Definition:

• S_N2 stands for Substitution Nucleophilic Bimolecular.
• This means that the rate of these reactions depends not only on the substrate concentration but also on the concentration of the substituting nucleophile.
• The rate of the disappearance of substrate = d[ substrate ]/dt = -k[ substrate ][ nucleophile ], negative slope asymptotic to both axis.

Mechanism:

• The S_N2 substitution occurs by a direct backside attack by a nucleophile on an electrophilic carbon to avoid the electrons on the front side and to interact with a sigma anti-bond.
• The nucleophile attaches itself while the group that made the carbon electrophilic leaves in a concerted fashion.
• The electrophilic carbon must be sp³ hybridized.
• The hybridization of the transition state of this process is sp².

Stereochemistry:

• This reaction leads to inversion of configuration (R goes to S and vice a versa) at carbons that are chiral centers.
• This control is called stereoselectivity.

Factors:

• The rate of this reaction is affected by:
  • Steric hindrance, rate greater for methyl > primary > secondary >> tertiary, neopentyl
  • Solvent, works best with polar aprotic solvents like acetone, dimethylformamide, etc.
    • A polar solvent is required for solubility.
    • A protic solvent would hydrogen bond to the nucleophile and reduce its effectiveness.
  • Nucleophile, works best with less electronegative, more basic but not too basic nucleophiles
    • NH₃ > OH₂ > HF
    • HO^- > H₂O
    • P > N
    • Se > S > O
    • I > Br > Cl > F
    • left-down, more left than down
    • anion > neutral
    • Too basic reagents lead to elimination reactions.
  • Leaving group, works best with leaving groups that are weak bases because this correlates to having weaker carbon leaving group bonds.
    • F > HO > H₂N > C
    • I > Br > Cl > F
    • right-down, more right than down
    • cation > neutral but cations may lead to other mechanisms including eliminations and rearrangements.
• Alkyl halides are most often used in the S_N2 substitutions but other leaving groups are possible:
  • Alcohols to alkyl halides with HX, ZnCl₂, SOCl₂, PX₃, or via arylsulfonates
  • Ethers to alkyl halides with HX (Br, I)
  • Epoxides (a strained ether) to alcohols with Grignard Reagents, Cyanide, Acetylides, Amines, Azides, Hydroxide, Alkoxides, Carboxylates, Thiolates, mineral acids, etc.

  S_N2 Substitution Products with Alkyl Halides

  (Product in Parenthesis)
  *with primary or methyl alkyl halides or arylsulfonates because the nucleophile is too basic

better leaving group
better nucleophile
C -:CN, cyanide (nitriles) *-:CCR, acetylide (alkynes) *Enolates(alpha-substituted carbonyl compounds)	N :NH3 (primary amines) :NH2R (secondary amines) :NHR2 (tertiary amines) :NR3 (quaternary ammonium salts) -:N3, azide, followed by LiAlH4 (primary amines) phthalimide and base followed by hydrazine (primary amines)	O *-:OH(alcohols) *-:OR , alkoxides, Williamson (ether) synthesis -:OCOR, carboxylates, (esters)	F fluorides	better nucleophile	better leaving group
	P :PR3, phosphine (phosphonium salts)	S -:SH, sulfide (thiols, mercaptans) -:SR, thiolate (dialkyl sulfides)	Cl NaCl (chlorides)
		Se selenides	Br NaBr (bromides)
			I NaI (iodides)