Nucleophilic Substitution Reactions: S N 2 Mechanism

The S N 2 Mechanism of Nucleophilic Substitution

Concerted One Step - Bimolecular Reactions

Many nucleophilic substitutions follow a second-order rate law. CH 3 Br + HO – CH 3 OH + Br – rate = k [CH 3 Br] [HO – ] What is the reaction order of each starting material? What can you infer on a molecular level? What is the overall order of reaction? Kinetics

HO – CH 3 Br + HOCH 3 Br – + one step concerted Bimolecular mechanism

HO – CH 3 Br + HOCH 3 Br – + one step concerted Bimolecular mechanism

HO – CH 3 Br + HOCH 3 Br – + one step concerted HO CH 3 Br  transition state Bimolecular mechanism

Question Assuming the reaction below takes place by a concerted process, which mechanistic scheme is correct?

Stereochemistry of S N 2 Reactions

Generalization Nucleophilic substitutions that exhibit second-order kinetic behavior are stereospecific and proceed with inversion of configuration.

nucleophile attacks carbon from side opposite bond to the leaving group Inversion of Configuration

nucleophile attacks carbon from side opposite bond to the leaving group three-dimensional arrangement of bonds in product is opposite to that of reactant Inversion of Configuration

Inversion of configuration (Walden inversion) in an S N 2 reaction is due to back side attack

A stereospecific reaction is one in which stereoisomeric starting materials give stereoisomeric products. The reaction of 2-bromooctane with NaOH (in ethanol-water) is stereospecific. (+)-2-Bromooctane (–)-2-Octanol (–)-2-Bromooctane  (+)-2-Octanol Stereospecific Reaction

CH CH 3 Br CH 3 (CH 2 ) 5 CH CH 3 HO (CH 2 ) 5 CH 3 NaOH (S)-(+)-2-Bromooctane (R)-(–)-2-Octanol Stereospecific Reaction

H Br CH 3 CH 2 (CH 2 ) 4 CH 3 1) Draw the Fischer projection formula for (+)-S-2-bromooctane. 2) Write the Fischer projection of the (–)-2-octanol formed from it by nucleophilic substitution with inversion of configuration. 2) Write the Fischer projection of the (–)-2-octanol formed from it by nucleophilic substitution with inversion of configuration. HOH CH 3 CH 2 (CH 2 ) 4 CH 3 A.) R- ? or B.) S- ?

A conceptual view of S N 2 reactions

Why does the nucleophile attack from the back side?

“Roundabout” S N 2 Reaction Mechanism

Physicist Roland Wester and his team in Matthias Weidemüller's group at the University of Freiburg, in Germany, in collaboration with William L. Hase's group at Texas Tech University, provide direct evidence for this mechanism in the gas phase. However, they also detected an additional, unexpected mechanism. In this new pathway, called the roundabout mechanism, chloride bumps into the methyl group and spins the entire methyl iodide molecule 360° before chloride substitution. Data at lower collision energies support the traditional SN2 mechanism. However, at higher collision energies, about 10% of the iodide ions fell outside of the expected distribution. "We saw a group of iodide ions with a much slower velocity than the rest," says Wester. "Since energy is conserved, if iodide ions are slow, the energy has to be somewhere else." On the basis of calculations performed by their colleagues at Texas Tech, the team concluded that the energy missing from the iodide transfers to the methyl chloride product in the form of rotational excitation, supporting the proposed roundabout mechanism. S N 2 Reaction Mechanisms: Gas Phase (2008) Traditional Roundabout

Roundabout S N 2 Mechanism Traditional S N 2 Mechanism

Published by AAAS J. Mikosch et al., Science 319, (2008) J. Mikosch et al., Science 319, (2008) Fig. 1. Calculated MP2(fc)/ECP/aug-cc-pVDZ Born-Oppenheimer potential energy along the reaction coordinate g = RC-I - RC-Cl for the SN2 reaction Cl- + CH3I and obtained stationary points

Published by AAAS J. Mikosch et al., Science 319, (2008) J. Mikosch et al., Science 319, (2008) Fig. 2. (A to D) Center-of-mass images of the I- reaction product velocity from the reaction of Cl- with CH3I at four different relative collision energies

Published by AAAS J. Mikosch et al., Science 319, (2008) J. Mikosch et al., Science 319, (2008) Fig. 3. View of a typical trajectory for the indirect roundabout reaction mechanism at 1.9 eV that proceeds via CH3 rotation

Steric Effects in S N 2 Reactions

The rate of nucleophilic substitution by the S N 2 mechanism is governed by steric effects. Crowding at the carbon that bears the leaving group slows the rate of bimolecular nucleophilic substitution. Crowding at the Reaction Site

RBr + LiI RI + LiBr AlkylClassRelative bromiderate CH 3 BrMethyl221,000 CH 3 CH 2 BrPrimary1,350 (CH 3 ) 2 CHBrSecondary1 (CH 3 ) 3 CBrTertiarytoo small to measure Reactivity toward substitution by the S N 2 mechanism

A bulky substituent in the alkyl halide reduces the reactivity of the alkyl halide: steric hindrance

CH 3 Br CH 3 CH 2 Br (CH 3 ) 2 CHBr (CH 3 ) 3 CBr Decreasing S N 2 Reactivity

CH 3 Br CH 3 CH 2 Br (CH 3 ) 2 CHBr (CH 3 ) 3 CBr Decreasing S N 2 Reactivity

Reaction coordinate diagrams for (a) the S N 2 reaction of methyl bromide and (b) an S N 2 reaction of a sterically hindered alkyl bromide

The rate of nucleophilic substitution by the S N 2 mechanism is governed by steric effects. Crowding at the carbon adjacent to the one that bears the leaving group also slows the rate of bimolecular nucleophilic substitution, but the effect is smaller. Crowding Adjacent to the Reaction Site

RBr + LiI RI + LiBr AlkylStructureRelative bromiderate EthylCH 3 CH 2 Br1.0 PropylCH 3 CH 2 CH 2 Br0.8 Isobutyl(CH 3 ) 2 CHCH 2 Br0.036 Neopentyl(CH 3 ) 3 CCH 2 Br Effect of chain branching on rate of S N 2 substitution

Which reaction will have the fastest rate of reaction? Question A)B)C)

Putting things together

IUPAC Nomenclature of Alkyl Halides

The two that are most widely used are: functional class nomenclature substituent nomenclature Both types can be applied alkyl halides and to alcohols. IUPAC Nomenclature There are several kinds of IUPAC nomenclature.

Name the alkyl group and the halogen as separate words (alkyl + halide). Functional Class Nomenclature of Alkyl Halides CH 3 F CH 3 CH 2 CH 2 CH 2 CH 2 Cl CH 3 CH 2 CHCH 2 CH 2 CH 3 Br H I

Name the alkyl group and the halogen as separate words (alkyl + halide). Functional Class Nomenclature of Alkyl Halides CH 3 F CH 3 CH 2 CH 2 CH 2 CH 2 Cl CH 3 CH 2 CHCH 2 CH 2 CH 3 Br Methyl fluoride Pentyl chloride 1-Ethylbutyl bromide Cyclohexyl iodide H I

Name as halo-substituted alkanes. Number the longest chain containing the halogen in the direction that gives the lowest number to the substituted carbon. Substituent Nomenclature of Alkyl Halides CH 3 CH 2 CH 2 CH 2 CH 2 F CH 3 CHCH 2 CH 2 CH 3 Br CH 3 CH 2 CHCH 2 CH 3 I

Name as halo-substituted alkanes. Number the longest chain containing the halogen in the direction that gives the lowest number to the substituted carbon. Substitutive Nomenclature of Alkyl Halides CH 3 CH 2 CH 2 CH 2 CH 2 F CH 3 CHCH 2 CH 2 CH 3 Br 1-Fluoropentane 3-Iodopentane 2-Bromopentane CH 3 CH 2 CHCH 2 CH 3 I

Substitutive Nomenclature of Alkyl Halides Halogen and alkyl groups are of equal rank when it comes to numbering the chain. Number the chain in the direction that gives the lowest number to the group (halogen or alkyl) that appears first. CH 3 Cl Cl

Substitutive Nomenclature of Alkyl Halides 5-Chloro-2-methylheptane 2-Chloro-5-methylheptane CH 3 Cl Cl

Question Name the compound on the right according to the IUPAC system. A)4-bromo-5-ethyl-2-methylheptane B)4-bromo-3-ethyl-6-methylheptane C)4-bromo-5-diethyl-2-methylpentane D)4-bromo-3-ethyl-6-dimethylhexane

Question A. (3S,4S)-3-bromo-4-chlorohexane B. (3S,4S)-3,4-dibromochloroheptane C. (3R,4R)-3-chloro-4-bromohexane D. (3R,4R)-3-bromo-4-chlorohexane E. (3S,4S)-4-bromo-3-chlorohexane A. (3S,4S)-3-bromo-4-chlorohexane B. (3S,4S)-3,4-dibromochloroheptane C. (3R,4R)-3-chloro-4-bromohexane D. (3R,4R)-3-bromo-4-chlorohexane E. (3S,4S)-4-bromo-3-chlorohexane What is the correct IUPAC name for the ABOVE structure?

Classes of Alkyl Halides

Alkyl halides & alcohols are classified as primary secondary tertiary according to their "degree of substitution." Degree of substitution is determined by counting the number of carbon atoms directly attached to the carbon that bears the halogen or hydroxyl group. Classification

Different Kinds of Alkyl Halides

CH 3 CH 2 CH 2 CH 2 CH 2 F CH 3 CHCH 2 CH 2 CH 3 Br primary alkyl halide secondary alkyl halide Classification CH 3 CCH 2 CH 2 CH 3 OH CH 3 tertiary alcohol H OH secondary alcohol

Question What type of alcohol is 2-methyl-3-pentanol? A)primary (1°) B)secondary (2°) C)tertiary (3°) D)quaternary (4°)