1. 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 o o

2. 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 o

3. CH CH3
CH3CHCH2CHCH3 CH3CCH3
Br I
2-bromo-4-methylpentane tert-butyl iodide
2-iodo-2-methylpropane
2o o
CH3
Cl-CHCH2CH3
sec-butyl chloride
2-chlorobutane 2o

4. Physical properties:
polar + no hydrogen bonding
=> moderate boiling/melting points
water insoluble
Uses: pesticides, refrigerants (freons), solvents, synthetic intermediates.
CH3Br CClF3 CCl4

5. Synthesis of alkyl halides:
1. From alcohols
a) HX b) PX3
Halogenation of certain hydrocarbons
3. (later)
4. (later)
5. Halide exchange for iodide

6. From alcohols. #1 synthesis!
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

7. CH3CH2CH2CH2-OH + NaBr, H2SO4, heat  CH3CH2CH2CH2-Br
n-butyl alcohol (HBr) n-butyl bromide
1-butanol bromobutane
CH CH3
CH3CCH 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

8. CH3CHCH2-OH + PBr3  CH3CHCH2-Br
…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
CH CH3
CH3CHCH2-OH PBr3  CH3CHCH2-Br
isobutyl alcohol isobutyl bromide
2-methyl-1-propanol bromo-2-methylpropane

9. 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.
CH CH3
CH3CCH Cl2, heat  CH3CCH2-Cl
CH CH3
neopentane neopentyl chloride
2,2-dimethylpropane chloro-2,2-dimethylpropane

10. 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 idodopropane

11. ROH HX
PX3
NaI
acetone RX
X2, Δ or hν RH

12. 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

13. CH3CH2CH2CH2-OH + PBr3  CH3CH2CH2CH2-Br
CH3CCH Cl2, heat  CH3CCH2-Cl
CH3CH2CH2-Br + NaI, acetone  CH3CH2CH2-I
CH3 CH3
CH3C-OH HBr  CH3C-Br

14. R-H R-X NR 
Acids
Bases
Active Metals
Oxidants
Reductants
Halogens

15. Reactions of alkyl halides:
Nucleophilic substitution Best with 1o or CH3!!!!!!
R-X :Z-  R-Z :X-
2. (later)
Preparation of Grignard Reagent
R-X Mg  RMgX
Reduction
R-X Mg  RMgX H2O  R-H
R-X Sn, HCl  R-H

16. nucleophilic substitution
R-W :Z  R-Z :W-
substrate nucleophile substitution leaving
product group
good nucleophile  strong base
good leaving group  weak base

17. R-X + :OH-  ROH + :X- alcohol
R-X H2O  ROH HX alcohol
R-X :OR´  R-O-R´ :X- ether
R-X :CCR´  R-CCR´ :X- alkyne
R-X :I  R-I :X- iodide
R-X :CN  R-CN :X- nitrile
R-X :NH  R-NH 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!

18. CH3CH2CH2-Br + KOH  CH3CH2CH2-OH + KBr
CH3CH2CH2-Br HOH  CH3CH2CH2-OH HBr
CH3CH2CH2-Br NaCN  CH3CH2CH2-CN NaBr
CH3CH2CH2-Br NaOCH3  CH3CH2CH2-OCH NaBr
CH3CH2CH2-Br NH3  CH3CH2CH2-NH HBr
CH3CH2CH2-Br NaI, acetone  CH3CH2CH2-I NaBr

19. Mechanism for nucleophilic substitution:
“substitution, nucleophilic, bimolecular”
“curved arrow formalism” uses arrows to show the movement of pairs of electrons in a mechanism.

20. 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”

21. 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.

22. SN2 stereochemistry CH3 CH3 H Br + NaOH  HO H (SN2 conditions)
(S)-(-)-2-bromooctane (R)-(+)-2-octanol
100% optical purity
SN2 proceeds with 100% inversion of configuration! (“backside attack” by the nucleophile)

23. SN2 100% backside attack by the nucleophile
Evidence: stereochemistry = 100% inversion of configuration
Reasonable?
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.

24. Relative rates for alkyl halides in SN2: CH3-X > 1o > 2o > 3o
37 : 1.0 : 0.2 :
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.

25. CH CH3
CH3CCH OH-  CH3CCH 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”

26. Substitution, nucleophilic, unimolecular (SN1) mechanism:
Kinetics: rate = k [R-W ]; only R-W is involved in the RDS! 1) 2)

27. 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.

28. 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
CH3C—Br ΔH = Kcal/mole 3o

29. 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-

30. 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–
+   +
CH CH3

31. 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”)

32. CH3 CH3   CH3CHCHCH3 + NaCN (SN1 conditions)  CH3CCH2CH3 ?????
Br CN
 
CH [ 1,2-H shift ] CH3
CH3CHCHCH  CH3CCH2CH CN-
2o carbocation 3o carbocation

34. 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
Rate? temp.
Increases rate
Rate? 2 x [RX]
Doubles rate
Rate? 2 x [Z-]
No effect

35. 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

36. 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

37. 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 )

38. Synthesis of alkyl halides:
1. From alcohols
a) HX b) PX3
Halogenation of certain hydrocarbons
3. (later)
4. (later)
5. Halide exchange for iodide

39. Reactions of alkyl halides:
Nucleophilic substitution Best with 1o or CH3!!!!!!
R-X :Z-  R-Z :X-
2. (later)
Preparation of Grignard Reagent
R-X Mg  RMgX
Reduction
R-X Mg  RMgX H2O  R-H
R-X Sn, HCl  R-H