Chapter Two Polar Reaction Under Basic Conditions Substitution and Elimination at C(sp3)-X σ bonds Addition of Nuclephiles to Electrophilic π bonds Substitution at C(sp2)-X σ bonds Base-promoted Rearrangements

Nuclephility and Basicity SN2 Nu- Good nuclephiles and good bases Unhindered RO-, R2N-, R3N, RC≡C-, Cl- Good nuclephiles and poor bases Br-, I-, R2S, RS-, R3P, malonate anion, R2CuLi Poor nuclephiles and good bases (bulky) t-BuO-, i-Pr2NLi(LDA), R3N, (TMS)2NK, i-Pr2NEt, t-BuLi SN1 R- E2 B- E1 SN2, E2: basic condition SN1, E1: acidic condition TMS: Trimethylsilane

Substitution by the SN2 Mechanisms R a. Back attack b. Sterospecific c. Only 1o and 2o C(sp3) undergo SN2 SP2 C and 3o C can’t undergo SN2 SNAr How to retent the configuration? Solvent: Polar Aprotic DMSO, DMF, Acetone, THF, MeCN, EA… Polar solvent can stabilize the intermediate. Aprotic solvent can avoid H+ react with Nu-. S S

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. a. b. d. c. E2 E2

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 carbonyl 1,3-Elimination(decarboxylation) CH2COOH

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.

Polar Reaction Under Basic Conditions Substitution and Elimination at C(sp3)-X σ bonds Addition of Nuclepphiles to Electrophilic π bonds Substitution at C(sp2)-X σ bonds 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 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 Substitution and Elimination at C(sp3)-X σ bonds Addition of Nuclephiles to Electrophilic π bonds Substitution at C(sp2)-X σ bonds 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 B A B Draw mechanisms for the following reaction

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 Substitution and Elimination at C(sp3)-X σ bonds Addition of Nuclepphiles to Electrophilic π bonds Substitution at C(sp2)-X σ bonds 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 R Mechanism

Draw mechanisms for the following reactions b. c. d. B e.

Draw mechanisms for the following reactions b. g. h. c. d. i. e.

Thanks For Your Attention