synthesis reactions

strong Lewis bases

• alkoxides (^-OR), good nucleophile)

• bulky alkoxides (^-OtBu)

• alkynide (^-C≡CR, good nucleophile)

• hydride (^-H)

• LDA (^-NiPr₂, bulky)

• amide (^-NH₂)

weak Lewis bases

• halides (moderate nucleophile)

• thiols (RSH, moderate nucleophile)

• alcohols (weak nucleophile)

• water (weak nucleophile)

• sulfides (moderate nucleophile)

• amines (RNH₂, moderate nucleophile)

requirements for S_N/E reactions

• saturated substrate with a leaving group

• reactant that is an attacking Lewis base

features of compounds that are good nucleophiles and good bases

unhindered anionic (no resonance)

features of compounds that are better nucleophiles than bases

• anionic or neutral heavy elements

• triple bonds

• halides

features of compounds that are better bases than nucleophiles

• bulky anionic (no resonance)

• low solubility anions

features of compounds that are poor nucleotides and poor bases

• neutral

• resonance anions

internal alkyne synthesis

• 2x E2 reactions with very strong base (usually NaNH₂)

• geminal or viscinal dihalides

geminal dihalide

halides are on the same carbon

viscinal dihalide

halides are on adjacent carbons

terminal alkyne synthesis

• 2x E2 reactions with very strong base (usually NaNH₂)

• third equivalent of base needed due to acidic sp C-H (product deprotonated as soon as it is formed)

• second step is quench step

quench step

acid-base reaction to neutralize product

alkynide anion as a nucleophile

• 1° substrates only

• S_N2 reaction

• C-C bond formation

• internal alkyne synthesis

alkynide anion as a strong base

• 2° and 3° substates

• E2 strong base

• alkene synthesis

alkoxide anion as nucleophile

• 1° substrates only

• S_N2 reaction

• C-O bond formation

• Williamson ether synthesis

alkoxide anion as a strong base

• 2° and 3° substrates

• E2 strong base

• alkene synthesis

organocuprates (Gilman reagent) as nucleophile

• 1° substrates best (2° at low temperatures)

• S_N2 reaction

• C-C bond formation

• alkane chain extension

organocuprates (Gilman reagent) as a strong base

• 2° and 3° substrates

• E2 strong base

• alkene synthesis

epoxide as substrate for S_N2 reaction under basic conditions

• S_N2 type opening with anionic nucleophile (least hindered carbon)

• opposite regiochemistry to acidic conditions

• anti-addition product

epoxide as substrate for S_N1 reaction under acidic conditions

• S_N1 type opening with neutral nucleophile, in acid (most substituted carbon)

• opposite regiochemistry to basic conditions

• anti-addition product

retrosynthesis strategy

1. break down change

2. identify nucleophile/electrophile (or key intermediate) for forward reaction

3. add charges/leaving group

4. formulate bottled reagents

linear synthesis

all synthetic steps performed in sequence

overall yield for linear synthesis

multiply yields for each consecutive step

convergent synthesis

portions synthesized separately then assembled

overall yield for convergent synthesis

multiply yields for consecutive steps