Chapter 6 Lecture Organic Chemistry, 8 th Edition L. G. Wade, Jr. Alkyl Halides: Nucleophilic Substitution and Elimination © 2013 Pearson Education, Inc. Rizalia Klausmeyer Baylor University Waco, TX

Classes of Alkyl Halides Alkyl halides: Halogen is directly bonded to sp 3 carbon. Vinyl halides: Halogen is bonded to sp 2 carbon of alkene. Aryl halides: Halogen is bonded to sp 2 carbon on benzene ring. CC H H H Cl vinyl halide C H H H C H H Br alkyl halide I aryl halide 2 © 2013 Pearson Education Inc.

Polarity and Reactivity Halogens more EN than C. Carbon—halogen bond is polar, so carbon has partial positive charge. Carbon can be attacked by a nucleophile. Halogen can leave with the electron pair. 3 © 2013 Pearson Education Inc.

IUPAC Nomenclature Name as haloalkane. Choose the longest carbon chain, even if the halogen is not bonded to any of those carbons. Use lowest possible numbers for position chlorobutane4-(2-fluoroethyl)heptane © 2013 Pearson Education Inc.

Examples bromo-2-methylnonane 1 3 cis-1-bromo-3-fluorocyclohexane 5 © 2013 Pearson Education Inc.

More Examples 6 3-fluoro-2,4-dimethylpentane 1-bromo-2-chloro-4-ethylcyclopentane 3-bromo-5-chloro-4-ethylheptane 5-chloro-4-(1-chloroethyl)-3-bromoheptane 2-bromo-4-(1-bromoethyl)-1-chlorocyclopentane 6-ethyl-3-iodo-5-isopropyl-4-propylnonane

Systematic Common Names You may encounter common names where the alkyl groups is a substituent on halide. Useful only for small alkyl groups. isobutyl bromidesec-butyl bromide tert-butyl bromide 7 © 2013 Pearson Education Inc.

Common Names of Halides CH 2 X 2 is called methylene halide. CHX 3 is a haloform. CX 4 is carbon tetrahalide. Common halogenated solvents: CH 2 Cl 2 is methylene chloride. CHCl 3 is chloroform. CCl 4 is carbon tetrachloride. 8 © 2013 Pearson Education Inc.

Alkyl Halides Classification Methyl halides: Halide is attached to a methyl group. Primary alkyl halide: Carbon to which halogen is bonded is attached to only one other carbon. Secondary alkyl halide: Carbon to which halogen is bonded is attached to two other carbons. Tertiary alkyl halide: Carbon to which halogen is bonded is attached to three other carbons. 9 © 2013 Pearson Education Inc.

Primary, Secondary, Tertiary Alkyl Halides 10 © 2013 Pearson Education Inc.

Types of Dihalides Geminal dihalide: Two halogen atoms are bonded to the same carbon. Vicinal dihalide: Two halogen atoms are bonded to adjacent carbons. 11 © 2013 Pearson Education Inc.

Uses of Alkyl Halides Industrial and household cleaners. Anesthetics: – CHCl 3 used originally as general anesthetic but it is toxic and carcinogenic. – CF 3 CHClBr is a mixed halide sold as Halothane. Freons are used as refrigerants and foaming agents. – Freons can harm the ozone layer, so they have been replaced by low-boiling hydrocarbons or carbon dioxide. Pesticides such as DDT are extremely toxic to insects but not as toxic to mammals. – Haloalkanes can not be destroyed by bacteria, so they accumulate in the soil to a level that can be toxic to mammals, especially humans. 12 © 2013 Pearson Education Inc.

Dipole Moments Electronegativities of the halides: F > Cl > Br > I Bond lengths increase as the size of the halogen increases: C—F < C—Cl < C—Br < C—I Bond dipoles: C—Cl > C—F > C—Br > C—I 1.56 D 1.51 D 1.48 D 1.29 D Molecular dipoles depend on the geometry of the molecule. 13 © 2013 Pearson Education Inc.

Dipole Moments and Molecular Geometry Notice how the four symmetrically oriented polar bonds of the carbon tetrahalides cancel to give a molecular dipole moment of zero. 14 © 2013 Pearson Education Inc.

Interparticle Forces 1.Dipolar forces: Attraction between positive end of one polar molecule and negative end of another (usually weak, ~ kcal) 2.Hydrogen Bonding: Attractive interaction of a hydrogen atom with an electronegative atom (e.g. N, O, F) from another molecule or chemical group. – The H must be covalently bonded to another electronegative atom. – Stronger than dipolar and dispersion ( kcal) 3.London Dispersion Forces: Momentary nonsymmetric electron distributions in molecules (very weak) δ-δ- δ-δ- δ+δ+ δ+δ+ Intermolecular dipolar Hydrogen bond δ+δ+ δ-δ- δ+δ+ δ-δ- 15 © 2013 Pearson Education Inc.

Boiling Points Greater intermolecular forces, higher b.p. – Dipole-dipole attractions not significantly different for different halides. – London forces greater for larger atoms. Greater mass, higher b.p. Spherical shape decreases b.p. (CH 3 ) 3 CBr CH 3 (CH 2 ) 3 Br 73  C 102  C 16 © 2013 Pearson Education Inc.

Densities Alkyl fluorides and alkyl chlorides (those with just one chlorine atom) are less dense than water (1.00 g/mL). Alkyl chlorides with two or more chlorine atoms are denser than water. All alkyl bromides and alkyl iodides are denser than water. 17 © 2013 Pearson Education Inc.

Preparation of Alkyl Halides Free radical halogenation (Chapter 4) – Chlorination produces a mixtures of products. This reaction is not a good lab synthesis, except in alkanes where all hydrogens are equivalent. – Bromination is highly selective. Free radical allylic halogenation – Halogen is placed on a carbon directly attached to the double bond (allylic). 18 © 2013 Pearson Education Inc.

Halogenation of Alkanes Chlorination is not selective. Bromination is highly selective: 3º carbons > 2º carbons > 1º carbons 19 © 2013 Pearson Education Inc.

Allylic Bromination Allylic radicals are resonance stabilized. Bromination occurs with good yield at the allylic position (sp 3 C next to C C). 20 © 2013 Pearson Education Inc.

Reaction Mechanism The mechanism involves an allylic radical stabilized by resonance. Both allylic radicals can react with bromine. 21 © 2013 Pearson Education Inc.

N-Bromosuccinimide N-Bromosuccinimide (NBS) is an allylic brominating agent. Keeps the concentration of Br 2 low. 22 © 2013 Pearson Education Inc.

Example of Allylic Halogenation with NBS File Name: AAAKWEA0 23 © 2013 Pearson Education Inc.

Reactions of Alkyl Halides 24 © 2013 Pearson Education Inc.

The S N 2 Reaction The halogen atom on the alkyl halide is replaced with the nucleophile (HO - ). Since the halogen is more electronegative than carbon, the C—I bond breaks heterolytically and the iodide ion leaves. 25 © 2013 Pearson Education Inc.

S N 2 Mechanism Bimolecular nucleophilic substitution (S N 2). Concerted reaction: New bond forming and old bond breaking at same time. Reaction is second order overall. Rate = k r [alkyl halide][nucleophile]. 26 © 2013 Pearson Education Inc.

S N 2 Energy Diagram The S N 2 reaction is a one-step reaction. Transition state is highest in energy. 27 © 2013 Pearson Education Inc.

Uses for S N 2 Reactions 28 © 2013 Pearson Education Inc.

S N 2: Nucleophilic Strength Stronger nucleophiles react faster. Strong bases are strong nucleophiles, but not all strong nucleophiles are basic. 29 © 2013 Pearson Education Inc.

Basicity Versus Nucleophilicity Basicity is defined by the equilibrium constant for abstracting a proton. Nucleophilicity is defined by the rate of attack on the electrophilic carbon atom 30 © 2013 Pearson Education Inc.

Steric hindrance (bulkiness) hinders nucleophilicity more than it hinders basicity. 31 © 2013 Pearson Education Inc.

Trends in Nucleophilicity A negatively charged nucleophile is stronger than its neutral counterpart: Nucleophilicity decreases from left to right: Increases down periodic table, as size and polarizability increase: 32 © 2013 Pearson Education Inc.

Polarizability Effect Bigger atoms have a soft shell that can start to overlap the carbon atom from a farther distance. 33 © 2013 Pearson Education Inc.

Solvent Effects: Protic Solvents Polar protic solvents have acidic hydrogens (O—H or N— H) that can solvate the nucleophile, reducing their nucleophilicity. Nucleophilicity in protic solvents increases as the size of the atom increases. 34 © 2013 Pearson Education Inc.

Solvent Effects: Aprotic Solvents Polar aprotic solvents do not have acidic protons and therefore cannot hydrogen bond. Some aprotic solvents are acetonitrile, DMF, acetone, and DMSO. S N 2 reactions proceed faster in aprotic solvents. 35 © 2013 Pearson Education Inc.

Crown Ethers Crown ethers solvate the cation, so the nucleophilic strength of the anion increases. Fluoride becomes a good nucleophile. 36 © 2013 Pearson Education Inc.

Leaving Group Ability The best leaving groups are: Electron-withdrawing, to polarize the carbon atom. Stable (not a strong base) once they have left. Polarizable, to stabilize the transition state. 37 © 2013 Pearson Education Inc.

Do not write S N 2 reactions that show hydroxide ions, alkoxide ions, or other strong bases serving as leaving groups. 38 © 2013 Pearson Education Inc.

Structure of Substrate on S N 2 Reactions Relative rates for S N 2: CH 3 X > 1° > 2° >> 3° Tertiary halides do not react via the S N 2 mechanism, due to steric hindrance. 39 © 2013 Pearson Education Inc.

Effect of Substituents on the Rates of S N 2 Reactions 40 © 2013 Pearson Education Inc.

Steric Effects of the Substrate on S N 2 Reactions Nucleophile approaches from the back side. It must overlap the back lobe of the C—X sp 3 orbital. 41 © 2013 Pearson Education Inc.

Stereochemistry of S N 2 S N 2 reactions will result in an inversion of configuration also called a Walden inversion. 42 © 2013 Pearson Education Inc.

Back-Side Attack in the S N 2 Reaction 43 © 2013 Pearson Education Inc.

(R) and (S) are just names. Don’t rely on names to determine the stereochemistry of a reaction. 44 © 2013 Pearson Education Inc.

The S N 1 Reaction The S N 1 reaction is a unimolecular nucleophilic substitution. It has a carbocation intermediate. Rate = k r [alkyl halide]. Racemization occurs. 45 © 2013 Pearson Education Inc.

S N 1 Mechanism If the nucleophile is an uncharged molecule like water or an alcohol, the positively charged product must lose a proton to give the final uncharged product. Step 1: Formation of the carbocation. Step 2: Attack of the nucleophile. 46 © 2013 Pearson Education Inc.

Formation of carbocation (rate-determining step) S N 1 Mechanism: Step 1 47 © 2013 Pearson Education Inc.

S N 1 Mechanism: Step 2 The nucleophile attacks the carbocation, forming the product. 48 © 2013 Pearson Education Inc.

If the nucleophile was neutral, a third step (deprotonation) will be needed. S N 1 Mechanism: Step 3 49 © 2013 Pearson Education Inc.

S N 1 Energy Diagram Forming the carbocation is an endothermic step. Step 2 is fast with a low activation energy. 50 © 2013 Pearson Education Inc.

Rates of S N 1 Reactions Order of reactivity follows stability of carbocations (opposite to S N 2). – 3° > 2° > 1° >> CH 3 X – More stable carbocation requires less energy to form. A better leaving group will increase the rate of the reaction. 51 © 2013 Pearson Education Inc.

Solvation Effect Polar protic solvent is best because it can solvate both ions strongly through hydrogen bonding. 52 © 2013 Pearson Education Inc.

Structure of the Carbocation Carbocations are sp 2 hybridized and trigonal planar. The lobes of the empty p orbital are on both sides of the trigonal plane. Nucleophilic attack can occur from either side, producing mixtures of retention and inversion of configuration if the carbon is chiral. 53 © 2013 Pearson Education Inc.

Carbocation Stability Carbocations are stabilized by inductive effect and by hyperconjugation. 54 © 2013 Pearson Education Inc.

Stereochemistry of S N 1 The S N 1 reaction produces mixtures of enantiomers. There is usually more inversion than retention of configuration. 55 © 2013 Pearson Education Inc.

Rearrangements Carbocations can rearrange to form a more stable carbocation. Move the smallest group on the adjacent carbon: – Hydride shift: H - on adjacent carbon moves. – Methyl shift: CH 3 - on adjacent carbon moves. 56 © 2013 Pearson Education Inc.

Hydride and Methyl Shifts Since a primary carbocation cannot form, the methyl group on the adjacent carbon will move (along with both bonding electrons) to the primary carbon, displacing the bromide and forming a tertiary carbocation. The smallest groups on the adjacent carbon will move: If there is a hydrogen, it will give a hydride shift. 57 © 2013 Pearson Education Inc.

S N 1 or S N 2 Mechanism? SN2SN2SN1SN1 CH 3 X > 1º > 2º3º > 2º Strong nucleophileWeak nucleophile (may also be used as solvent) Polar aprotic solventPolar protic solvent Rate = k[alkyl halide][Nuc]Rate = k[alkyl halide] Inversion at chiral carbonRacemization No rearrangementsRearranged products 58 © 2013 Pearson Education Inc.

Elimination Reactions Elimination reactions produce double bonds. Also called dehydrohalogenation (-HX). 59 © 2013 Pearson Education Inc.

The E1 Reaction Unimolecular elimination. Two groups lost: a hydrogen and the halide. Nucleophile acts as base. The E1 and S N 1 reactions have the same conditions so a mixture of products will be obtained. 60 © 2013 Pearson Education Inc.

E1 Mechanism Step 1: Ionization to form a carbocation. Step 2: Solvent abstracts a proton to form an alkene. 61 © 2013 Pearson Education Inc.

A Closer Look 62 © 2013 Pearson Education Inc.

E1 Energy Diagram The E1 and the S N 1 reactions have the same first step: Carbocation formation is the rate-determining step for both mechanisms. 63 © 2013 Pearson Education Inc.

Double Bond Substitution Patterns The more substituted double bond is more stable. In elimination reactions, the major product of the reaction is the more substituted double bond: Zaitsev’s rule. tetrasubstitutedtrisubstituteddisubstitutedmonosubstituted 64 © 2013 Pearson Education Inc.

Zaitsev’s Rule If more than one elimination product is possible, the most-substituted alkene is the major product (most stable). major product (trisubstituted) 65 © 2013 Pearson Education Inc.

E1 Competes with the S N 1 Substitution results from nucleophilic attack on the carbocation. Ethanol serves as a base in the elimination and as a nucleophile in the substitution. 66 © 2013 Pearson Education Inc.

A Carbocation Can… React with its own leaving group to return to the reactant. React with a nucleophile to form a substitution product (S N 1). Lose a proton to form an elimination product (E1). Rearrange to give a more stable carbocation, then react further. 67 © 2013 Pearson Education Inc.

The E2 Reaction Elimination, bimolecular. Requires a strong base. This is a concerted reaction: The proton is abstracted, the double bond forms, and the leaving group leaves, all in one step. 68 © 2013 Pearson Education Inc.

The E2 Mechanism Order of reactivity for alkyl halides: 3° > 2 ° > 1° Mixture may form, but Zaitsev product predominates. 69 © 2013 Pearson Education Inc.

E2 Stereochemistry The halide and the proton to be abstracted must be anti-coplanar (  = 180º) to each other for the elimination to occur. The orbitals of the hydrogen atom and the halide must be aligned so they can begin to form a pi bond in the transition state. The anti-coplanar arrangement minimizes any steric hindrance between the base and the leaving group. 70 © 2013 Pearson Education Inc.

E2 Stereochemistry 71 © 2013 Pearson Education Inc.

E1 or E2 Mechanism? Tertiary > secondary Base strength unimportant (usually weak) Good ionizing solvent Rate = k[alkyl halide] Zaitsev product No required geometry Rearranged products Tertiary > secondary Strong base required Solvent polarity not important. Rate = k[alkylhalide][base] Zaitsev product Coplanar leaving groups (usually anti) No rearrangements 72 © 2013 Pearson Education Inc.

Substitution or Elimination? Strength of the nucleophile determines order: Strong nucleophiles or bases promote bimolecular reactions. Primary halides usually undergo S N 2. Tertiary halides are a mixture of S N 1, E1, or E2. They cannot undergo S N 2. High temperature favors elimination. Bulky bases favor elimination. 73 © 2013 Pearson Education Inc.

Secondary Alkyl Halides Secondary alkyl halides are more challenging: – Strong nucleophiles will promote S N 2/E2. – Weak nucleophiles promote S N 1/E1. Strong nucleophiles with limited basicity favor S N 2. Bromide and iodide are good examples of these. 74 © 2013 Pearson Education Inc.

Predict the mechanisms and products of the following reaction. Solved Problem 1 Solution 75 © 2013 Pearson Education Inc.

Solved Problem 2 Solution Predict the mechanisms and products of the following reaction. 76 © 2013 Pearson Education Inc.