Alkyl Halides

R-X (X = F, Cl, Br, I)

Classification of alkyl halides according to the class of the carbon that the halogen is attached to.

RCH2-X R2CH-X R3C-X

1o 2o 3o

Nomenclature:

common names: “alkyl halide”

(fluoride, chloride, bromide, iodide)

IUPAC names: use rules for alkanes

halogen = halo (fluoro, chloro, bromo, iodo)

Cl

CH3CH2CH2CH2-Br CH3CHCH3

n-butyl bromide isopropyl chloride

1-bromobutane 2-chloropropane

1o 2o

CH3 CH3

CH3CHCH2CHCH3 CH3CCH3

Br I2-bromo-4-methylpentane tert-butyl iodide

2-iodo-2-methylpropane 2o 3o

CH3

Cl-CHCH2CH3

sec-butyl chloride2-chlorobutane 2o

Physical properties:

polar + no hydrogen bonding

=> moderate boiling/melting points

water insoluble

Uses: pesticides, refrigerants (freons), solvents, synthetic intermediates.

CH3Br CClF3 CCl4

Synthesis of alkyl halides:

1. From alcohols

a) HX b) PX3

2. Halogenation of certain hydrocarbons

3. (later)

4. (later)

5. Halide exchange for iodide

1. From alcohols. #1 synthesis!

a) With HX

R-OH + HX R-X + H2O

i) HX = HCl, HBr, HI

ii) may be acid catalyzed (H+)

iii) ROH: 3o > 2o > CH3 > 1o

iv) rearrangements are possible except with most 1o ROH

CH3CH2CH2CH2-OH + NaBr, H2SO4, heat CH3CH2CH2CH2-Br

n-butyl alcohol (HBr) n-butyl bromide

1-butanol 1-bromobutane

CH3 CH3

CH3CCH3 + HCl CH3CCH3

OH Cl tert-butyl alcohol tert-butyl chloride 2-methyl-2-propanol 2-chloro-2-methylpropane

CH3-OH + HI, H+,heat CH3-I methyl alcohol methyl iodide methanol iodomethane

…from alcohols: b) PX3

i) PX3 = PCl3, PBr3, P + I2

ii) ROH: CH3 > 1o > 2o

iii) no rearragements

CH3CH2-OH + P, I2 CH3CH2-I

ethyl alcohol ethyl iodide

ethanol iodoethane

CH3 CH3

CH3CHCH2-OH + PBr3 CH3CHCH2-Br isobutyl alcohol isobutyl bromide

2-methyl-1-propanol 1-bromo-2-methylpropane

2. Halogenation of certain hydrocarbons.

R-H + X2, Δ or hν R-X + HX

(requires Δ or hν; Cl2 > Br2 (I2 NR); 3o>2o>1o)

yields mixtures! In syntheses, limited to those hydrocarbons that yield only one monohalogenated product.

CH3 CH3

CH3CCH3 + Cl2, heat CH3CCH2-Cl CH3 CH3

neopentane neopentyl chloride 2,2-dimethylpropane 1-chloro-2,2-dimethylpropane

5. Halide exchange for iodide.

R-X + NaI, acetone R-I + NaX

i) R-X = R-Cl or R-Br

ii) NaI is soluble in acetone, NaCl/NaBr are insoluble.

CH3CH2CH2-Br + NaI, acetone CH3CH2CH2-I

n-propyl bromide n-propyl idodide

1-bromopropane 1-idodopropane

ROH

RX

RH

HX PX3

X2, Δ or hν

NaIacetone

Outline a possible laboratory synthesis for each of the following alkyl halides using a different synthesis for each compound:

1-bromobutane neopentyl chloride

n-propyl iodide tert-butyl bromide

CH3CH2CH2CH2-OH + PBr3 CH3CH2CH2CH2-Br

CH3 CH3

CH3CCH3 + Cl2, heat CH3CCH2-Cl

CH3 CH3

CH3CH2CH2-Br + NaI, acetone CH3CH2CH2-I

CH3 CH3

CH3C-OH + HBr CH3C-Br

CH3 CH3

NR NR

NR NR NR NR

NR NR NR

R-H R-X

Acids

Bases

Active Metals

Oxidants

Reductants

Halogens

Reactions of alkyl halides:

1. Nucleophilic substitution Best with 1o or CH3!!!!!!

R-X + :Z- R-Z + :X-

2. (later)

3. Preparation of Grignard Reagent

R-X + Mg RMgX

4. Reduction

R-X + Mg RMgX + H2O R-H

R-X + Sn, HCl R-H

nucleophilic substitution

R-W + :Z- R-Z + :W-

substrate nucleophile substitution leaving product group

good nucleophile strong base

good leaving group weak base

R-X + :OH- ROH + :X- alcohol

R-X + H2O ROH + HX alcohol

R-X + :OR´- R-O-R´ + :X- ether

R-X + -:CCR´ R-CCR´ + :X- alkyne

R-X + :I- R-I + :X- iodide

R-X + :CN- R-CN + :X- nitrile

R-X + :NH3 R-NH2 + HX primary amine

R-X + :NH2R´ R-NHR´ + HX secondary amine

R-X + :SH- R-SH + :X- thiol

R-X + :SR´ R-SR´ + :X- thioether

Etc.

Best when R-X is CH3 or 1o!

CH3CH2CH2-Br + KOH CH3CH2CH2-OH + KBr

CH3CH2CH2-Br + HOH CH3CH2CH2-OH + HBr

CH3CH2CH2-Br + NaCN CH3CH2CH2-CN + NaBr

CH3CH2CH2-Br + NaOCH3 CH3CH2CH2-OCH3 + NaBr

CH3CH2CH2-Br + NH3 CH3CH2CH2-NH2 + HBr

CH3CH2CH2-Br + NaI, acetone CH3CH2CH2-I + NaBr

Mechanism for nucleophilic substitution:

“substitution, nucleophilic, bimolecular”

“curved arrow formalism” uses arrows to show the movement of pairs of electrons in a mechanism.

SN2

Z: + C W Z C + :WRDS

Kinetics – study of the effect of changes in concentration on rates of reactions.

CH3—Br + NaOH CH3—OH + NaBr

rate = k [ CH3-Br ] [ OH- ]

Tells us that both CH3-Br and OH- are involved in the rate determining step of the mechanism. “bimolecular”

Relative rates of R—X

R-I > R-Br > R-Cl

“element effect” C—X bond is broken in the rate determining step of the mechanism.

SN2 stereochemistry

CH3 CH3

H Br + NaOH HO H

(SN2 conditions)

C6H13 C6H13

(S)-(-)-2-bromooctane (R)-(+)-2-octanol

100% optical purity

SN2 proceeds with 100% inversion of configuration! (“backside attack” by the nucleophile)

SN2 100% backside attack by the nucleophile

Evidence: stereochemistry = 100% inversion of configuration

Reasonable?

1) incoming nucleophile and negatively charged leaving group are as far apart as they can get.

2) there is more room on the backside of the carbon for the incoming nucleophile to begin to bond to the carbon.

Relative rates for alkyl halides in SN2:

CH3-X > 1o > 2o > 3o

37 : 1.0 : 0.2 : 0.0008

The transition state has five groups crowded around the carbon. If the substrate is CH3X then three of the the five groups are Hydrogens. If the alkyl halide is 3o then there are three bulky alkyl groups crowded around the carbon in the transition state. “Steric factors” explain the relative reactivity of alkyl halides in the SN2 mechanism.

Z: + C W Z C + :W

Z C W

CH3 CH3

CH3CCH3 + OH- CH3CCH3 + Br- + alkene Br OH

rate = k [ tert-butyl bromide ]

The rate of this reaction depends on only the concentration of the alkyl halide. Therefore the nucleophile is not involved in the RDS here, cannot be SN2 mechanism!? “unimolecular”

Substitution, nucleophilic, unimolecular (SN1) mechanism:

Kinetics: rate = k [R-W ]; only R-W is involved in the RDS!

C WRDS

C + :W

C + :Z C Z

carbocation

1)

2)

SN1 stereochemistry

CH3 CH3 CH3

H Br + NaOH HO H + H OH

(SN1 conditions)

C6H13 C6H13 C6H13

(-)-2-bromooctane (+)-2-octanol (-)-2-octanol

SN1 proceeds with partial racemization. The intermediate carbocation is sp2 hybridized. The nucleophile can attack the carbocation from either the top or the bottom and yield both enantiomeric products.

SN1 reactivity: 3o > 2o > 1o > CH3

R—Br R+ + Br-

CH3—Br ΔH = 219 Kcal/mole CH3+

CH3CH2—Br ΔH = 184 Kcal/mole 1o

CH3CH—Br ΔH = 164 Kcal/mole 2o

CH3

CH3

CH3C—Br ΔH = 149 Kcal/mole 3o

CH3

SN1 order of reactivity = 3o > 2o > 1o > CH3

Stability of carbocations = 3o > 2o > 1o > CH3+

RDS in SN1: R—W R+ + :W-

R—X [ R---------X ] R+ + X-

δ+ δ-

Rearrangement of carbocations.

Carbocations can rearrange by 1,2-hydride or 1,2-methyl shifts:

[1,2-H] --C—C-- --C—C– + + H H

[1,2-CH3] --C—C-- --C—C– + + CH3 CH3

Carbocations can rearrange by 1,2-hydride or 1,2-methyl shifts but only do so when the resultant carbocation is more stable.

1o carbocation will rearrange to 2o

1o carbocation will rearrange to 3o

2o carbocation will rearrange to 3o

(only goes “down hill”)

CH3 CH3

CH3CHCHCH3 + NaCN (SN1 conditions) CH3CCH2CH3 ????? Br CN

CH3 [ 1,2-H shift ] CH3

CH3CHCHCH3 CH3CCH2CH3 + CN-

+ + 2o carbocation 3o carbocation

Competing mechanisms for nucleophilic substitution

SN2

Z: + C W Z C + :WRDS

SN1

C WRDS

C + :W

C + :Z C Z

stereochemistry 100% inversion Partial racemization

Kinetic order Rate = k[RX][Z-] Rate = k[RX]

Rearrangements None Possible

Rates CH3,1o,2o,3o CH3>1o>2o>3o 3o>2o>1o>CH3

Rates RCl,RBr,RI RI>RBr>RCl RI>RBr>RCl

Rate? temp. Increases rate Increases rate

Rate? 2 x [RX] Doubles rate Doubles rate

Rate? 2 x [Z-] Doubles rate No effect

SN2 SN1

R-X + Z- R-Z + X- which mechanism?

SN2 -

CH3 1o 2o 3o

- SN1

SN2 “steric factors” CH3 > 1o > 2o > 3o

SN1 carbocation stability 3o > 2o > 1o > CH3

Effect of solvent polarity on SN1/SN2:

water = polar ethanol = less polar

Solvent: mixture of ethanol/water

Add more water = more polar; add more ethanol = less polar.

SN1: R-W R+ + W-

ionization favored by polar solvents

SN2: Z:- + R-W Z-R + :X-

solvent polarity does not affect rate

Alkyl halide + base ????

SN2: best with CH3 or 1o RX, concentrated, strong base

(SN1: 2o or 3o, dilute, weak base, polar solvent; rearrangements are possible , alkene by-products )

Synthesis of alkyl halides:

1. From alcohols

a) HX b) PX3

2. Halogenation of certain hydrocarbons

3. (later)

4. (later)

5. Halide exchange for iodide

Reactions of alkyl halides:

1. Nucleophilic substitution Best with 1o or CH3!!!!!!

R-X + :Z- R-Z + :X-

2. (later)

3. Preparation of Grignard Reagent

R-X + Mg RMgX

4. Reduction

R-X + Mg RMgX + H2O R-H

R-X + Sn, HCl R-H

Mechanisms

SN2

Z: + C W Z C + :WRDS

SN1

C WRDS

C + :W

C + :Z C Z