Transcript Alkyl halides

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
1o
R2CH-X
2o
R3C-X
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
CH3CHCH2CHCH3
Br
2-bromo-4-methylpentane
2o
CH3
Cl-CHCH2CH3
sec-butyl chloride
2-chlorobutane
2o
CH3
CH3CCH3
I
tert-butyl iodide
2-iodo-2-methylpropane
3o
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 
n-butyl alcohol
(HBr)
n-butyl bromide
1-butanol
CH3
CH3CCH3
OH
CH3CH2CH2CH2-Br
1-bromobutane
+ HCl
tert-butyl alcohol
2-methyl-2-propanol
CH3-OH
methyl alcohol
methanol
+

CH3
CH3CCH3
Cl
tert-butyl chloride
2-chloro-2-methylpropane
HI, H+,heat  CH3-I
methyl iodide
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
CH3CHCH2-OH
isobutyl alcohol
2-methyl-1-propanol
+ PBr3
CH3
 CH3CHCH2-Br
isobutyl bromide
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
CH3CCH3
CH3
+ Cl2, heat 
neopentane
2,2-dimethylpropane
CH3
CH3CCH2-Cl
CH3
neopentyl chloride
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
HX
NaI
acetone
PX3
RX
X2, Δ or hν
RH
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
R-H
R-X
Acids
NR
Bases
NR
NR

Active Metals
NR

Oxidants
NR
NR
NR
NR

NR
Reductants
Halogens
Reactions of alkyl halides:
1. Nucleophilic substitution
R-X
Best with 1o or CH3!!!!!!
+ :Z-  R-Z + :X-
2. (later)
3. Preparation of Grignard Reagent
R-X
+ Mg

RMgX

RMgX
4. Reduction
R-X
+ Mg
R-X
+ Sn, HCl

R-H
+ H2O

R-H
nucleophilic substitution
R-W
substrate
+
:Znucleophile

R-Z
substitution
product
good nucleophile  strong base
good leaving group  weak base
+
:Wleaving
group
R-X + :OH-
 ROH
+ :X-
alcohol
R-X + H2O
 ROH
+ HX
alcohol
R-X + :OR´-

R-O-R´ + :X-
ether
 R-CCR´ + :X-
alkyne
R-X + :I-

iodide
R-X + :CN-
 R-CN
+ :X-
nitrile
R-X + :NH3

+ HX
primary amine
R-X +
-:CCR´
R-I
R-NH2
+ :X-
R-X + :NH2R´  R-NHR´ + HX
R-X + :SH-
 R-SH
R-X + :SR´

+ :X-
R-SR´ + :X-
Etc.
Best when R-X is CH3 or 1o!
secondary amine
thiol
thioether
CH3CH2CH2-Br
+
KOH

CH3CH2CH2-Br
+
HOH
 CH3CH2CH2-OH + HBr
CH3CH2CH2-Br
+
NaCN
CH3CH2CH2-Br
+
NaOCH3  CH3CH2CH2-OCH3 + NaBr
CH3CH2CH2-Br
+
NH3
CH3CH2CH2-Br
+
NaI, acetone 


CH3CH2CH2-OH
+
KBr
CH3CH2CH2-CN + NaBr
CH3CH2CH2-NH2 + HBr
CH3CH2CH2-I + NaBr
Mechanism for nucleophilic substitution:
“substitution, nucleophilic, bimolecular”
SN2
RDS
Z:
+
C W
Z C
+
:W
“curved arrow formalism” uses arrows to show the movement
of pairs of electrons in a mechanism.
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
H
CH3
Br +
NaOH

HO
H
(SN2 conditions)
C6H13
(S)-(-)-2-bromooctane
C6H13
(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
Z:
+
C W

Z C W

Z C
+
:W
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.
CH3
CH3CCH3
Br
+ OH-

CH3
CH3CCH3
OH
+ Br- + alkene
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:
1)
RDS
C W
C
+
:W
carbocation
2)
C
+
:Z
C Z
Kinetics: rate = k [R-W ]; only R-W is involved in the RDS!
SN1 stereochemistry
CH3
H
CH3
Br +
NaOH

HO
CH3
H +
H
OH
(SN1 conditions)
C6H13
(-)-2-bromooctane
C6H13
(+)-2-octanol
C6H13
(-)-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:
R—Br 
3o > 2o > 1o > CH3
R+ + Br-
CH3—Br
ΔH = 219 Kcal/mole
CH3+
CH3CH2—Br
ΔH = 184 Kcal/mole
1o
CH3CH—Br
CH3
ΔH = 164 Kcal/mole
2o
ΔH = 149 Kcal/mole
3o
CH3
CH3C—Br
CH3
SN1 order of reactivity = 3o > 2o > 1o > CH3
Stability of carbocations = 3o > 2o > 1o > CH3+
RDS in SN1:
R—W  R+
R—X
[ R---------X ] 
δ+
δ-
+
:W-
R+
+ X-
Rearrangement of carbocations.
Carbocations can rearrange by 1,2-hydride or 1,2-methyl shifts:
 
--C—C-+ 
H
[1,2-H]  

--C—C–
 +
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
CH3CHCHCH3 + NaCN (SN1 conditions) 
Br

CH3
CH3CHCHCH3
+
2o carbocation
CH3
CH3CCH2CH3
CN
?????

[ 1,2-H shift ]

CH3
CH3CCH2CH3
+
3o carbocation
+
CN-
Competing mechanisms for nucleophilic substitution
SN2
RDS
Z:
+
SN1
RDS
C W
C
Z C
C W
+
:Z
C
+
+
:W
C Z
:W
SN2
SN1
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
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+ + Wionization favored by polar solvents
SN2: Z:- + R-W  Z-R + :Xsolvent 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
R-X
Best with 1o or CH3!!!!!!
+ :Z-  R-Z + :X-
2. (later)
3. Preparation of Grignard Reagent
R-X
+ Mg

RMgX

RMgX
4. Reduction
R-X
+ Mg
R-X
+ Sn, HCl

R-H
+ H2O

R-H
Mechanisms
SN2
RDS
Z:
+
SN1
RDS
C W
C
Z C
C W
+
:Z
C
+
+
:W
C Z
:W