Orgo 2 Nitrogen Related Rxns

[Slides 4, 6] Aldehyde or ketone + 1° amine (RNH2), cat. H+

Hemiaminal (N,O-acetal) via PAD (Protonation, Addition, Deprotonation); then -H2O via PED (Protonation, Elimination, Deprotonation) gives an imine (C=N-R). Whole sequence = PADPED. Imines can be E or Z.

[Slide 8] Aldehyde or ketone + RNH2 / HO-NH2 / H2N-NH2

Imine / oxime (C=N-OH) / hydrazone (C=N-NH2). Imine + LiAlH4 or NaBH4 gives an amine (imines are electrophilic).

[Slide 10] Aldehyde or ketone + H2N-NH2, KOH, heat

Wolff-Kishner reduction: C=O becomes CH2, plus N2 (carbonyl deoxygenation; hydrazone need not be isolated).

[Slide 11] Aldehyde or ketone + 2° amine (e.g. pyrrolidine), cat. H+

Enamine, via iminium ion (deprotonation at the alpha-carbon; N equivalent of an enol). Iminium + NaBH3CN gives a tertiary amine.

[Slides 12-18] Aldehyde or ketone + NH3 or amine (1° or 2°), NaBH3CN or NaBH(OAc)3, pH 4-5 (or H2 with Pd/Ni)

Reductive amination: 1°, 2°, or 3° amine, via imine to iminium, then hydride adds to the C=N+ carbon. Intramolecular version gives cyclic amines (amino-ketone makes a ring). Aldehyde sets the N-substituent: formaldehyde gives Me, acetaldehyde Et, propanal Pr, benzaldehyde Bn; phenyl can't be done (use Buchwald-Hartwig). Retrosynthesis: disconnect any C-N bond, put C=O back on that carbon.

[Slide 20] Carboxylic acid + amine (RNH2), then heat

Ammonium carboxylate salt (acid-base), then heat (-H2O) gives an amide. Intramolecular (amino acid + heat or H+) gives a lactam.

[Slide 21] Acyl chloride + NH3 / 1° amine / 2° amine / 3° amine

1° amide / 2° amide / 3° amide / acyl ammonium salt (very electrophilic, no neutral amide). Most general amide synthesis.

[Slide 22] Sulfonyl chloride (ArSO2Cl) + 1° amine; then H3O+, heat

Sulfonamide (ArSO2NHR) + HCl; H3O+/heat hydrolyzes it back to the amine (protecting group). Sulfonamide + base, then R'-X gives an N-alkylated sulfonamide, then hydrolysis gives a substituted amine.

[Slides 23-24] Acid anhydride + NH3 / 1° amine / 2° amine. Cyclic anhydride + NH3, then heat

1° / 2° / 3° amide + carboxylic acid byproduct. Cyclic anhydride gives an amide-acid, and heat (-H2O) gives a cyclic imide (phthalimide; N analog of an anhydride).

[Slides 25-26] Phthalimide + KH (or KOH), then R-CH2-Br (1° alkyl halide), then H2N-NH2 and heat (or NaOH or H3O+, heat)

Gabriel synthesis: potassium phthalimide, SN2 to N-alkylphthalimide, then cleavage (Ing-Manske with hydrazine) to a 1° amine + phthalhydrazide. No over-alkylation; only 1° halides; phthalimide is an amine protecting group.

[Slide 27] Ester + NH3 / 1° amine / 2° amine

1° / 2° / 3° amide + alcohol (much slower than acyl chlorides).

[Slide 28] Alkyl halide + NaN3 (SN2), then LiAlH4 or H2/Pd-C

Alkyl azide, then 1° amine (R-NH2).

[Slides 29-30] Ketone / aldehyde + HN3 (or NaN3), H2SO4

Schmidt reaction: ketone gives amide (like Baeyer-Villiger; more electron-rich group migrates: 3° alkyl > 2° alkyl > aryl > 1° alkyl > Me > H). Aldehyde gives nitrile (R-C#N). N2 is lost in both.

[Slide 31] Acyl chloride + NaN3, then heat (-N2), then ROH / H2O / R'NH2

Curtius rearrangement: acyl azide, then isocyanate (R-N=C=O), then carbamate (ROH) / 1° amine after -CO2 (H2O) / urea (R'NH2).

[Slide 34] 1° Amide + Br2 (or Cl2), aq. NaOH, heat

Hofmann rearrangement: N-bromoamide, then isocyanate, then carbamic acid, then 1° amine + CO2 (one carbon shorter).

[Slide 36] Carboxylic acid + SOCl2 / R'OH, H+ / HNR'2, heat

Acyl chloride / ester (Fischer) / amide. Reactivity: acyl chloride > anhydride > ester > amide; can go down the series, not up. Any derivative + -OH or H3O+ (heat) gives back the acid. Nitrile + H3O+ (controlled) gives an amide; R-Br + Mg, then CO2, then workup gives the acid.

[Slide 37] 1° Amide + P2O5 (or boiling acetic anhydride)

Nitrile (R-C#N) by dehydration (N must carry two H's).