CHEM 41C Reactions

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Aldehyde and Ketone Reduction (LiAlH4, NaBH4, NaH)

Irreversibly forms alcohols (1* for aldehyde, 2* for ketones)

Aldehyde and Ketone Grignard Addition (MgX-R)

Irreversibly orms alcohols (1* for formaldehyde, 2* for aldehydes, 3* for ketones)

Aldehyde and Ketone Hydration (H2O)

Reversibly forms diols under acid or base catalysis

Aldehyde and Ketone Addition of Alcohol (ROH)

Reversibly forms hemiacetals (acid/base catalysis) then acetals (acid catalysis)

Aldehyde and Ketone Addition of Primary Amine

Reversibly forms hemiaminals and then imines under acid catalysis

Aldehyde and Ketone Addition of Secondary Amine

Reversibly forms hemiaminal then enamine

Aldol Condensation

1) Base catalyst forms enolate

2) Enolate attacks C=O as nucleophile

3) Resulting O- is protonated

Forms aldols (aldehyde, alcohol)

REVERSIBLE

Aldol Dehydration (heat)

From aldol,

1) Base deprotonates at alpha C, forming enolate

2) Enolate forms double bond between alpha and beta carbons, kicking OH off beta carbon (new = is in conjugation with C=O)

IRREVERSIBLE

Michael Addition

1) Addition of base → enolate

2) Enolate attacks alpha,beta-unsaturated carbonyl at the beta carbon, double bond shifts over and oxygen becomes O-.

3) New double bond grabs H+, leaving carbon center + charged, so O- reforms C=O.

GOES TO COMPLETION

Robinson Annulation

1) Michael Addition

2) Intramolecular aldol condensation → 5/6 membered rings

Protonation of Carboxylic Acid

Requires strong acid, results in alkyl oxonium ion with resonance stabilized O+ charge. Low pKa indicates unfavorability. COOH typically poor base

Oxidation to form Carboxylic Acids

Primary alcohols are oxidized to aldehydes then oxidized again to COOH

Grignard Reagent → Carboxylic Acids

1) Mg + X-R forms Grignard reagent

2) Addition of Grignard reagent to CO2 forms COO-

3) Protonation of COO- → COOH

Nitriles → Carboxylic Acids

1) Base creates CN- from HCN

2) CN- attacks carbon center containing LG in SN2 fashion (inversion of ST)

3) CN- is hydrolyzed using H+, H2O to form COOH and NH3/NH4+ byproduct

Addition-Elimination (Acid Catalyzed for Moderate Nu)

1) C=O is protonated

2) Nu-H attacks C=O with LG, forming 4 membered intermediate

3) LG picks up H intramolecularly, C-OH forms C=OH+ and LG-H leave simultaneously

4) C=OH+ is deprotonated to C=O, regenerating acid catalyst

**Preferred when starting material is COOH, because base would cause deprotonation.

Addition Elimination (Base Catalyzed for Preparation of Strong Nu)

1) Base creates strong Nu from moderate Nu, H-Nu → Nu

2) Strong Nu attacks C=O containing LG, forming O-

3) O- goes back to C=O, kicking LG off in the process.

4) LG- grabs proton from conjugate acid to regenerate base catalyst

Halogenation of COOH to Acyl Halides

RCOOH + PX3 → RCOX

RCOOH + SOX2 → RCOX

Acyl Halides + COOH

Form Anhydrides (RCO-O-OCR)

Thermal Dehydration of Dicarboxylic Acids

Form Cyclic Anhydrides (5/6 membered rings)

Esterification (COOH + ROH, Acid)

1) C=O protonated

2) Alcohol attacks C=O, alcohol deprotonates → OR,

3) Protonation of hydroxyl group to form oxonium LG (H2O)

4) Oxonium leaves, C-OH forms C=OH+

5) C=OH+ deprotonates, forming ester

Intramolecular Esterification

Forms lactones (ring with O as member)

Formation of Amides (NH3 + COOH)

1) NH3 attacks C=O forming 4 membered intermediate

2) OH picks up proton from positively charged RNH3+, forming oxonium LG

3) Oxonium leaves and O- reforms C=O → amide

Cyclic Amide Formation

Forms lactams (ring with N as member)

Reduction of Carboxylic Acids (LiAlH4, NaBH4)

Carboxylic acids are reduced to aldehydes and then primary alcohols (reverse of oxidation of primary alcohols to aldehydes to COOH)

Hydrolysis of Carboxylic Acid Derivatives

A) Acyl Halide + H2O → COOH + HX (fastest)

B) Anhydride + H2O → 2COOH (slower)

C) Ester + H2O → COOH + R’OH (very slow, need heat and catalyst)

D) Amide + H2O → COOH + NH3/R2NH (slowest, need heat and catalyst)

Keto Enol Tautomerization

Occurs under acidic or basic conditions. Keto is usually more stable. Protons can be transferred via solvent

Acidity of Carboxylic Acid Derivatives

Amide < Ester < Anhydride/Ketone < Acyl Halide

Acyl Halides Form Other Derivatives

A) Hydrolysis → COOH

B) +ROH → Ester

C) + NH3 → Amide

Nucleophilic Attack of Anhydrides

Yields COOH and Nu COOH derivative

Transesterification

RCOOR’ + R’’OH → RCOOR’’ + R’OH

Amine + Ester → Amide

Ester undergoes addition elimination with Amine as Nu and heat.

Nitrile Hydrolysis (Mechanism)

1) RCN is protonated → RCNH+

2) RC+=NH is formed, H2O attacks carbocation res. structure

3) Added H2O is deprotonated intramolecularly by nitrogen to form OH and =NH2+

4) C=OH+ is formed to neutralize + on N, then deprotonated to form amide

5) Amide hydrolysis with concentrated acid/base and heat