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Alkylation introduces an alkyl group into a molecule. The new group may attach to carbon, nitrogen, oxygen, sulfur, or another suitable atom; the name alone does not specify the mechanism.

For example, an alkoxide can react with a suitable alkyl halide to form an ether by nucleophilic substitution, while Friedel-Crafts alkylation attaches an alkyl group to an aromatic ring through an electrophilic pathway. Competing elimination, multiple substitution, or rearrangement depends on the particular reacting partners.

The compound $\mathrm{C}{\mathrm{H}}_2=\mathrm{CHC}{\mathrm{H}}_2\mathrm{Br}$. nucleophilic substitution at its bromomethylene carbon introduces an allyl group without consuming the alkene.

Basicity measures a chemical species' tendency to act as a base. For proton transfer, it is the tendency to accept a proton; for a Lewis base, it concerns association with a Lewis acid through an electron pair. A comparison must specify the reaction partner and medium.^[ref]

For a base $B$ in water,The $a_i$ are thermodynamic activities, with the solvent convention absorbed into $K_b$. At the same temperature and standard-state conventions, $K_a(B{H}^{+})K_b(B)=K_w$. Thus a higher conjugate-acid $p{K}_a$ corresponds to stronger basicity in that medium. Basicity is an equilibrium property; a fast nucleophilic substitution need not identify the stronger equilibrium base.

A nucleophilic addition forms a bond by attack of a nucleophile on an electrophilic multiple bond, reducing its bond order. A common case is attack on the carbon of a carbonyl group, with its pi electrons displaced toward oxygen.

Protonation of the resulting oxygen-centered intermediate can give an alcohol. Unlike nucleophilic substitution, the basic addition step does not expel a leaving group from the attacked carbon. Carbonyl polarization and orbital geometry explain both why carbon is attacked and why the incoming bond follows a preferred approach direction.

A nucleophilic substitution replaces a leaving group by a nucleophile. In a concerted SN2 reaction, bond formation and departure occur in the same elementary step, commonly with inversion at the attacked stereocenter.

An SN1 reaction instead forms an intermediate before capture, often a carbocation, so rearrangement and a different stereochemical outcome may be possible. Substrate structure, solvent, leaving-group ability, and nucleophile properties influence which pathway is available. The substitution product alone does not uniquely identify the mechanism.

Prepare a chlorophosphazene ring from phosphorus pentachloride and ammonium chloride, isolate the cyclic trimer, open the rings to make the linear chloropolymer, and finally replace P–Cl by P–OEt:The first stage can produce a mixture of cyclic oligomers, so isolation of hexachlorocyclotriphosphazene is important. Controlled thermal ring-opening polymerization, conventionally around $250{}^{\circ }\mathrm{C}$ for the classical route, gives soluble linear polydichlorophosphazene before excessive cross-linking. Moisture exclusion avoids uncontrolled hydrolysis of the reactive P–Cl precursor.

The target is poly[bis(ethoxy)phosphazene]. The final step is nucleophilic substitution with an ethoxide salt in a compatible dry medium, replacing two chlorides per phosphorus. Polymerize the chlorinated ring first, then substitute the linear polymer: complete ethoxylation of the isolated ring does not by itself produce the requested high polymer. The primary macromolecular-substitution work explicitly includes the ethoxy derivative.^[ref]

Primary amines can favor geminal disubstitution through a proton-abstraction route. The first substitution leaves an exocyclic $\mathrm{PCl}(\mathrm{NHR})$ group. Its remaining N–H proton provides a pathway unavailable to a fully substituted amino group: base removes H, chloride elimination gives a reactive low-coordinate phosphorus intermediate with increased exocyclic P–N bonding, and a second amine attacks that same phosphorus. proton transfer then gives $\mathrm{P}(\mathrm{NHR}{)}_2$. Thus the directing effect is not simply the inductive effect of an amino group.

This needs a qualification: “primary amine” alone does not specify a universal product distribution. Substituent, solvent and base concentration affect whether the proton-abstraction route outcompetes direct nucleophilic substitution. Kinetic and trapping experiments with aromatic primary amines support the base-catalyzed route to geminal products, while also finding direct substitution pathways under other conditions.^[ref]

The products are hexanenitrile, $\mathrm{C}{\mathrm{H}}_3(\mathrm{C}{\mathrm{H}}_2{)}_4\mathrm{C}\equiv \mathrm{N}$, and ethyl triphenylmethyl ether, $\mathrm{P}{\mathrm{h}}_3\mathrm{C}-\mathrm{O}-\mathrm{C}{\mathrm{H}}_2\mathrm{C}{\mathrm{H}}_3$. The nitrile carbon comes from cyanide, so replacing chloride in the five-carbon chain gives a six-carbon product.

For the primary chloride, the carbon-end lone pair of $\mathrm{C}{\mathrm{N}}^{-}$ attacks the carbon carrying Cl from the back side while the C–Cl bond pair moves onto Cl. The single concerted nucleophilic substitution step forms the C–C bond and releases $\mathrm{C}{\mathrm{l}}^{-}$. Attack through the carbon end gives the nitrile, not an isocyanide.

For the triphenylmethyl chloride, the C–Cl bond first undergoes heterolysis to $\mathrm{P}{\mathrm{h}}_3{\mathrm{C}}^{+}$ and $\mathrm{C}{\mathrm{l}}^{-}$. An ethanol oxygen lone pair then attacks the carbocation, giving $\mathrm{P}{\mathrm{h}}_3\mathrm{C}-{\mathrm{O}}^{+}(\mathrm{H})\mathrm{Et}$. Finally pyridine accepts that O–H proton, with the O–H bond pair returning to oxygen, giving the neutral ether and pyridinium chloride.

Disconnect the N–cyclohexyl bond as a late reductive amination of a primary amine with cyclohexanone. Disconnect the exocyclic methylene as a Wittig methylenation of a substituted cyclohexanone. The useful ring precursor is 3-methyl-5-substituted cyclohex-2-en-1-one, accessible by a Robinson annulation. The pendant substituent throughout ring construction should be $(\mathrm{C}{\mathrm{H}}_2{)}_4\mathrm{NHBoc}$.

Start with nucleophilic substitution of the supplied bromo ester by cyanide:Reduce the nitrile selectively to the primary amine while retaining the ester, for example by controlled catalytic hydrogenation with Raney nickel in the presence of ammonia, and trap the amine promptly as its Boc carbamate. Avoid heating or concentrating the free amino ester, which can cyclize to a lactam. lithium aluminium hydride would be unsuitable at this stage because it also reduces the ester.

Partial reduction of the protected ester with DIBAL at low temperature gives $\mathrm{BocNH}(\mathrm{C}{\mathrm{H}}_2{)}_4\mathrm{CHO}$. The carbon of the original nitrile is now the methylene nearest nitrogen; the original ester carbonyl is the aldehyde carbon. Condense this aldehyde with acetone and dehydrate to $\mathrm{BocNH}(\mathrm{C}{\mathrm{H}}_2{)}_4\mathrm{CH}=\mathrm{CHCOMe}$.

Now add the enolate of a second acetone molecule in a Michael addition. With $R=(\mathrm{C}{\mathrm{H}}_2{)}_4\mathrm{NHBoc}$, the resulting chain isIntramolecular aldol condensation gives 3-Me-5-R-cyclohex-2-en-1-one. The beta methyl derives from the carbonyl end attacked in the ring closure; the pendant aminoalkyl chain remains at C5. Hydrogenate the ring C=C selectively, retaining the ketone, then methylenate the ketone with preformed $\mathrm{P}{\mathrm{h}}_3\mathrm{P}=\mathrm{C}{\mathrm{H}}_2$. Do the hydrogenation before installing the exocyclic methylene so that it is not hydrogenated away.

Remove Boc under brief mild conditions, checking for acid-induced exocyclic alkene isomerization. reductive amination of the resulting primary amine with cyclohexanone, followed by selective imine reduction, installs the secondary N-cyclohexyl group. Use controlled stoichiometry to suppress tertiary amine formation. The methyl and four-carbon aminoalkyl substituents occupy the required 1,3-related ring positions, with the exocyclic methylene at the former carbonyl. No ring stereochemistry is specified. The target contains eighteen carbons: six ring carbons, one ring methyl, one methylene, four in the linker, and six in the N-cyclohexyl group.

A limiting unimolecular nucleophilic substitution mechanism with rate-determining ionization, commonly producing a carbocation, followed by nucleophile capture. Its ideal rate law is first order in substrate.

The silylating reagent $\mathrm{tBuM}{\mathrm{e}}_2\mathrm{SiCl}$, commonly abbreviated TBSCl. nucleophilic substitution at silicon converts an alcohol into a silyl ether.