbenes
a.
b.
c.
d.
-
+
Reaction of Carbene
Exercises
Please draw the mechanisms of following reaction
a.
b.
c.
d.
e.
Polar Reaction Under Basic Conditions
a. Substitution and Elimination at C(sp3)-X σ bonds
b. Addition of Nuclepphiles to Electrophilic π bonds
c. Substitution at C(sp2)-X σ bonds
d. Base-promoted Rearrangements
Carbonyl Group
Under basic conditions, carbonyl compounds are electrophilic at carbonyl C and nuclephilic at
α C’s.
R is donating group
Stabilize the carbocation
decrease the reactivity
Arrange the stabilities and reactivities of carbonyl compounds as follow.
Carbonyl Group As Electrophile
a. M-Nu (R-MgBr, NaBH4, LiAlH4, R2CuLi)
b. Amines as nuclephiles (Please draw the mechanism)
c. Water and alcohols as nuclephiles under basic conditions.
base
Carbonyl Group As Nuclephiles (Aldol Reaction)
Aldol reaction: Enolates react with ketones and aldehydes.
Draw mechanisms for the following aldol reactions
Michael Addition
Michael addition: The 1,4-(conjugated) addition of a carbon nuclephile to an α, β-unsaturated
carbonyl system is referred to as Michael addition.
Draw mechanisms for the following reactions
d.
a.
b.
e.
c.
Baylis-Hillman Reaction and Robinson Annulation
a. Baylis-Hillman reaction: An acrylate ester reacts with an aldehyde in the presence of an
amine or phosphine catalyst.
b. Robinson annulation
Polar Reaction Under Basic Conditions
a. Substitution and Elimination at C(sp3)-X σ bonds
b. Addition of Nuclephiles to Electrophilic π bonds
c. Substitution at C(sp2)-X σ bonds
d. Base-promoted Rearrangements
Substitution at Carbonyl C
Draw mechanisms for the following reaction and explain why carbonyl acid can’t undergo
similar reaction
Reduction of aldehyde, ketone or ester.
Organometallic reagents as Nu-(RMgBr, R2CuLi…)
Substitution at Carbonyl C
Claisen condensation: An ester enolate is condensed with a ketone, aldehyde, or ester.
Dieckmann condensation: An intramolecuar version of the Claisen condensation
Draw mechanisms for the following reactions
Substitution at Alkenyl C and Aryl C(SNAr)
α, β-Unsaturated carbonyl compounds with a leaving group in the β position are susceptible
to addition-elimination reactions.
SNAr: Aromatic compounds that are substituted with electron-withdrawing groups undergo
nuclephilic aromatic substitution.
Favor
Unfavor
Nuclephilic Aromatic Substitution(SNAr)
Explain the results which was showed below
A
A
Draw mechanisms for the following reaction
B
B
Substitution at Aryl C(SNAr)
Aryl halides undergo substitution reactions with very strong base such as –NH2, terbutyl
lithium.
Why alkenyl halides such as CH3CBr=ChCH3 don’t undergo substitution upon treatment
with a strong base(-NH2)? Ans: ring strain.
Sandmeyer reaction
Nu: CuX, H2O, X-, CN-, H3PO2
Ex
Polar Reaction Under Basic Conditions
a. Substitution and Elimination at C(sp3)-X σ bonds
b. Addition of Nuclepphiles to Electrophilic π bonds
c. Substitution at C(sp2)-X σ bonds
d. Base-promoted Rearrangements
Migration from C to C
Favorskii rearrangemet
Please draw the mechanisms
Diazomethane(CH2N2) reacts with ketones(R2C=O) to insert CH2 unit between C=O and R
Baeyer-Villiger rearrangement
Wolf rearrangement
Please draw the mechanisms
Migration from C to O or N
Baeyer-Villiger rearrangement
base
Curtius rearrangement (acyl chloride to amine)
Hofmann rearrangement (amide to amine)
Please draw the mechanisms of Hofmann rearrangement
The Swern Oxidation
1o alcohol to aldehyde; 2o alcohol to ketone
Mechanism
The Mitsunobu Reaction
A 2o alcohol and a carboxylic acid are converted to an ester. A poor leaving group is
converted to an excellent leaving group.
S
Mechanism
R
Draw mechanisms for the following reactions
a.
b.
c.
d.
B
e.
Draw mechanisms for the following reactions
a.
f.
b.
g.
h.
c.
d.
i.
e.
Thanks For Your Attention