Preparation of Alkyl Halides, R-X Reaction of alkanes with Cl 2 & Br2 (F2 is too reactive, I2 is unreactive): R H + X2 UV or heat R X + HX

This mechanism involves a free radical chain reaction. A chain reaction involves a series of steps in which a product formed in a later step is a reactant in an earlier step.
InitiationX X heat or UV R X H 1 H 2 2 X

PropagationX R + H + X

X R

H + R X + X

Termination2 X X 2 + R R X R R X X R

Ho in kJ/mole R = CH3 +6 +72 -108 1o R -12 +54 -95 2o R -31 +35 -96 3o R -42 +24 -87

H1, Cl 2 H1, Br2 H2, Cl 2

-100 -92 -87 -70 H2, Br2 Note that the second propagation step (H2) is quite exothermic in all cases. The first step (H1) is less exothermic or endothermic. It is reasonable to conclude that the first step would have the larger G and is rate limiting. It also follows that the rate of reaction for substitution of hydrogens by halogens would be 3o > 2o > 1o > methane. This is also the order of stability of the alkyl free radicals that are formed: the more stable intermediate radical is formed faster.

At room temperature, the relative rate of replacement of hydrogen atoms in alkanes by chlorine is 3o : 2o : 1o = 5.0 : 3.5 : 1.0 (per hydrogen).
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At 125o C, the relative rate of replacement of hydrogen atoms in alkanes by bromine is 3o : 2o : 1o = 1600 : 80 : 1 (per hydrogen). Bromination is more selective than chlorination. Owing to its lack of selectivity, free radical chlorination is of limited usefulness in synthesis. Another problem with free radical chlorination in synthesis is polychlorination. Bromination is more selective than chlorination but polybromination can be a problem.

Alkyl Halides from Alcohols

X = Cl, Br, I Reactivity of ROH: 3o > 2o > 1o Rearrangement of 2o R (to 3o) possible; rearrangement of 1o (to 2o or 3o) occasionally occurs. Reactivity of HX: HI > HBr > HCl Other reagents that are used with 1o & 2o alcohols: thionyl chloride, SOCl 2, to make alkyl chlorides; phosphorous tribromide, PBr3, to make alkyl bromides; phosphorous + iodine, P + I2, to make alkyl iodides. Rearrangements are less likely with these reagents.

Reactions of Alkyl Halides

R = 1o, 2o, or 3o alkyl, vinylic, aromatic; vinylic and aromatic are less reactive. X = Cl, Br, I; usually not F; reactivity: I > Br > Cl. Structure in solution complex mixture partly:

2R

Mg

R2Mg + MgX2

R2Mg*MgX2

+ but acts like R Mg X ; thus the R-group has both nucleophilic and basic character.

Base If the R-group is alkyl, R-Mg-X will react with any material that is more acidic than an alkane, eg R H + Mg(OH)X R Mg X + H2O

stronger base

stronger acid

weaker acid

weaker base

Thus, R-Mg-X cannot be prepared in the presence of any material that is slightly acidic, including compounds with H attached to O or N.
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A major reason for making Grignard reagents is to synthesize alcohols by reacting the Grignard with carbonyl compounds:

Mg

X +

acid

OH

Alkyl Halides in Nucleophilic Substitutions Halide ions, except F, are weak bases (The conjugate acids, HX, (except HF) are strong acids). Concomitantly, halogen attached to sp 3 carbon can be easily (except F) displaced by stronger bases (nucleophiles). Thus, a typical reaction of alkyl halides is nucleophilic substitution: R - X + :Nu or, R - X + :Nu > R - Nu + X > R - Nu + + X

R - X = substrate, X = leaving group, :Nu = nucleophile Halide ions are good leaving groups (except F). (Aryl and vinyl halides undergo this reaction with extreme difficulty.) Because of the many nucleophiles available, this reaction is very useful in synthesis. The table below lists just a few possibilities.

Nucleophile R-CC: :NC:

Substrate CH3Br CH3Br CH3Br CH3Br CH3Br

Product R-CC-CH3 :NC-CH3 HO-CH3 I-CH3

HO I
H3N:

H3N CH3 Br

Halide exchange Preparation of alkyl fluorides and iodides: SbF3 R - Cl SbF3 eg CCl4 > CF2Cl2 (dichlorodifluoromethane: Freon-12) acetone R - X + NaI X = Cl, Br > R - I + NaX (ppt.) > R-F

Preparation of alcohols R-X + KOH > ROH + KX X = Br, Cl Best if R is methyl, primary; may not work if R is tertiary (owing to competition from the elimination reaction that would convert the alkyl halide to an alkene).

Kinetics of Nucleophilic Aliphatic Substitution Consider: CH3I + OH > CH3OH + I

If reaction occurs by collision between CH3I and OH: rate = k2[CH3I][OH], where k2 is a constant.

[ This is observed. We say the rate equation is

rate = k1[(CH3)3C-I], where k1 is a constant.

[ This is observed. In this case the rate

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To account for differences in kinetics, and other observations: two mechanisms for aliphatic nucleophilic substitution SN2 and SN1. In the SN2 (Substitution, Nucleophilic, Bimolecular) mechanism the reaction takes place in one step when the substrate and nucleophile collide. Since both substrate and nucleophile are involved in this step, the rate is second order; it depends on [substrate] and [nucleophile]. In the SN1 (Substitution, Nucleophilic, Unimolecular) mechanism the reaction takes place in two steps. In the first slow step a carbocation is formed by ionization of the halide. The second fast step is the reaction of this carbocation with the nucleophile. The rate of this reaction depends on the rate of the first step: the formation of the carbocation. Therefore, the rate is first order; it depends on [substrate] and not on [nucleophile] since the nucleophile is not involved in the first step.

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Experiment:
HC 6 H13 Br CH 3 (-)-2-bromooctane []= -36 o C H3 (-)-2-octanol []= -10.3o H C 6 H13 OH C 6H 13 H HO C H3 (+)-2-octanol []= +10.3 o

Under conditions where second-order kinetics is followed:

HC6H13 Br CH3 (-)-2-bromooctane []= -36o

OH-

(+)-2-octanol [] = +10.3o, measured at the end of the reaction.

So, the -OH group is not located where the Br was, but rather is on the other side of the carbon atom: the configuration is inverted.

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An SN2 reaction proceeds with inversion of configuration (Walden inversion). Every molecule is inverted owing to backside attack of the nucleophile; ie, the nucleophile attacks the carbon holding the leaving group on the side opposite the leaving group. As this happens the leaving group departs and the nucleophile becomes attached to the carbon that had held the leaving group.

Nu

C X

Nu

Nu

Reactivity in SN2 mechanism effect of substrate structure Steric factors (ie bulk of groups attached to or near the site of nucleophilic attack) are important since bulky groups block attack by the nucleophile and decrease the probability of a "successful" collision. Therefore, in SN2 reactions, order of reactivity = CH3X > 1o > 2o > 3o

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SN1 Reaction Mechanism (CH3)3C-I + OH rate = k1[(CH3)3C-I] Since the rate does not involve [OH], the reaction whose rate is being measured does not involve OH. Consistent with + slow 1) (CH3)3C-I fast 2) (CH3)3C + OH
+

> (CH3)3OH + I

> (CH3)3C+ + I> (CH3)3C-OH

1) is the rate determining step. Stereochemistry of the SN1 mechanism Under conditions where first order kinetics is observed: OH-, H2O (-)-2-bromooctane > 2/3 (+)-2-octanol + 1/3 ()-2-octanol [ from inversion [ from racemization This is consistent with a planar (sp 2) carbocation intermediate
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HC 6H13 Br CH3 (-)-2-bromooctane OH Attack easier from this side. Therefore, this isomer is formed more easily --C 6H13 H HO CH3 (+)-2-octanol 5/6 of product Partial Racemization of Carbocation Ion-pair H C 6H13
+

H C 6H13 Br CH3

Attack more difficult here.

Br --- than this one. H C 6H13 OH CH3 (-)-2-octanol 1/6 of product

CH3

If the carbocation were completely free of the halide ion, racemization would be complete. This case is more typical.

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Elimination Reactions: E2 and E1 E2: Elimination, bimolecular (second order kinetics).

X C C H :B :X:+

H:B

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E1: Elimination, unimolecular (first order kinetics)

X C C H C C H :B Important only for 3o substrates at low base concentration. Reactivity toward E1 & E2: 3o > 2o > 1o Fast C C
+

Slow

:X:-

C C H H:B

L L

E2 E1

order of stability of alkenes formed. order of stability of the carbocations being formed.

Evidence in support of the E1 mechanism A) Kinetics first order in substrate, zeroth order in base: first order overall. Same effect of structure on reactivity as in SN1.

B)

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C) Rearrangements observed, suggesting carbocation intermediate. Evidence in support of the E2 mechanism A) Kinetics first order in substrate, first order in base: second order overall. No rearrangements, suggesting no carbocation intermediates.

B)

C) Anti- elimination of H and X. This requirement of an anti orientation of H and X (Br) suggests a one step mechanism, because if anintermediate were involved (eg a carbocation) free rotation would destroy the stereospecificity.

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H H3C H C6H5 C6H5 Br 1R,2R H H3C C6H5 Br H 1S,2R C6H5 or or

H CH3 C6H5 C6H5 H 1S,2S H C6H5 H 1R,2S Br CH3 C6H5 C6H5 H CH3 C6H5 Br C6H5 C6H5 CH3 H

Stereospecific Anti- Eliminations

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Halide Type RCH2X (primary)

SN1 Does not occur: 1 o carbocation too unstable

SN2 Favored/ for steric reasons/ by high conc. of good nucleophile/ at room temp Competes with E2. Favored by high conc of good nucleophile/ weak base

E1 Does not occur: 1 o carbocation too unstable

E2 Occurs with strong base at high temp.

R2CHX (secondary)

Depends on conditions: favored by low conc of weak nucleophile/ allyl & benzyl groups Favored in hydroxylic solvents

Depends on conditions: favored by low conc of weak base/ allyl & benzyl groups Competes with SN1/ favored by poor nucleophile

Favored by high conc of strong base at high temp.

R3CX (tertiary)

Does not occur

Favored when bases are used: subst. alkene is produced.

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