Chapter 11, Part 1: Polar substitution reactions involving alkyl halides

Overview: The nature of alkyl halides and other groups with electrophilic sp3 hybridized C leads them to react with nucleophiles and bases Two types of reactions covered in Ch 11, which often compete with each other: 1. Substitution: CH3CH2Cl + Nu- CH3CH2Nu + Cl- 2. Elimination: CH3CH2Cl + B:- CH2=CH2 + HB + Cl- Both are common in compounds where the sp3-carbon is bonded to an electronegative atom

alkyl halides, alcohols, ethers due to electronegativity of the halogen, C-X bond breaks easily: the

halogen is a good leaving group

Part 1: Substitution reactions Two possible scenarios lead to substitution products:

A nucleophile is attracted to the polar C-X bond; as it approaches and begins to bond with C, the C - X bond breaks and the halide ion leaves

Under certain conditions, a weak C - X bond breaks to form a

carbocation. As X - leaves, a nucleophile is able to bond to the carbocation

Which pathway actually occurs depends on several factors:

the nature of the nucleophile the nature of the leaving group the structure of the molecule at the sp3 carbon reaction conditions

Scenario #1: A one-step reaction with the nucleophile = The SN2 reaction SN2 = substitution, nucleophilic, bimolecular

The rate law for this process: Rate = k [alkyl halide] [nucleophile]

Two key aspects of SN2 mechanism:

HO- + CH3 – Br HO – CH3 + Br-

One step process (concerted)

Back-side attack of the nucleophile at the carbon produces an inversion in stereochemistry at the carbon:

Four key factors that increase the likelihood of an SN2 type substitution: 1) Easy access to the substrate (alkyl halide): 1o works best

The pathway occurs much more slowly for substituted (2o or 3o) alkyl halides

due to steric hindrance by the alkyl groups attached to the C

Reactivity: methyl > 1o RX > 2o RX > 3o RX

2) A strong attacking nucleophile This is a key factor since rate depends on both R-X and Nu. “Nucleophilicity” = ability of a nucleophile to speed up the reaction: Factors influencing reactivity of the nucleophile: A. Basicity: When comparing nucleophiles that have the same attacking atom, the stronger the base, the better it is as a nucleophile

Base strength increases as pKa of conjugate acid increases *NOTE: Acting as a base is NOT the same as acting as a nucleophile B. Charge: Negatively charged species are usually better nucleophiles than neutral Some atoms (such as C) aren’t nucleophilic at all unless they are (-) charged Basic reaction conditions can help keep nucleophile negatively charged

C. Size: Within a group in the periodic table, the larger the size of the attacking atom, the better the nucleophile, due to increased polarizability

Compare I- vs. Cl-; SH- vs. OH-

3) A good “leaving group” The better the leaving group, the faster an SN2 reaction occurs Poor leaving groups raise the energy of the TS while good ones lower ΔG+ Example: for the halide ions, the weaker bases are better leaving groups: Increasing basicity For any R-X, reactivity by SN2 pathway: R-I > R-Br > R-Cl > R-F

Good leaving groups: I-, Br-, -OTos So-so: Cl- Poor leaving groups: F-, OH-, NH2-, OR-

(Alcohols, ethers, amines do not react directly by the SN2 mechanism!) 4) A solvent that doesn’t interfere with the process (aprotic is best) Protic solvents: Can donate a hydrogen in a hydrogen-bonding interaction Examples: water, alcohols (CH3OH, CH3CH2OH) They prevent the nucleophile from getting to its destination by solvation Result: Slower reaction rate, particularly for normally “good” nucleophiles Aprotic solvents: Cannot donate a hydrogen in a hydrogen-bonding interaction and

therefore are not attracted to the nucleophilic species. Examples: CH2Cl2, diethyl ether, THF, toluene, acetone In aprotic solvents, the nucleophile is not affected; in fact the solvents help to

stabilize the transition state, thus lowering activation energy…SN2 reactions can proceed more quickly in aprotic solvents!

Practical applications of the SN2 reaction: A wide range of nucleophiles can react with alkyl halides, replacing the halide with new functional groups and making substitution a versatile synthetic tool:

C C CH3 CH3CH2 C C CH3 + Br-Alkynes:

Alcohols: CH3CH2 + OHBr

CH3CH2 Br

CH3CH2 +OH Br-

Ethers: CH3CH2 Br +

+

OCH3 CH3CH2 +OCH3 Br-

CH3CH2 Br + NH3 CH3CH2 NH3BrAmines:

Esters: CH3CH2 Br C CH3

O

HO+ CH3CH2 C CH3

O

O + Br-

C N CH3CH2 C N + Br-Nitriles: CH3CH2 Br

Thiols: CH3CH2 Br +

+

SCH3 CH3CH2 +SCH3 Br-

Coupling: CH3CH2 Br + RMgBr CH3CH2 R + MgBr2 Intermolecular reactions (above examples) involve two separate molecules Intramolecular SN2: If the alkyl halide also contains another nucleophilic group, it can undergo an intramolecular reaction between the halide C and the Nu, forming a ring:

Br

NH2

NHH

Br-

Using SN2 reactions: Will reaction proceed spontaneously in the forward direction? Yes, if

The halide to be replaced is a better leaving group than the incoming group

This usually requires that the incoming group is a stronger nucleophile

If incoming and outgoing groups are nearly equal in basicity, reaction is reversible; can be driven forward by removing product as it forms (LeChatelier's principle)

Scenario #2: A two-step substitution reaction with a carbocation intermediate = The SN1 reaction

A 3o R-X isn’t likely to react by SN2 pathway, but 3o alkyl halides do react with bases to produce substitution products, and conc. of Nu has no effect on rate

An alternate mechanism: SN1 = substitution, nucleophilic, unimolecular rate = k [alkyl halide] Two step reaction: 1) Slow step: Loss of leaving group to form carbocation intermediate 2) Faster step: Reaction of carbocation with nucleophile

H2OC

H3C CH3

CH3

Br-C

H3C CH3

CH3HO

CH3C CH3

CH3Br+

3o alkyl halide 3o carbocation 3o alcohol What affects SN1 reactivity?

1o, 2o, 3o RX: Relative reactivity by SN1 depends on structure of carbocation

Leaving group: How good is it at leaving?

1o RX < 2o RX < 3o RX

A typical SN1 reaction

Strength of the nucleophile—doesn’t matter so much! The ability of the solvent to stabilize the carbocation:

Protic solvents that hinder SN2 rxns actually help SN1 rxns

Additional considerations when dealing with carbocation-based mechanisms: 1) Stereochemistry: Recall stereochemistry of addition reactions: simple carbocations form racemic mixture:

Ph Et

H H

HBr C

Ph Et

CH3

Br- C

Ph Et

CH3

C

Ph Et

H3C

+Br Br

SN1 reactions that produce a chiral center also give a racemic mixture of products

H2OC

Ph Et

CH3

Br-C

Ph Et

CH3

C

Ph Et

H3C

+HO OH

CPh Et

CH3Br+

2) Resonance makes carbocations more stable, favors SN1 pathway 3) Carbocations are prone to rearrangement, may affect final product of SN1 Ex:

CH

H3C

H3C

HC

Br

CH3H2O

S

N2

mec

hani

sm

SN1

mec

hani

sm

So, a substitution product has formed… was it SN1 or SN2? Both pathways are possible. Which one is favored? In a competition, the pathway which occurs most rapidly will be favored. Some factors that may influence pathway SN2 1. Structure of alkyl halide: 3o 2o 1o SN1 2. Concentration of nucleophile: Rate of SN1 pathway does not depend on [Nu] Rate of SN2 = k [RX][Nu] 3. Reactivity of nucleophile: affects rate of SN2 but not rate of SN1

SN2 pathway is favored by higher concentration and more reactive nucleophile.

Conversely, low concentration or use of weaker nucleophile may favor SN1 4. Choice of solvent:

SN1 reactions are favored by solvents capable of stabilizing a transition state that closely resembles the (+)-charged carbocation intermediate - polar solvents best

SN2 reactions are favored by aprotic solvents and slowed down by protic solvents

Summary: SN2 is favored by: SN1 is favored by: High conc. of strong nucleophile A weaker nucleophile A polar aprotic solvent A polar protic solvent

Less bulky & 1o R-X Substituted R-X that form stable carbocations

Outcome of SN2: Outcome of SN1:

Inversion of configuration Products are racemic mixtures No rearrangement of C skeleton Rearrangements are likely

Some substitution reactions involving alkyl halides from Ch. 10 (Part 2)

The polarity of the C – X bond is key to understanding most RX reactions

1. Transforming alcohols to alkyl halides by polar substitution Alkyl halides and alcohols have in common a polar bond between C and functional group: R – CH2 – Br R – CH2 – Cl R – CH2 – OH However, the OH group of alcohols is a poor leaving group compared to Br, Cl, or I 3o alcohols react readily with HCl, HBr or HI by SN1 mechanism to make 3o alkyl halides; this works because they form a stable carbocation intermediate, but is unlikely with 1o or 2o ROH

CH3

OH

CH3

Br

HBr

ether

Preparation of 1o and 2o alkyl halides from alcohols by SN2 reaction:

• 1o & 2o alcohols require a bit more “encouragement” to get rid of the OH group • Halogenating reagents help “activate” the removal of the OH group • These reagents reduce the risk of undesired elimination reactions. • Reactions proceed with inversion

Some advantages to preparing alkyl halides from alcohols

• The alcohols are often inexpensive and readily available

• These reactions tend to produce only the desired major product, not mixtures like you would get by radical halogenation

2. Organometallic Reagents: Using metals to “activate” carbon towards SN2 substitution

Alkyl halides have a partial positive charge on the C bearing the halogen

Reaction of alkyl halides with certain metals results in “insertion” of metal

Produces a new carbon-metal bond in which the carbon now bears the

partial negative charge Useful way to make the carbon nucleophilic

Earlier example: A nucleophilic C is generated in deprotonation of acetylene

to make acetylide ions – these then react with alkyl halide to form C-C bond 2A. Grignard Reagents:

• Used to form new C – C bonds • Used in reactions with carbonyl compounds (more on this in CHM252) • Used in substitution reactions with alcohols to make ethers

Magnesium inserts itself into the C – X bond of 1o, 2o or 3o alkyl halides: CH3 – Br + Mg CH3 – Mg – Br Dry ether bromomethane Methylmagnesium bromide (a Grignard reagent) Grignard reagents react readily with any electrophile which makes them useful, but you can also get unwanted side reactions with any source of H+

Since they behave like bases, they react readily with H2O to replace X with H:

CH3CH2CH2-Mg-Br H2O, H+ CH3CH2CH3 + MgBrOH Note: The formation of a Grignard reagent can be considered an organic reduction since the electron density on the carbon atom increases Reduction: increasing e- density on C by forming C – H , C – M (metal) or by breaking C – O, C – N, or C – X Reactions that form alkyl halides are considered oxidations

2B. Other organometallic reagents with nucleophilic C Organolithium reagents Lithium is small and strongly electropositive; makes the bonded carbon strongly basic 2 Li CH3CH2CH2CH2-Br CH3CH2CH2CH2–Li + LiBr Pentane

• The resulting organolithium reagents are very strong nucleophiles • Can be used in many of the same reactions as Grignard reagents • RLi reagents are used in the preparation of the Gilman reagent (below), which is a

milder form of the nucleophile Gilman reagents: Further reaction of RLi with copper produces: R2CuLi ether 2 CH3CH2Li + CuI (CH3CH2)2CuLi + LiI 2C: SN2 substitution: organometallic coupling reactions Alkyl bromides, iodides & chlorides can react with Gilman reagents (or Grignards) in a carbon-skeleton building reaction, by SN2 mechanism: Ex:

H2C CH2CH2CH3

H0 oC

ether

H

I

+ (CH3CH2)2CuLi

Choice of halogens in making & using alkyl halides in substitution rxns

• Our focus has been primarily on alkyl bromides, chlorides & iodides because they contain a good leaving group and are readily available commercially

• Alkyl fluorides are not readily prepared by the same methods; for example, fluorine

radicals are extremely reactive & unpredictable so radical fluorination is impractical

• Alkyl fluorides also are less useful as starting reagents; F is a poor leaving group and thus not easily substituted out

Practice problems: Substitution of Alkyl Halides For each reaction, predict the mechanism (SN1 or SN2) and the structure of the substitution product(s). If stereoisomers are possible, indicate which ones are produced. 1 M Na+ -OCH2CH3 1) (R)-2-bromopentane DMSO 2) (R)-2-bromopentane CH3CH2OH 1 M Na+ -OCH3 3) trans-1-chloro-2-methylcyclohexane DMSO 4) trans-1-chloro-2-methylcyclohexane CH3OH 5) 3-bromo-3-methylpentane H2O 6) 3-bromo-3-methylpentane -OH 7) bromocyclopentane Na+ -:C=C-CH2CH3 ether 8) bromocyclopentane (CH3CH2)2CuLi ether

Chapter 10 problems