Fall, 2009 Organic Chemistry I The Chemistry of Alkyl Halides Unit 10 Dr. Ralph C. Gatrone Department of Chemistry and Physics Virginia State University 1

Objectives

• • • Nomenclature Preparation Reactions – Organometallic Reagents – Nucleophilic Substitution Reactions – Elimination Reactions Fall, 2009 2

What Is an Alkyl Halide?

• • • • • An organic compound containing at least one carbon halogen bond (C-X) – X = F, Cl, Br, I Can contain many C-X bonds – Entirely halogenated = perhalo Wide-spread in nature Common industrial chemicals Properties and some uses – Fire-resistant solvents – Refrigerants – Pesticides – Pharmaceuticals and precursors Fall, 2009 3

•

Nomenclature

Name is based on longest carbon chain – (Contains double or triple bond if present) – Number from end nearest any substituent (alkyl or halogen) Fall, 2009 4

Nomenclature with Multiple Halogen • If more than one of the same kind of halogen is present, use prefix di, tri, tetra • If there are several different halogens, number them and list them in alphabetical order Fall, 2009 5

Naming if Halides Are Equidistant • Begin at the end nearer the substituent whose name comes first in the alphabet Fall, 2009 6

Common Names • • • • • Chloroform Carbon tetrachloride Methylene chloride Methyl iodide Trichloroethylene Fall, 2009 7

Structure of Alkyl Halides

• C-X bond is longer as you go down periodic table • C-X bond is weaker as you go down periodic table • C-X bond is polarized – some positive charge on carbon – some negative charge on halogen • The carbon is an electrophilic center Fall, 2009 8

Electrophilic Carbon

C

X Fall, 2009 9

Preparation

• Alkyl halide - addition of HCl, HBr, HI to alkenes to give Markovnikov product (see Alkenes chapter) • Alkyl dihalide from anti addition of bromine or chlorine Fall, 2009 10

Allylic Bromination of Alkenes

• N-bromosuccinimide (NBS) selectively brominates allylic positions • • Requires light for activation A source of dilute bromine atoms Fall, 2009 11

Use of Allylic Bromination

• • Bromination with NBS creates an allylic bromide Reaction of an allylic bromide with base produces a conjugated diene, useful in synthesis of complex molecules Fall, 2009 12

Alkyl Halides from Alcohols Tertiary Alcohols • Reaction of tertiary C-OH with HX is fast and effective – Add HCl or HBr gas into ether solution of tertiary alcohol • Primary and secondary alcohols react very slowly and often rearrange, so alternative methods are used Fall, 2009 13

Alkyl Halides from Alcohols Primary and Secondary Alcohols • Specific reagents avoid acid and rearrangements of carbon skeleton • Thionyl chloride converts alcohols into alkyl chlorides – SOCl 2 : ROH to RCl • Phosphorus tribromide converts alcohols into alkyl bromides – PBr 3 : ROH to RBr Fall, 2009 14

Reactions of Alkyl Halides The Grignard Reagent • • RX reacts with Mg in ether or THF Product is RMgX – an organometallic compound – alkyl-metal bond – R : alkyl (1°, 2°, 3°), aryl, alkenyl – X = Cl, Br, I Fall, 2009 15

The Grigard Reagent

C

X

C

MgX Polarity is reversed Electrophilic Carbon becomes Nucleophilic Carbon Fall, 2009 16

Organo-Metallic Compounds

• • • • RX + Zn gives R 2 Zn RX + Li gives RLi RX + Al gives R 3 Al Behave similar to Grignard • Others use RLi Fall, 2009 17

Organo-Metallics

• • RLi + CuI gives R 2 CuLi – Organocuprate – Useful coupling reaction • R 2 CuLi + RX gives R-R RLi + CdCl 2 gives R 2 Cd Fall, 2009 18

Observations

PCl 5 HO 2 C CO 2 OH (-)-malic acid (-2.3) H Ag 2 O HO 2 C CO 2 H Cl (-)-chlorosuccinic acid HO 2 C CO 2 H Cl (+)-chlorosuccinic acid Ag 2 O PCl 5 HO 2 C CO OH (+)-malic acid (+2.3) 2 H Optical rotation is related to chirality Optical rotation and chirality are changing Fall, 2009 19

Significance of the Walden Inversion

• • • • Stereochemistry at the chiral C is inverted The reactions involve substitution at that center by a nucleophile Therefore, nucleophilic substitution appears to invert the configuration at a chiral center The presence of carboxyl groups in malic acid led to some dispute as to the nature of the reactions in Walden’s cycle Fall, 2009 20

Stereochemistry of Nucleophilic Substitution • • • Isolate step so we know what occurred (Kenyon and Phillips, 1929) using 1-phenyl-2-propanol Only the second and fifth steps are reactions at carbon Inversion occurs during the substitution step Fall, 2009 21

Kinetics

• • • • • Review Chapter 5 Reactions are considered fast or slow How fast is given by reaction rate Reaction rates are measurable Relationship between rate and concentration Fall, 2009 22

CH

3

Br + HO

-

CH

3

OH + Br

• • • • • Rate determined at given temp and [conc] Double [HO ] – rate doubles Double [CH 3 Br] – rate doubles Double both – rate increases by 4X Rate is dependent upon both [reactants] – Second order kinetics – Rate = k[RX][Nu] • k is the rate constant Fall, 2009 23

What We Know

• • • • • • • Substitution reaction Inversion of stereochemistry Second-order kinetics Proposed mechanism S N 2 Substitution, nucleophilic, bimolecular Single step from SM to Product Primary and secondary alkyl halides Fall, 2009 24

The S

N 2

Reaction

• • • Reaction - inversion at reacting center Follows second order reaction kinetics Ingold nomenclature to describe characteristic step: – S=substitution – N (subscript) = nucleophilic – 2 = both nucleophile and substrate in characteristic step (bimolecular) Fall, 2009 25

S

N

2 Process

• The reaction must involve a transition state in which both reactants are together Fall, 2009 26

Mechanism

CH 3 Br + HO [TS] [TS] = [ Nu C LG ] Nu attacks from opposite face as leaving group departs leading to inversion of stereochemistry Substrate and nucleophile appear in rate determining step Fall, 2009 CH 3 OH + Br 27

•

S

N 2

Transition State

The transition state of an S remaining three groups N 2 reaction has a planar arrangement of the carbon atom and the Fall, 2009 28

Additional Observations: S N 2 Reaction • • • • • • Sensitive to steric effects Methyl halides are most reactive Primary are next most reactive Secondary might react Tertiary are unreactive by this path No reaction at C=C (vinyl halides) Fall, 2009 29

Influencing a Reaction

• To increase the rate of a reaction – raise the energy of the reactants – lower the energy of the transition state • To slow a reaction, – Lower the energy of the reactants – Raise the energy of the transition state Fall, 2009 30

Reactant and Transition-state Energy Levels Affect Rate Higher

reactant energy level

(red curve) = faster reaction (

smaller

 G ‡ ).

Higher

transition state energy level

(red curve) = ( slower reaction

larger

 G ‡ ).

Fall, 2009 31

Variables that Influence the Reaction • Substrate • Nucleophile • Leaving Group • Solvent Fall, 2009 32

Substrate Steric Effects on S N 2 Reactions The carbon atom in (a) bromomethane is readily accessible resulting in a fast S N 2 reaction. The carbon atoms in (b) bromoethane (primary), (c) 2-bromopropane (secondary), and (d) 2-bromo-2-methylpropane (tertiary) are successively more hindered, resulting in successively slower S N 2 reactions. Fall, 2009 33

Substrate: Transition State

• In the Transition State – Bonds between C and Nu are forming – Bonds between C and LG are breaking – Approach to hindered C raises TS energy Fall, 2009 34

Substrate: Transition State Energy Very hindered • • Steric effects destabilize transition states Severe steric effects can also destabilize ground state Fall, 2009 35

Substrate: Order of Reactivity in S N 2 • The more alkyl groups connected to the reacting carbon, the slower the reaction Fall, 2009 36

Substrate

• • • Aryl – do not react Vinyl – do not react Recall: acetylide anion reacts with methyl or primary alkyl halides – Better bases lead to elimination reactions Fall, 2009 37

Nucleophile

• • Neutral or negatively charged Lewis bases Reaction increases coordination at nucleophile – Neutral nucleophile acquires positive charge – Anionic nucleophile becomes neutral Fall, 2009 38

Nucleophiles

• • • • Depends on reaction and conditions Nucleophilicity parallels basicity Nucleophilicity increases down a group in the periodic table (Cl < Br < I) Anions are usually more reactive than neutrals Fall, 2009 39

• • •

The Leaving Group

A good leaving group reduces the barrier to a reaction Stable anions that are weak bases are usually excellent leaving groups and can delocalize charge Negative charge builds in LG Fall, 2009 40

H 3 C Tosylate The Best Leaving Group • TsO supports negative charge • Resonance stabilized anion O S O O O S O O H 3 C H 3 C O S O O Fall, 2009 41

Poor Leaving Groups

• If a group is very basic or very small, it prevents the reaction from occurring Fall, 2009 42

• • •

The Solvent

Solvents that can donate hydrogen bonds (-OH or –NH) slow S N 2 reactions by associating with reactants Energy is required to break interactions between reactant and solvent Polar aprotic solvents (no NH, OH, SH) form weaker interactions with substrate and permit faster reaction Fall, 2009 43

Protic Polar Solvents

• • • • • • Protic polar solvents bind to X Hydrogen Bonding Solvent cage around nucleophile Stabilizes negative charge Lowering ground state energy Increases rate of reaction Fall, 2009 44

Aprotic Polar Solvents

• • Bind to M + X is unsolvated – More reactive – At a higher energy – Decreases rate of reaction Fall, 2009 45

S

N 2

Review

• • • • Favored – Basic Nu: – By aprotic polar solvents – Stable anions as leaving groups Disfavored – In protic solvents (water, alcohol) Sensitive to steric factors Second Order Kinetics Fall, 2009 46

ROH + HX RX + H

2

O

• • Observations – 3 o > 2 o > 1 o >> CH 3 – Protic solvent used – Acidic to neutral conditions utilized – Non-basic nucleophiles Substitution by nucleophile Fall, 2009 47

ROH + HX RX + H

2

O

• • • Rate is affected by changes in [ROH] Rate is unaffected by changes in [H 2 O] Rate expression – Rate = k[ROH] – First Order Kinetics – Rate Determining Step involves ROH not Nu – Rate Determining Step is slowest step of reaction and nothing occurs slower Fall, 2009 48

Mechanism

• Data suggests: slow RX intermediate nucleophile fast R-Nu • • • Intermediate = R+ (carbocation) S N 1 mechanism R+ reacts fast with Nu Fall, 2009 49

S

N

1 Energy Diagram

Step through highest energy point is rate-limiting (k 1 in forward direction) Rate = k[RX] • Rate-determining step is formation of carbocation Fall, 2009 50

The S

N

1

Reaction

• • • Tertiary alkyl halides react rapidly in protic solvents by a mechanism that involves departure of the leaving group prior to addition of the nucleophile Called an S N 1 reaction – occurs in two distinct steps while S N 2 occurs with both events in same step If nucleophile is present in reasonable concentration (or it is the solvent), then ionization is the slowest step Fall, 2009 51

Stereochemistry

• • • • Reaction involves carbocation Carbocation is sp 2 hybridized Carbocation is planar Expect to see racemization of any chiral C Fall, 2009 52

Stereochemistry of S

N 1

Reaction

• • The planar intermediate leads to loss of chirality – A free carbocation is achiral Product should be racemic Fall, 2009 53

S

N 1

in Reality

Fall, 2009 54

S

N 1

in Reality

• Carbocation is biased to react on side opposite leaving group • Suggests reaction occurs with carbocation loosely associated with leaving group during nucleophilic addition • Alternative that S N 2 is also occurring is unlikely Fall, 2009 55

Proposed Mechanism

Fall, 2009 56

Effect of Ion Pair Formation

• If leaving group remains associated, then product has more inversion than retention • Product is only partially racemic with more inversion than retention • Associated carbocation and leaving group is an ion pair Fall, 2009 57

Variables that Influence the Reaction • Substrate • Nucleophile • Leaving Group • Solvent We will examine each one separately.

Fall, 2009 58

Substrate

• • Hammond Postulate Stabilize a high energy intermediate you stabilize the transition state leading to it • More stable R+ favors S N 1 Reaction Fall, 2009 59

Substrate • Tertiary alkyl halide is most reactive by this mechanism • Controlled by stability of carbocation Fall, 2009 60

Effect of Leaving Group on S N 1 • Critically dependent on leaving group – Reactivity: the larger halides ions are better leaving groups • • • In acid, OH of an alcohol is protonated and leaving group is H 2 O, which is still less reactive than halide p-Toluensulfonate (TosO ) is excellent leaving group Stable negative charge better LG Fall, 2009 61

Nucleophiles in S

N 1 • Since nucleophilic addition occurs nucleophile after formation of carbocation, reaction rate is not affected by nature or concentration of Fall, 2009 62

Solvent • • Is Critical in S N 1 Stabilizing carbocation also stabilizes associated transition state and controls rate Solvation of a carbocation by water Fall, 2009 63

Polar Solvents Promote Ionization • Polar, protic and unreactive Lewis base solvents facilitate formation of R + • Reaction is faster in polar solvents Fall, 2009 64

Effects of Solvent on Energies

• Polar solvent stabilizes transition state and intermediate more than reactant and product Fall, 2009 65

Substitution in Biological Systems • • S N 2 and S N 1 observed Substrate is generally an organo diphosphate C O O P O O P O O Mg++ O Fall, 2009 66

Methylations

• S-Adenosylmethionine O 2 C H NH 3 + CH 3 S + N N NH 2 N N OH OH Fall, 2009 67

Elimination Reactions

substitution

X nucleophile/base H alkyl halide

elimination

Nu H • • • Elimination is competitive with substitution Zaitsev’s rule dominates – the most substituted alkene generally forms Three mechanisms for elimination will be considered (E1, E2, and E1cB) Fall, 2009 68

E2 Reaction Kinetics

• • • • • One step – rate law has base and alkyl halide Transition state bears no resemblance to reactant or product rate=k[R-X][B] Reaction faster with stronger base, Reaction faster with better leaving groups Fall, 2009 69

Transition State

base-H bond forming base H X C-C pi bond forming C-X bond breaking H-C bond breaking Fall, 2009 70

•

Geometry of Elimination – E2

Antiperiplanar (proton and LG) allows maximum orbital overlap and minimizes steric interactions • Allows us to predict product formed.

Fall, 2009 71

• • •

E2 Stereochemistry

Overlap of the developing transition state requires periplanar geometry, anti arrangement  orbital in the Allows maximum orbital overlap Stereospecific reaction Fall, 2009 72

• • •

Predicting Product

E2 is stereospecific Meso-1,2-dibromo-1,2-diphenylethane with base gives cis 1,2-diphenyl RR or SS 1,2-dibromo-1,2-diphenylethane gives trans 1,2-diphenyl Fall, 2009 73

Elimination From Cyclohexanes • • Abstracted proton and leaving group should align trans-diaxial to be anti periplanar in approaching transition state Equatorial groups are not in proper alignment Fall, 2009 74

• •

The E1 Reaction Mechanism

Competes with S N 1 and E2 at 3° centers Rate = k [RX] Fall, 2009 75

Stereochemistry of E1 Reactions

• • E1 is not stereospecific and there is no requirement for alignment Product has Zaitsev orientation because step that controls product is loss of proton after formation of carbocation Fall, 2009 76

• • •

Comparing E1 and E2

Strong base is needed for E2 but not for E1 E2 is stereospecifc, E1 is not E1 gives Zaitsev orientation Fall, 2009 77

EcB1 Mechanism

• • • • Intermediate is a carbanion Base removal of H Anion is formed + is rate determining Common with poor leaving groups (OH) OH O OH _ O base H O Fall, 2009 78

Elimination in Biological Systems

• • • EcB1 mechanism is most common E1 and E2 occur less often 3-hydroxy carbonyls convert into unsaturated carbonyl compounds Fall, 2009 79

Summary of Reactions S N 1 , S N 2 , E 1 , E 2 1 o RX 2 o RX S N 2 E 2 S N1 E1 S N 2 E 2 favored with good nucleophiles favored with strong (hindered) bases never observed never observed mixtures from both mechanisms are often observed S E N 2 2 predominates in aprotic polar solvents and with good Nu and weak bases predominates with strong bases 3 o RX S N 2 E 2 S N1 E1 never observed favored with strong bases mixtures due to E1 observed under non-basic conditions mixtures due to S N1 observed under non-basic conditions Fall, 2009 80