Substitution Reactions of Alkyl Halides: Chapter 8

Contents of Chapter 8 Reactivity Considerations The SN2 Reaction Reversibility of the SN2 Reaction The SN1 Reaction Stereochemistry of SN2 and SN1 Reactions Benzylic, Allylic, Vinylic & Aryl Halides Competition between SN2 and SN1 Reactions Role of the Solvent No Biological Methylating Reagents Chapter 8

Substitution and Elimination A compound with an sp3 hybridized carbon bonded to a halogen can undergo two types of reactions Two different mechanisms for substitution are SN1 and SN2 mechanisms These result in diff prods under diff conditions Chapter 8

SN2 Mechanism SN2 mechanism: C–X bond weakens as nucleophile approaches all in one step Chapter 8

SN1 Mechanism SN1 mechanism: C–X bond breaks first without any help from nucleophile slow step fast step This is a two-step process Chapter 8

Substitution Reactions Both mechanisms are called nucleophilic substitutions Which one takes place depends on the structure of the alkyl halide the reactivity and structure of the nucleophile the concentration of the nucleophile, and the solvent in which reaction is carried out Chapter 8

The SN2 Reaction Bimolecular nucleophilic substitution rate = k [alkyl halide][nucleophile] Chapter 8

The SN2 Reaction The inversion of configuration resembles the way an umbrella turns inside out in the wind If a single chiral enantiomer reacts a single chiral product (inverted) results. Chapter 8

Steric Accessibility in the SN2 Reaction Chapter 8

The SN2 Reaction: Leaving Group Stability Chapter 8

The SN2 Reaction: Nucleophile Basicity stronger base weaker base better nucleophile poorer nucleophile HO– > H2O CH3O– > CH3OH –NH2 > NH3 CH3CH2NH– > CH3CH2NH2 Chapter 8

The SN2 Reaction: Nucleophile Basicity Comparing nucleophiles with attacking atoms of approximately the same size, the stronger base is also the stronger nucleophile Chapter 8

The SN2 Reaction: Nucleophile Size In nonpolar solvents nucleophilicity order same as basicity order- size doesn’t matter Chapter 8

The SN2 Reaction: Nucleophile Size Size is related to polarizability Chapter 8

The SN2 Reaction: Nucleophile Size and Type Nucleophilicity ~ both size and basicity Chapter 8

The SN2 Reaction: Nucleophile Bulkiness Nucleophilicity is affected by steric effects A bulky nucleophile has difficulty getting near the back side of a sp3 carbon ethoxide ion tert-butoxide ion better nucleophile stronger base Chapter 8

The SN1 Reaction The more stable the C+ the lower the DG‡, and the faster the rxn Chapter 8

The SN1 Reaction Chapter 8

The SN1 Reaction The SN1 reaction leads to a mixture of stereoisomers Chapter 8

The SN1 Reaction: Factors Affecting the Rate Two factors affect the rate of formation of the carbocation ease with which the leaving group leaves RI > RBr > RCl > RF increasing reactivity stability of the carbocation 3º alkyl halide > 2º alkyl halide > 1º alkyl halide increasing reactivity Chapter 8

The SN1 Reaction: Carbocation Rearrangements Chapter 8

Stereochemistry of SN2 and SN1 Reactions inversion both enantiomers Chapter 8

Competition Between SN2 and SN1 Reactions Chapter 8

Competition Between SN2 and SN1 Reactions TABLE 9.6 Summary of the Reactivity of Alkyl Halides in Nucleophilic Substitution Reactions methyl & 1o alkyl halides SN2 only 2o alkyl halides SN2 & SN1 3o alkyl halides SN1 only vinylic & aryl halides neither SN2 nor SN1 benzylic & allylic halides SN2 & SN1 3o benzylic & allylic halides SN1 only Chapter 8

Competition Between SN2 and SN1 Reactions What are the factors that determine which mechanism operates? concentration of the nucleophile reactivity of the nucleophile solvent in which the reaction is carried out For SN2 rate = k2 [alkyl halide][nucleophile] For SN1 rate = k1 [alkyl halide] Chapter 8

Competition Between SN2 and SN1 Reactions An increase in the concentration of the nucleophile increases the rate of the SN2 reaction but has no effect on rate of SN1 reaction An increase in the reactivity of nucleophile also speeds up an SN2 rxn but not an SN1 rxn Chapter 8

Role of the Solvent The solvent in which a nucleophilic substitution reaction is carried out has an influence on whether the reaction proceeds via an SN2 or an SN1 mechanism Two important solvent aspects include solvent polarity whether it is protic or aprotic Chapter 8

Solvent Polarity The dielectric constant is a measure of how well the solvent can insulate opposite charges from each other Chapter 8

Role of the Solvent Polar solvents have a high dielectric constant Water Alcohols Dimethylsulfoxide (DMSO) Solvents having O–H or N–H bonds are called protic solvents Polar solvents without O-H or N-H bonds called polar aprotic solvents Chapter 8

Role of the Solvent If charge on reactants(s) in slow step is greater than the charge on the transition state, a polar solvent will slow down rxn (by stabilizing reactants) If all reactant(s) involved in slow step are neutral polar solvent will speed up rxn If reactant(s) involved in slow step are charged polar solvent slows down rxn Chapter 8

SN1 Reaction: Effect of Solvent Most SN1 reactions involve a neutral alkyl halide which needs to produce a C+ Consequently a polar solvent stabilizes the transition state more than the reactant Increasing the polarity of the solvent speeds up such an SN1 reaction Protic solvents stabilize the leaving group by H-bonding and thus stabilize the transition state Chapter 8

SN2 Reaction: Effect of Solvent Most SN2 reactions involve a neutral alkyl halide and a charged nucleophile Consequently a polar solvent stabilizes the nucleophile more than the transition state and slows rxn The nucleophiles used in SN2 reactions however are generally insoluble in nonpolar solvents - some solvent polarity is needed, but it’s best to use an aprotic solvent to avoid overstabilizing nucleophile reactant Chapter 8

Competition Between SN2 and SN1 Reactions When a halide can undergo both an SN2 and SN1 reaction: SN2 will be favored by a high concentration of a good (negatively charged) nucleophile SN2 will be favored in a polar aprotic solvent SN1 will be favored by a poor (neutral) nucleophile in a polar protic solvent Chapter 8

Problem-solving Info Nucleophile strength Protic solvent Size most important Look at basicity if same row of periodic table Aprotic solvent- look at basicity only Strength in aprotic solvent > protic solvent First two points not strictly true but will work in this course Chapter 8

Problem-solving Info Electrophile strength SN2 reactions SN1 reactions Steric accessibility Electron withdrawing group (EWG) attached to C reaction site Good leaving group SN1 reactions Carbocation stability EWG not attached to reaction site Chapter 8

Problem-solving Info Solvent polarity Reduces rate with charged reactants Charge on both nucleophile and electrophile important in SN2 Only electrophile important in SN1 Increases rate with uncharged reactants Reduces nucleophilicity Stabilizes leaving group for SN1 Chapter 8

Problem-solving Info Reaction speed comparisons Increasing speed in SN1 reaction Polar solv/uncharged electrophile, vice-versa Relief of steric strain making C+ More stable carbocation formed Anything which destabilizes electrophile Increased leaving group stability (less basic) Increasing speed in SN2 reaction Charge on electrophile & nuc vs. solv polarity Chapter 8

Problem-solving Info Stereochemistry Increased leaving group stability Less steric hindrance (both nuc & electrophile) Switch from protic to aprotic solvent Higher concentration of nucleophile More basic nucleophile Larger size of nucleophile’s attacking atom Anything which destabilizes nuc or electrophile Stereochemistry SN1 reactions give both isomers at chiral C SN2 reactions give only inversion at chiral C Chapter 8

Problem-solving Info Carbocation rearrangements SN1 vs SN2 chemistry Will occur if posible with SN1 Will not occur with SN2 SN1 vs SN2 chemistry Conditions which give SN1 Tertiary C reaction center C+ stability  2 & weak nuc (H-nuc pKa <7) Carboxylates and sulfonates Neutral O nucleophiles Halides Neutral large-atom (row >2) nucleophiles Chapter 8

Problem-solving Info Conditions which give SN2 C+ stability index = 1 and unhindered rxn site C+ stability  2, not 3°, strong nucleophile Any nuc with conj acid pKa  7 (Table 10.3 pg 373) Alkoxides and hydroxide Ammonia and amines Carbanions Sulfides Hydride Nitrogen anions In this text “high conc” of nuc is code for SN2 Other conditions give SN1/SN2 mixture Chapter 8