Aliphatic nucleophilic substitution

Alcohol to alkyl halide: tetrahydrofurfuryl alcohol (a primary alcohol) with PBr3, pyridine; benzene, −5 °C gives 2-(bromomethyl)oxolane (the primary alkyl bromide).

Leaving group displacement: 1-bromododecane (a primary alkyl bromide) with KCN gives tridecanenitrile (the substitution product).

N-alkylation: 4-amino-3-(isopropyl)phenol (an aniline) with 2.2 equiv. MeI; Na2CO3; EtOH gives 4-(dimethylamino)-3-isopropylphenol (the aniline). 48% yield.

Williamson ether synthesis: 4-aminophenol with NaH; DMF gives 4-ethoxyaniline (the aryl alkyl ether). 78% yield.

Epoxide opening: ethylene oxide (an epoxide) with 46% HBr gives 2-bromoethanol (the halohydrin).

S-alkylation: 2-chloroethanol (a halohydrin) with NaSCH3; CH3CH2OH, Δ gives 2-(methylthio)ethanol (the thioether).

Carboxylate alkylation: 4-nitrobenzyl chloride (a benzylic alkyl chloride) with NaOAc; AcOH, Δ gives (4-nitrophenyl)methyl acetate (the ester).

Ether cleavage: tetrahydrofuran (a cyclic ether) with KI, ortho-phosphoric acid; phosphoric anhydride, Δ gives 1,4-diiodobutane (the cleaved product).

Acetylide alkylation: acetylide ion (a metal acetylide), sodium ion and butyl bromide (a primary alkyl bromide) with Na; NH3 gives 1-hexyne (the terminal alkyne).

Epoxide from halohydrin: 2-chlorocyclohexanol (a halohydrin) with aq. NaOH gives cyclohexene oxide (the epoxide).

Finkelstein: 1-bromohexane (a primary alkyl bromide) with KF, Δ; ethylene glycol gives 1-fluorohexane (the primary alkyl fluoride).

Grignard alkylation: a Grignard reagent with (2 equiv.); CH3CH2OCH2CH3 gives pentylbenzene (the alkylated product).

Ether cleavage: 3,3'-dimethoxybiphenyl (an aryl alkyl ether) with BBr3; CH2Cl2, −80 °C gives 3,3'-biphenyldiol (the cleaved product).

Epoxide opening: a Grignard reagent with CH3CH2OCH2CH3 gives the ring-opened product.

Williamson ether synthesis: chloroacetic acid (an α-halo acid) with NaOCH2CH3 gives sodium ethoxyacetate (the ether).

Alcohol to alkyl halide: 1,6-hexanediol (a primary alcohol) with HCl, H2O; toluene, Δ gives 6-chloro-1-hexanol (the primary alkyl chloride).

Alcohol to alkyl halide: tert-butanol (a tertiary alcohol) with conc. HCl gives 2-chloro-2-methylpropane (the tertiary alkyl chloride).

Leaving group displacement: benzyl chloride (a benzylic alkyl chloride) with aq. NaCN; CH3CH2OH, Δ gives phenylacetonitrile (the substitution product).

Alcohol to alkyl halide: isobutanol (a primary alcohol) with PBr3 gives 1-bromo-2-methylpropane (the primary alkyl bromide).

S-alkylation: 1,4-dichlorobutane (a primary alkyl chloride) with Na2S; DMF, H2O, Δ gives tetrahydrothiophene (the thioether).

N-alkylation: 6-benzamido-2-bromohexanoic acid (an α-halo acid) with NH4OH gives 2-amino-6-benzamidohexanoic acid (the primary amine).

Alcohol to alkyl halide: 1,10-decanediol (a primary alcohol) with HBr; 135 °C gives 1,10-dibromodecane (the primary alkyl bromide).

Williamson ether synthesis: guaiacol (a phenol) with K2CO3 gives 1-methoxy-2-prop-2-enoxybenzene (the allyl aryl ether).

N-alkylation: (1,1-dimethylethyl)urea and phthalic anhydride (a cyclic anhydride) with H2NNH2 · HCl; CH3CH2OH, HCl gives tert-butylamine (the primary amine) and 2,3-dihydro-1,4-phthalazinedione (the heteroarene).

Carboxylate alkylation: 5-(4-methoxy-phenyl)-5-oxo-pentanoic acid (a carboxylic acid) with Br2; Et2O gives 5-(4-methoxybenzoyl)oxolan-2-one (the five-membered lactone). 87% yield.

N-alkylation: 2-bromo-3-phenylpropanoic acid (an α-halo acid) with NH3; NH4Br gives dl-phenylalanine (the primary amine).

Acetylide alkylation: 1-bromo-3-chloropropane (a primary alkyl chloride) and a metal acetylide with NH3 (l) gives 6-chlorohex-2-yne (the internal alkyne).

S-alkylation: 2-chloroethanol (a halohydrin) with Na2S, H2O; Δ; (2 equiv.) gives thiodiglycol (the thioether).

Ether cleavage: tetrahydropyran (a cyclic ether) with Br2, Δ; H2O, SO2 gives 1,5-dibromopentane (the cleaved product).

Alcohol to alkyl halide: tetrahydrofurfuryl alcohol (a primary alcohol) with SOCl2; pyridine gives 2-chloromethyl tetrahydrofuran (the primary alkyl chloride).

Leaving group displacement: sodium chloroacetate (an α-halo ester) with NaCN gives sodium cyanoacetate (the substitution product).

N-alkylation: 2-chloro-1,1-diethoxyethane (a primary alkyl chloride) with NH3, CH3OH; 140 °C gives 2,2-diethoxyethylamine (the primary amine).

Leaving group displacement: 1-chloropinacolone (an α-halo ketone) with 1) NaN3, aq. acetone, Δ; 2) H2, Pd/C, CH3OH gives 1-amino-3,3-dimethylbutan-2-one (the substitution product).

Williamson ether synthesis: a phenoxide with NaOH, H2O, Δ gives 3-bromopropoxybenzene (the aryl alkyl ether).

Williamson ether synthesis: a secondary alcohol and chloroacetic acid (an α-halo acid) with Na (2 equiv), Δ; then H2O / HCl gives the ether.

N-alkylation: chloroacetic acid (an α-halo acid) with NH4OH; H2O gives glycine (the primary amine).

N-alkylation: benzyl chloride (a benzylic alkyl chloride) with PhNH2, Δ; aq. NaHCO3 gives benzylaniline.

Leaving group displacement: 1,3-dibromopropane (a primary alkyl bromide) with NaCN; aq. CH3CH2OH, Δ gives glutaronitrile (the substitution product).

S-alkylation: 1-bromo-2,2-dimethylpropane (a primary alkyl bromide) and sodium benzenethiolate (a thioanisole) with C16H33P(CH3)3+ Br–; H2O, 70 °C gives 2,2-dimethylpropylsulfanylbenzene (the thioether).

Alcohol to alkyl halide: 1-dodecanol (a primary alcohol) with HBr; 100 - 120 °C gives 1-bromododecane (the primary alkyl bromide).

Alcohol to alkyl halide: 1-butanol (a primary alcohol) with ZnCl2, HCl; Δ gives butyl chloride (the primary alkyl chloride).

Leaving group displacement: methylamine (a primary amine) and chloroacetic acid (an α-halo acid) with NaOH; H2O; (2 equiv.) gives N-methyliminodiacetic acid (the substitution product).

Leaving group displacement: 2-bromoethyl ethyl ether (a primary alkyl bromide) with NaCN, H2O; CH3CH2OH, Δ gives 3-ethoxypropanenitrile (the substitution product).

Alcohol to alkyl halide: glycol monoethyl ether (a primary alcohol) with PBr3 gives 2-bromoethyl ethyl ether (the primary alkyl bromide).

Williamson ether synthesis: 2-acetylhydroquinone (a phenol) with CH3I, K2CO3; acetone, Δ gives 1-(2-hydroxy-5-methoxyphenyl)ethan-1-one (the aryl alkyl ether).

Alcohol to alkyl halide: pentaerythritol (a primary alcohol) with 48% HBr; AcOH, Δ gives 2-(bromomethyl)-2-(hydroxymethyl)propane-1,3-diol (the primary alkyl bromide).

Williamson ether synthesis: a phenoxide with CH3CH2OH, Δ gives 3-phenoxy-1,2-propanediol (the aryl alkyl ether).

Epoxide opening: an epoxide with Camphor Sulfonic Acid (CSA); pKa = 1.2; CH2Cl2 gives the ring-opened product.

O-silylation: 1,4-butanediol (a primary alcohol) with 0.5 eq.; catalytic Me3SiCl gives 4-trimethylsilyloxybutan-1-ol (the silyl ether).

S-alkylation: 1,4-dibromo-2,2-dimethylbutane (a primary alkyl bromide) with Na2S, DMSO gives 3,3-dimethyl-thiacyclopentane (the thioether).

Alcohol to alkyl halide: phenyl(2-thienyl)methanol (a benzylic alcohol) with HCl gives phenyl-2-thienylmethyl chloride (the benzylic alkyl chloride).

Carboxylate alkylation: 2-bromopropane (a secondary alkyl bromide) and 3-hydroxy-2,2-dimethylpropionic acid (a carboxylic acid) with Cs2CO3; DMF gives methylethyl 3-hydroxy-2,2-dimethylpropanoate (the ester).

Alcohol to alkyl halide: 1,6-hexanediol (a primary alcohol) with KI, ortho-phosphoric acid; phosphoric anhydride, Δ gives 1,6-diiodohexane (the primary alkyl iodide).

S-alkylation: 1,3-propanedithiol and 1,4-dibromobutane (a primary alkyl bromide) with Cs2CO3; DMF gives 1,5-dithionane (the thioether).

Epoxide opening: an epoxide with MeNH2; MeOH gives the tertiary alcohol.

Alcohol to alkyl halide: a benzylic alcohol with HBr, H2SO4 gives (Z)-2-(bromomethyl)-3-(4-formylphenyl)prop-2-enoic acid (the allylic alkyl bromide).

N-alkylation: indole with KOH; DMSO gives 1-benzylindole (the heteroarene). 87% yield.

Epoxide opening: a secondary sulfonate ester with NH3 / NH4OH, iPrOH gives the secondary alcohol.

Epoxide opening: 2,2-diphenyloxirane (an epoxide) with HClO4 gives 2,2-diphenyl-2-prop-2-enoxyethanol (the primary alcohol).

Alcohol to alkyl halide: 4-methoxybenzyl alcohol (a benzylic alcohol) with HCl gives 4-methyloxybenzyl chloride (the benzylic alkyl chloride).

Williamson ether synthesis: chloroacetyl chloride (an α-halo acid chloride) and D(-)-leucinol (a primary alcohol) with 1) K2CO3 / H2O / THF; 2) tBuOK / tBuOH; 3) aq HCl workup gives the cyclic ether.

Alcohol to alkyl halide: ethyl (R)-2-hydroxy-2-methylbutanoate (a tertiary alcohol) with 1) MsCl / pyridine; 2) CsF; triethylene glycol (solvent); net inversion gives the tertiary alkyl fluoride.

Epoxide opening: an epoxide with J Med Chem 2000 43 4045 gives the tertiary alcohol and dinitrogen-N-sulfide (the ring-opened product).

Leaving group displacement: 1-bromo-3-chloropropane (a primary alkyl chloride) with KCN, Δ; aq. CH3CH2OH gives 4-chlorobutyronitrile (the substitution product).