1. Text 1: chapter 6 Text 2: 第九章
Chapter 4 Alkyl halides (卤代烷): Nucleophilic substitution and elimination (亲核取代和消除)
Text 1: chapter 6
Text 2: 第九章

2. Contents Classification and Nomenclature of Alkyl halides
Physical properties of alkyl halides
Preparation of Alkyl halides
Reactions of alkyl halides
Nucleophilic Substitution Reactions
Elimination Reactions

3. 4.1 Classification and Nomenclature of Alkyl halides
Halohydrocarbons (卤代烃)
alkyl halides
(卤代烷烃):
vinyl halides
(卤代烯烃):
aryl halides
(卤代芳烃):
sp3
sp2
sp2

4. Classification of alkyl halides
Primary halides
伯卤代烷; 1°
Secondary halides
仲卤代烷; 2°
Tertiary halides
叔卤代烷; 3°
a geminal dihalide
偕二卤代
a vicinal dihalide
邻（连）二卤代

5. Nomenclature of alkyl halides
Common name:
“alkyl halide” (某基卤)
IUPAC name:
“haloalkane” (卤代烷),
-X is treated as a substituent
fluoride fluorine fluoro-
chloride chlorine chloro-
bromide bromine bromo-
iodide iodine iodo-

6. fluoroethane (氟乙烷)
ethyl fluoride (乙基氟)
2-chloro-2-methylpropane
t-butyl chloride (叔丁基氯)
Bromocyclohexane
(溴代环己烷)
cyclohexyl bromide
环己基溴
2-bromobutane
(2-溴 丁烷)
sec-butyl bromide
(仲丁基溴)

7. (1R,3R)-1-chloro-3-methylcyclopentane
trans-1-chloro-3-methylcyclopentane
(1R,3R)-1-甲基-3-氯环戊烷
trans- 1-甲基-3-氯环戊烷
3-(chloromethyl)pentane
3-氯甲基戊烷
dichloromethane
(二氯甲烷)
methylene dichloride
trichloromethane
chloroform (氯仿)
perchloromethane
tetrachloromethane
carbon tetrachloride
(四氯化碳)
perfluoropropane
全氟丙烷

8. Common uses of alkyl halides
reading material: text 1: 6-3
solvents (溶剂): CHCl3, CH2Cl2, ClCH2CH2Cl
reagents (试剂):
anesthetics (麻醉剂): CF3CHClBr
　refrigerants (致冷剂) :
　　　　CF2Cl2 (Freon-12，氟里昂-12)
　　　　CHClF2 (Freon-22)
pesticides (农药): DDT,
poly(vinyl chloride) (聚氯乙烯), Teflon（特氟隆，聚四氟乙烯）

9. 4.2 Physical properties of alkyl halides
Solubilities（溶解性）:
very poor in water;
Miscible with each other and with other relatively nonpolar solvents.(彼此互溶, 与其它非极性溶剂互溶.)
Boiling point (bp, 沸点):
　monohalides (一卤代烷): 规律与烷烃相似.
Density (d, 密度):
R-F, R-Cl, < 1; R-Br, R-I, > 1.
多卤代烷大于1.
随碳链增长, 同类型卤代烷密度降低.
一卤代烷具有不愉快的气味, 有毒.
在铜丝上燃烧时产生绿色火焰, 可用于鉴定卤素.

10. 4.3 Preparation of alkyl halides (6-6)
(Reading material: text 1 6-6, p )
1) Free-radical halogenation (自由基卤代) 6-6A

11. Allylic radical is resonance-stableilized. 烯丙基自由基稳定．
Allylic halogenation (烯丙位卤化) 6-6B
NBS
N-bromosuccinimide
N-溴代丁二酰亚胺
Allylic radical is resonance-stableilized. 烯丙基自由基稳定．
Important reactions !!

12. 2) From alkenes (烯烃加成)
3) From alcohol (醇的取代)
4) From other halides (halogen exchange, 主要用于制备碘代烷)

13. 4.4 Reactions of alkyl halides
Nucleophilic substitution (亲核取代反应)
Elimination (消除反应): 　
　　　dehydrohalogenation (脱卤化氢)
Formation of organometallic compounds (形成有机金属化合物)

14. Reactive intermediates
(反应活性中间体)

15. Nucleophilic substitution reactions (亲核取代反应):
Structure of alkyl halides
Carbon-halogen bond lengths
Bond
Bond Length (Å)
CH3F
1.39
CH3Cl
1.78
CH3Br
1.93
CH3I
2.14
In a nucleophilic sibstitution, a nucleophile(Nuc:- or Nu­ ) replaces a leaving group (X-) from a carbon, using its lone pair of electrons to form a new bond to the carbon atom.

16. Nu: Nucleophiles 亲核试剂
X: Cl, Br, I，　
reactivity: I>Br>Cl
For examples:

17. 任何具有亲核性的试剂或中间体都可能与卤代烃反应，SH-, carbanion, etc

18. 2) Elimination reactions (消除反应):
B: base, OH－, CH3O－, CH3CH2O－
X: Cl, Br, I
1,2-elimination, β-elimination
81%
19%

19. Positional Orientation of elimination 消去反应的取向
Saytzeff rule: (扎衣切夫规则)
In elimination reactions, the most highly substituted alkene usually predominates.
在β-消去中，主要得到双键碳上取代基较多的烯烃，也称扎衣切夫烯烃。
21%
79%
Most Nu are also basic and can engage in either substitution or elimination, depending on the alkyl halide and the reaction conditions.

20. Formation of organometallic compounds
(形成有机金属化合物) (T2: p234; T1 p , 9 )
M: Li, Na; Mg; B, Al, Ga; Si, Ge, Sn, Pb; P, As, Sb; etc.
organomagnethium compound
“Grignard reagent” (格利雅试剂, 格氏试剂)
活性顺序：
Important reagents in organic synthesis　！！！

21. organolithium compound 有机锂化合物
Wurtz reaction (武慈反应)

22. 4) Reduction of alkyl halides to alkanes (还原反应)
Reductive agents (还原剂)：LiAlH4, NaBH4
reactivity: ＞ ＞
primary ＞
secondary ＞
tertiary halides

23. Testing of RX
Physical methods:
IR, 1H NMR, MS
在铜丝上燃烧时产生绿色火焰.
Chemical methods:
Reaction with AgNO3 / EtOH solution.

24. 4.5 Nucleophilic substitution reactions
(text 1: p ; text 2: p )
Experimental facts:

25. SN2：second-order nucleophilic substitution (双分子亲核取代反应)
SN1：first-order nucleophilic substitution
(单分子亲核取代反应)
20世纪30年代英国伦敦大学教授英果(C. Ingold)

26. Mechanism SN2：Second-order nucleophilic substitution (双分子亲核取代反应) δ–
slow
nucleophile
substrate (底物)
transition state (过渡态, TS)
fast
product (产物)

27. ： L Nu ： L Nu L Nu ： ： ： L Nu

28. The reaction-energy diagram (反应能线图)TS E
Eact
reaction coordination δ–
exothermic reaction
放热反应
The reaction-energy diagram (反应能线图)

29. Characteristics of SN2 (1) second-order reaction (二级反应) ν= k[RX][Nu]
(2) concerted reaction (协同进行，一步完成。)
(3) having a transition state, no intermediate.
(反应中经过一个过渡态，没中间体。)
stereochemistry: inversion of configuration (构型转化)
Walden inversion (瓦尔登转化)

30. + +
optically pure
racemization (外消旋化)
inversion of configuration (构型转化)
Walden inversion (瓦尔登转化)

31. +
（R）
（S） +
（R）
（R）
瓦尔登转变是指骨架构型转变，不是指R转为S, 或S转为R。

32. Factors affecting SN2 reactions
Nu, Substrate, Solvent, Temperature
A. The effect of nucleophile
A base is always a stronger nucleophile than its conjugate acid.

33. basicity ≠ nucleophilicity
In a group of nucleophiles in which the nucleophilic atom is the same, nucleophilicities parallel basicities. (一般情况下, 含有相同亲核性原子的亲核试剂, 其碱性越强, 亲核能力越强.)
Order of basicity and nucleophilicity:
RO－ > HO－ >> RCOO－> ROH > HOH
But:
basicity ≠ nucleophilicity

34. basicity: > nucleophilicity: < Steric hindrance (空间位阻)
Strong Nu : less electronegative, large valence shell, more polarizable, soft base, less steric hindrance (位阻小)

35. strong weak strong R3P, HS-, I-, -CN, HO-, CH3O- , R2NH moderate
Br-, Cl-, NH3, CH3OH, CH3SCH3, CH3COO-
weak
F-, H2O, CH3OH
weak
strong

36. B. The effect of the structure of the substarate (底物结构的影响）
R---X(L)
General order of reactivity in SN2 reaction
CH3- > 1° > 2°> 3 °

37. R-: steric effects

38. A good leaving group must be electron withdrawing;
Leaving group effects
A good leaving group must be
electron withdrawing;
stable after leaving; (usually weak base)
polarizable, to stablize the TS
I-, Br-, Cl-,
HOH, ROH, NR3, etc.

39. ×
poor leaving group

40. C. Solvent effects on SN2 reactions
Protic solvent (质子性溶剂)
Protic solvent
H2O, ROH, HCOOH, NH3, etc.
Aprotic solvent (非质子性溶剂)
Aprotic solvent (非质子性溶剂)
hexane, acetone(丙酮), acetonitrile(乙腈), etc.
Polar solvent (极性溶剂):
H2O, ROH, acetone(丙酮), acetonitrile(乙腈), etc.
Apolar solvent (非极性溶剂):
Hexane, carbon tetrachloride

41. Polar Aprotic Solvents （极性非质子溶剂）
acetonitrile 乙腈
acetone 丙酮
Dimethyl sulfoxide
(DMSO)
二甲亚砜
N,N-Dimethylformamide
(DMF)
N,N-二甲基甲酰胺

42. in protic solvents: I- > Br- > Cl- > F-
Generally, polar solvents are required in the nucleophilic substitution reaction.
Relative Nucleophilicity
in protic solvents: I- > Br- > Cl- > F-
in aprotic solvents: I- < Br- < Cl- < F- F-

43. Factors affecting SN2 reactionsNu
Strong Nucleophiles are needed. R
less steric hindrance
Substrate L
good leaving groups are required.
Solvent
Wide variety, polar aprotic
Temperature
Higher temperature can increase the rate.

44. SN1: First-order nucleophilic substitution (单分子亲核取代)

45. Mechanism of SN1 step 1 step 2 rate-limiting step carbocation TS 1
intermediate
step 2
TS 1
TS 2

46. reaction coordination
TS 1
TS 2 E
reaction coordination
rate-limiting step
The reaction-energy diagram (反应能线图)

47. The structure of carbocations

48. Stereochemistry
racemization
(外消旋化)

49. Factors affecting SN1 reactionsNu
No effects, weak ones are OK.
Stability of carbocation,
or Substituent effects R
Substrate L
Good leaving groups are required.
Similar as SN1.
Solvent
Good ionizing solvents needed, protic solvents
Temperature
Higher temperature can increase the rate.

50. The relative stabilities of carbocations
How a methyl group helps stabilize the positive charge of a carbocation?

51. . . . sp2 sp3 sp2 hyperconjugation 超共轭效应, σ-p
+CH2CH3
+CH3
electron-donating of alkyl group
烷基的给电子效应 .
+CH2(CH3)3
+CH2(CH3)2

52. Rearrangement (重排) of carbocation
stable
stable

53. Characteristics of SN1 (1) first-order reaction (一级反应) ν= k[RX]
(2) multi-step reaction (多步反应)
(3) having a carbocation intermediate.
(反应经过碳正离子中间体。)
stereochemistry:　racemization (外消旋化)
(5) rearrangement (重排)

54. Allylic halides 烯丙基卤
SN1
stable intermediate
SN2
stablized TS

55. SN2
SN1
kinetics
Rate = k[R–X][Nu],
second-order
Rate = k[R–X], first-order
Mechanism
Bimolecular, Concerted, TS
Two Steps, intermediate, carbocation, rearrangements
Stereochemistry
Stereospecific (立体专一的)
(inversion)
Loss of Stereochemistry
(racemization)
Substrate (R-)
Sterics
(methyl >1°> 2°, No 3°)
Cation Stability
(benzylic > allylic > 3° > 2°)(No 1° or methyl)
Leaving Group
Moderately Important
(same trend as SN1)
Very Important
(– I > –Br > –Cl, H2O > -OH)
Nucleophile
Strong/Moderate Required
strong: RS–, I–, R2N–, R2NH, RO–, HO–, CN–
moderate: RSH, Br–, RCO2–
Not important
Solvent
wide variety,
(especially polar aprotic)
Polar protic

56. ？？ But： 离子对机理 + 紧密离子对 碳正离子 分子骨架 溶剂分割离子对 骨架构型转化 外消旋化 构型转化 部分外消旋化 典型SN1

57. 4.6 Elimination reactions (消除反应)
alkene
B: base, OH－, RO－, etc.
X: Cl, Br, I, HOH, OTs, etc.
1,2-elimination, β-elimination
Dehydrohalogenations (脱卤化氢)

58. Rate = k[R–X], first-order
Rate = k[R–X][B], second-order

59. Mechanisms of Elimination
E1 reaction： Unimolecular Elimination
First-order Elimination
单分子消除
E2 reaction： Bimolecular Elimination
Second-order Elimination
双分子消除

60. 1) The E1 mechanism E1 compete with SN1 Rearrangement exist. step 1
rate-limiting step
step 1
step 2
intermediate
TS 1
step 3

62. single-step, concerted H-C-C-X: anti-coplanar (反式共平面) anti elimination
2) The E2 mechanism
slow
fast
Transition state
single-step, concerted
H-C-C-X: anti-coplanar
(反式共平面)
anti elimination
B is far from X, stable TS

63. + C Stereochemistry of elimination:
Anti elimination(反式消除) for the E2 reaction. Br H + B C Br H B H Br
The orbitals are aligned.
B is far away from L.

64. X H H X Anti coplanar staggered conformation Syn coplanar
eclipsed conformation

65. (1)
(2)
trans-1,4-
cis-1,4-
k1 > k2
syn elimination

66. problem 6-38
diastereomers
cis-trans isomers

67. Positional orientation of elimination
(消除反应的定位方向)
81%
19%
Saytzeff product
Hoffman prduct
Saytzeff rule: (Zaitsev, 扎衣切夫规则)
In elimination reactions, the most highly substituted alkene usually predominates.
在β-消去中，当有两种β-H时，总是从含H最少的β-C上消去H，即得到双键碳上取代基较多的烯烃—扎衣切夫烯烃。
why ?
原因：取代基多的烯烃能量更低。

68. The competition of SN2 with E2

69. (a)
(b)
(c)
(d)

70. Factors affecting the relative rates of E2 and SN2 reaction E2 SN2
Structure of substrate
secondary and tertiary alkyl halide
primary alkyl halide
Basicity of nucleophile
stronger sterically hindered base
Stronger basic nucleophile
Temperature
high temperature
low temperature

71. E2 E1
Mechanism
Concerted
Two Steps
(carbocation rearrangements.)
Rate Equation
Rate = kr[R–X][Base]
Rate = kr[R–X]
Stereochemistry
Stereospecific
(anti coplanar TS)
Not Stereospecific
Substrate
Alkene Stability
(3° > 2° > 1°)
Cation Stability
(benzylic > allylic > 3 ° > 2 °
Base
Strong Base Required
(RO–, R2N–)
Not Important:
Usually Weak(ROH, R2NH)
Leaving Group
Moderately Important
(same trend as SN1)
Very Important
Solvent
Wide Range of Solvents
Polar Protic
Product Ratio
Saytzeff Rule: The most highly substituted alkene usually predominates.
Hofmann Product: Use of a sterically hindered base will result in formation of the least substituted alkene (Hofmann product).

72. Predicting the Products: Substitution versus Elimination
Start no
Bimolecular
Reaction
yes
What kind of substrate?
Is Nuc/Base strong? 1°
2°, 3°, or
stabilized 1°
Is Nuc/Base bulky?
yes
Unfavorable
Reaction
Unimolecular
Reaction no E2 3°
What kind of substrate?
yes
Is Nuc/Base bulky?
mostly E1* 2°
methyl or 1°
SN2+E2 no
mostly SN1*
SN2
* Under conditions that favor a unimolecular reaction (weak Nu/base and polar protic solvent), mixtures of SN1 and E1 are usually obtained.

73. Essential problem-solving skills
Correctly name RX, and identify them as 1°, 2°, or 3°.
Predict the products of SN1, SN2, E1, and E2 reactions, including stereochemistry.
Draw the mechanisms and energy profiles of SN1, SN2, E1, and E2 reactions,
Predict and explain the rearrangement of cations in first-order reactions.
Predict which substitutions and eliminations will be faster, based on differences in substrats, base/nucleophile, leaving group, or solvent.
Predict whether a reaction will be first-order or second-order.
When possible, predict predominance of substitution or elimination.
Use the Saytzeff rule to predict major and minor elimination pfoducts.

74. Assignments
text 1: 6-43, 44, 45, 46, 51, 53, 55, 56
6-59, 60, 61, 63, 66
text 2(selected): p 254: 6, 7, 8, 10,11, 13, 14, 15