Reactions of Alkyl Halides Unit 4 - 2 4/16/2017 Reactions of Alkyl Halides “Ninety-five percent of the reactions that we see in organic chemistry occur between a nucleophile and an electrophile.” Klein, D.R., Organic Chemistry as a Second Language, 2004, John Wiley & Sons, Inc. The alkyl halides undergo a variety of reactions that will help us begin the study of reactions between nucleophiles and electrophiles.

Nucleophiles and Electrophiles Nucleophiles are chemical species with a negative charge or an unbonded pair of electrons. Nucleophile = Lewis base Electrophiles are chemical species that can accept an electron pair. Electrophile = Lewis acid Being able to draw Lewis structures is vital to understanding the material in this and following units.

Nucleophiles and Electrophiles Which species are nucleophiles?

Reactions of Alkyl Halides Alkyl halides undergo a variety of reactions because Cl-, Br-, and I- are good leaving groups. This makes possible two types of reactions. Substitution, where a nucleophile replaces the leaving group. Elimination, where H+ leaves as well and an alkene is formed.

Nucleophilic Substitution leaving group

Elimination B:- is a species acting as a base. leaving group B:- is a species acting as a base. FYI: Some species can act as both bases and nucleophiles.

Kinetics of Substitution Reactions: SN1 and SN2 There are two different mechanisms by which nucleophilic substitution can happen. SN1: substitution, nucleophilic, unimolecular rate = k[substrate] SN2: substitution, nucleophilic, bimolecular rate = k[substrate][nucleophile]

SN2 Reaction Mechanism   nucleophile substrate (electrophile) δ- δ- δ- δ+  nucleophile substrate (electrophile) transition state  leaving group product

SN2 Reaction Profile rate = k[CH3I][OH-] -EA/RT k = Ae EA

SN2 Reactions SN2 reactions are exothermic. SN2 reactions are concerted: they occur in a single step as the result of a collision between the nucleophile and the substrate. The Arrhenius equation shows that the rate constant k is a function of the activation energy EA and the temperature. (True for all reactions.)

SN2 Reaction Products from Alkyl Halides - A Partial List R-I alkyl iodide R-OH alcohol R-OR’ ether R-SH thiol R-NH2 amine R-C≡C-R’ alkyne R-CN nitrile R’-COO-R ester What would the starting alkyl halide be? What would the starting nucleophile be?

Factors Affecting SN2 Reactions Strength of the nucleophile Stronger nucleophiles give faster reactions. The solvent in which the reaction is run. Nature of the leaving group Structure of the substrate Can the nucleophile easily reach the electropositive C atom? FYI: You will use this template to study many other types of organic reactions.

Factors Affecting SN2 Reactions - Strength of the Nucleophile Look at the nucleophile in terms of the transition state. Nucleophiles that decrease the energy of the transition state increase the rate of reaction. A species with a negative charge is a stronger nucleophile than a similar species that is neutral. OH- is a better nucleophile than H2O. A base is a better nucleophile than its conjugate acid.

Factors Affecting SN2 Reactions - Strength of the Nucleophile Good nucleophiles must be polarizable. This facilitates the formation of the partial bond in the transition state and makes EA lower. Polarizability increases down a group, due to the increase in size and decrease in electronegativity. I- > Br- > Cl- > F-

Factors Affecting SN2 Reactions - Strength of the Nucleophile Good nucleophiles must be electronegative (we say electron withdrawing), but not too electronegative. The nucleophile must be able to hold nonbonding electrons, but it must be able to let the electrons go as it forms the bond to the substrate. F- is a weak nucleophile. I- is an excellent nucleophile.

Strength of some nucleophiles in water or alcohol solvents Strong (CH3CH2)3P: HS- I- (CH3CH2)2NH CN- (CH3CH2)3N: HO- CH3O- Moderate Br- NH3 CH3SCH3 Cl- .. increasing strength Weak CH3COO- F- HOH CH3OH

Nucleophilicity vs. Basicity These terms describe functions. The nucleophilicity of a species is a kinetic term referring to how fast the species will attack an electrophilic C atom. The basicity of a species is how well it abstracts a proton H+. This refers to the position of the equilibrium and is a thermodynamic term. CH3O- or I- : Which is the better base? Which is the better nucleophile?

Factors Affecting SN2 Reactions - Steric Effects on Nucleophilicity Good nucleophiles must be able to get close enough to form a bond to the electrophilic C atom. Bulky groups on the nucleophile can hinder this approach.  stronger base stronger nucleophile  Bulky groups don’t affect basicity much.

Factors Affecting SN2 Reactions - Solvent Effects In SN2 reactions, the main effect of the solvent is on nucleophilicity. Protic solvents such as water and alcohols can solvate nucleophiles through H-bonding. This solvation impedes the formation of the partial bond in the transition state. These must leave for the reaction to proceed.

Factors Affecting SN2 Reactions - Solvent Effects Polar aprotic solvents such as acetone, THF, and acetonitrile solvate the cation but not the nucleophile. Polar aprotic solvents enhance nucleophilicity.

Factors Affecting SN2 Reactions - the Leaving Group The leaving group (LG) serves two purposes in an SN2 reaction. It polarizes the bond that makes the C atom electrophilic. It carries away a pair of electrons from the electrophilic C atom.

Factors Affecting SN2 Reactions - the Leaving Group A good LG must be: electron withdrawing, to polarize the bond and make the C atom electrophilic, polarizable, to stabilize the transition state, and stable in the solvent (so it cannot be a strong base). Best LGs are neutral species or anions with a stabilized charge. The first two are the same as for a strong nucleophile, but the last one is not!

Good Leaving Groups - Ions that are weak bases Cl- Br- I- sulfonates sulfates phosphates

Good Leaving Groups - Molecules that are weak bases alcohols amines phosphines

Rotten Leaving Groups - strong bases hydroxide alkoxides amide

How to Make a Rotten LG Better Protonate the LG by acidifying the solution. Example: Use HBr instead of NaBr to make methyl bromide from methanol. This turns a poor leaving group (OH-) into a good one (H2O).

Factors Affecting SN2 Reactions - Structure of the Substrate To be a good substrate for SN2 attack, a molecule must have an electrophilic C atom with a good leaving group and which is not too sterically hindered for the nucleophile to attack. Alkyl halides are not the only substrates for SN2 reactions.

Factors Affecting SN2 Reactions - Structure of the Substrate The substrate is the species undergoing nucleophilic attack. The substrate contains the electrophilic C and the LG. Bulky groups on the electrophilic C atom can hinder nucleophilic attack. Relative rates for SN2: CH3X>1°>2°

Factors Affecting SN2 Reactions - Structure of the Substrate Relative rates for SN2: CH3X >1°>2° 3° halides do not react by SN2. 2° halides give much slower SN2 rates due to steric hindrance of the nucleophile. Methyl halides give fastest SN2 rates.

Stereochemistry of the SN2 Reaction Because of the attack from the side opposite the LG, the configuration of the product is inverted around the electrophilic C atom.  (S)-2-bromobutane (R)-2-butanol

SN2 Reactions - Summary The structure of the substrate around the electrophilic C affects the rate: Relative rates for SN2: CH3X>1°>2°. The nucleophile should be moderate to strong and not solvated by the solvent. The LG should be more stable in the solvent than the nucleophile. The solvent should dissolve the nucleophile but not solvate it…polar aprotic solvents are best. There will be an inversion of configuration around the electrophilic C.