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Chapter Two
Polar Reaction Under Basic Conditions a. Substitution and Elimination at C(sp 3 )-X σ bonds b. Addition of Nuclephiles to Electrophilic π bonds c. Substitution at C(sp 2 )-X σ bonds d. Base-promoted Rearrangements
Nuclephility and Basicity
S N 2 Good nuclephiles and good bases Unhindered RO , R 2 N , R 3 N, RC≡C , Cl R Good nuclephiles and poor bases Br , I , R 2 S, RS , R 3 P, malonate anion, R 2 CuLi Nu B S N 1 E2
Poor nuclephiles and good bases (bulky)
t
-BuO ,
i
-Pr 2 NLi(LDA), R 3 N, (TMS) 2 NK,
i
-Pr 2 NEt,
t
-BuLi E1 TMS: Trimethylsilane S N 2, E2: basic condition S N 1, E1: acidic condition
Substitution by the S N 2 Mechanisms
a. Back attack b. Sterospecific c. Only 1 o and 2 o
S
SP C(sp 3 ) undergo S N 2 2 C and 3 o
R
C can’t undergo S N 2
S N Ar
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, 3 o C Stereochemistry of E2
Sawhore projection
Please draw the structure of product.
a.
b.
E2 E2 c.
Newman projection
d.
Syn Elimination
If the base were part to the substrate, the acidic hydrogen be removed in an intramolecular reaction(syn elimination).
Hofmann Elimination major Syn elimination
E1cb and 1,3-Elimination
E1cb: β hydrogen is particularly acidic(carbonyl) and leaving group is poor( OH, OR) hemiacetal 1,3-Elimination(decarboxylation) carbonyl CH 2 COOH
Substitution by the Elimination-Addition Reaction
Nu: OMe E + : carbonyl group, Br No S N 2 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
c.
d.
Exercises
Please draw the mechanisms of following reaction a.
e.
b.
CO 2 CO 2
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
d.
e.
b.
c.
a.
Exercises
Please draw the mechanisms of following reaction
Polar Reaction Under Basic Conditions a. Substitution and Elimination at C(sp 3 )-X σ bonds b. Addition of Nuclepphiles to Electrophilic π bonds c. Substitution at C(sp 2 )-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, NaBH 4 , LiAlH 4 , R 2 CuLi) 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.
a.
Draw mechanisms for the following reactions b.
c.
d.
e.
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(sp 3 )-X σ bonds b. Addition of Nuclephiles to Electrophilic π bonds c. Substitution at C(sp 2 )-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, R 2 CuLi…)
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(S N Ar)
α, β-Unsaturated carbonyl compounds with a leaving group in the β position are susceptible to addition-elimination reactions.
S N
Ar: Aromatic compounds that are substituted with electron-withdrawing groups undergo nuclephilic aromatic substitution.
Favor Unfavor
Nuclephilic Aromatic Substitution(S N Ar)
Explain the results which was showed below
A A B B
Draw mechanisms for the following reaction
Substitution at Aryl C(S N Ar)
Aryl halides undergo substitution reactions with very strong base such as – NH 2 , terbutyl lithium.
Why alkenyl halides such as CH 3 CBr=ChCH 3 with a strong base(-NH 2 )? Ans: ring strain.
don’t undergo substitution upon treatment Sandmeyer reaction Nu: CuX, H 2 O, X , CN , H 3 PO 2 Ex
Polar Reaction Under Basic Conditions a. Substitution and Elimination at C(sp 3 )-X σ bonds b. Addition of Nuclepphiles to Electrophilic π bonds c. Substitution at C(sp 2 )-X σ bonds d. Base-promoted Rearrangements
Migration from C to C
Favorskii rearrangemet Please draw the mechanisms Diazomethane(CH 2 N 2 ) reacts with ketones(R 2 C=O) to insert CH 2 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
1 o alcohol to aldehyde; 2 o alcohol to ketone Mechanism
The Mitsunobu Reaction
A 2 o 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.
c.
d.
e.
B b.
Draw mechanisms for the following reactions a.
f.
b.
g.
h.
c.
d.
i.
e.