1. ???????,??????????????,????

1
??? ???
??????????????
2

3
??? ?????????

• ????

4
????????????
5
????

• 1. ???????,??????????????,?????????????????????,
  ?????????
• 2.???????????????,???????

6
(No Transcript)
7
??? ???

• ??????
• 1. ???
• 2.????????,????????
• 3.???????
• 4.????????????????,?????1

R-F R-Cl R-Br R-I
1.82 1.94 1.79 1.64
8
??????
??(nm) 0.139 0.176 0.194 0.214
??(kJ/mol) 456 351 293 243
C-X????? ????????????????????
9
1.??????

• ?????????????,??????????,?Nu-?????OH-?NH3??

10
????
????
?????????
????
??
??
????

• ????

????
??
????
??
(a)?????,????????????
11
(b) ?????????
(c) ???????,??????????
(d) ???????,?????????
12

???
???

?????
????????
????????
13
?
14
????
??? ?? ?? ??

15
???(??????)???

????gt?????gt?????gt?????gt????
16
???(?????)???
RI RBr RCl RF

• ???
• ????

??????
17
???? ????????????????
????????
??????
ß-??
???????????????? ???,????????
???????????????, ????
a-??
1,1-??
18
1,3-??
??????????????,??????? ???
19
Saytzeff Rule ????? ??????????????????
20
????????
21
3. ?????
R???3???

• 1). ??????
• Wurtz???

22
Corey-House???
23
?1
24
?2

25
2).Grignard?????

26
?????????,???Grignard??,?????,?????
27
??????????,?????
28
Grignard?????????
29
Grignard??????????????????,?????????????
????????????
RLi?RNagtRMgXgtRZnXgtR2Cd
30
4. ??

(1)????H2,Ni?Pd?Pt (2)????LiAlH4?NaBH4?
Zn/HCl
31
LiAlH4?NaBH4???
LiAlH4 NaBH4

?? ? ??
??? ? ?
???? COOH ? CHO? CHO COOR?
RCOR RCOR -NO2?-CN
???? ?????? ???
32
??? ????????

• ?. ???? (Reaction Mechanism)
• 1). SN1??
• 2). SN2??
• 3). ?????
• ?. ????
• 1). SN2??
• 2). SN1??

33

?. ????????? 1). ??????? 2). ???? (L) 3). ????
(Nu) 4). ?? ?. ?????? ?. ????????

34
?. ????
1). ??????? (Substitution Nucleophilic
Unimolecular) ( SN 1)????
??? ???????
???????
??? ??????????
?????? ????????
35
?
36
????-???
37
?? ??????????????
?SN 1 ??????? ????????? ?????????? ??????????
2). ??????? (Substitution Nucleophilic
Bimolecular) ( SN 2)????
???????????????????? ???????????????
????
38
??????
T
????
??
-????????
????
??
?????
????????????????
?????????????????,???? ??????,????????????????
???????,?????????????? T.
39
S N 2 ????
40
?
41
?????,??????????????????????
p??????????????????? p?????????
? SN 2 ?????????
????????????? ?????
3). ?????
??SN1 ? SN2 ?????,?? ?SN1???????
?????????????????,???? ????
42
????
(a) ???????????????,????? ?????
(b) ????????,??????????
(c) ???????????
???????????????,?????? ????
43
3. ???????

• ????

??????????????
SN2??
???????????????????,?? ????????-Walden???
L-
Nu
44
(R) - (-) - 2 - ?? a25D -34.25 ??????100
(S) - (-) - 2 - ?? a25D -9.90 ??????100
a 23.5
45
SN1??

• ????

?????????????????,???? ??????
???????,???????
???? (Racemization)
46
???,SN1??????????????
?C???????,??L ?????, Nu? L
??????????????,?? ????? ?
???
47
?. ?????????

• ????????????????
• ?????
• ????????????
• ???????
• ????

(1)???????
???????????
SN 2??
?? gt ? gt ? gt ?
?????????
48
???????????SN 2??
?????,?? ???????4? ???????? ?????5??? ???,????? ??
??
???????????????, Nu??????????
49
SN1??
A. ????
??????????????,???SN 1 ?????????
???? (k1)
0.26 0.69 0.86 100 10 5 10 10
??????I? ??????C??, SN 1??????, ?? ?????
50
???????????????(R-ZCH2-L), SN 1????????
109 1.0
0.2
SN 1?? ??
?????????????,???? ????,??????????
?SN 2????,???????? ?????SN1??????
B. ????
????, ????? ????, ????? ????? ??
RBr???????????
RBr ???50? MeBr
1.00 EtBr 1.00 i-pBr
11.6 t-BuBr 1.2106
???
?????
51
???????

• ??????????SN1,????SN2
• ??SN1???,?????????,??p-?????,????????,?????????

52
??SN2?????,???????,???????????,????????,?????SN2?

53
????????SN1,????SN2?

• SN2?????????????????,???????,??????

54
??SN1?????,???????????,???????????????,???????????

55
(2)???????
Nu
Nu? SN2?????????
??
1???????????????????? -OH gt H2O, CH3O- gt
CH3OH
2)???????,??????,????? ?????,?????????????
, ??????
A. ???????????,??????????
?????????????????????????????????????
RO- gt HO- gtgt RCO2- gt ROH gt H2O
CH3O- gt PhO- gt CH3CO2- gt NO2-
56
????????????,???????? ?????????
B. ??????,?????,????????, ??????,?????
H2N- gt OH- gt F-
C. ??????????????,??????? ??,????????
57
F- lt Cl- lt Br- lt I-
R - O - lt R - S - lt R - Se -
D. ?????????????????,???? ???????????,???????
?,? ??????????????
????,???????,????? ?????????,????????
???????
??
???????,???????
58
(3)???? (Leaving groups)
?????????? ???????,?? ????
??????????,???????????
a) ??????????????
??????? ??
??? 1
??? 2
??? 1
??? 2
???????? pKa lt 5??????,? I- ??? HI?????
59
TsOH
MsO-
CF3SO3- ?????????
b) ???????????,?????????
F Cl Br I
?? ?? ?? ??
??????????
60
Question

• ????I-????????,?????????

61
(4)????
????????? ?????????, ???????? ???
?????
???? e??, ????????
?????CCl4,, CS2,
µ- ???
(µ 0)
???EtOH, H2O, CH3COOH
????????? ???????
????
????THF, Et2O, DMF, DMSO,
HMPT
(µ? 0)
??????
?????
??????
???????????
?? ?????????,????????
62
SN 1??
??????????? ???????,???? ???,???????, ????????
SN 2??
????????????,????????, ???????,????????,???
??? ???
????????? ?????????, ?????????? ?,????????
????????????? ?????SH- gt CN- gt I- gt OH- gt N3- gt
Br- gt CH3CO2- gt Cl - gt F- gt H2O
63
SN 2????????????????
???????? (Polar Aprotic Solvents) ???
Nu????,??????????, ?????????????,?????? ????
????????????
64
??????????,X - ????????
F - gt Cl - gt Br - gt I -
???????????????
?????????????SN 2?????
?? k2
DMF 3
103 CH3OH 3
10-2
????????????????,?DMF?? CH3OH? ????
65
????????

• ????????(?????)??????????????????,????????
• ???????1)??????2)???????????
• ??????-CO2-?-O-?-OH?
• -OR?NR2?-X?etc.

66
???????(SN2)
67
(S)-2-?????NaOH????,??????????(SN2).

68
(R)-2-?????NaOH???Ag2O?????????(R)-2-?????,???????
????????(??SN2)?
69
Wenstein?Lucas????-3-?-2-????HBr??,??????2,3-????
???-3-?-2-????HBr??,??????2,3-?????
70
??

71
??????????

• ??????

72
??SN1?SN2????????????

73
1???????????
74
1???????????
75
1???????????

• ????????????????,???????????????
• ??????

76
1???????????
77
1???????????

• ????????????
• SO2Cl??????,?????????????,??????????????

Cl
H
Cl
H
Et2O
78
1???????????

• Alkyl Halides from Alcohol by Treatment with
  Phosphorus Trihalides

79
1???????????

• ---- A simple SN2 reaction of three equivalents
  of the alcohol with the reagent leads to the
  formation of a phosphite ester with three
  phosphorus-oxygen bonds.
• The high strength of the phosphorus-oxygen bond
  provides the driving force for this step.
• Bromide ion then effects SN2 displacement

80
1???????????

• ??????????????

81
2?Williamson ???

• How to synthesize the following ether

82
2?Williamson ???

• The answer is ---- path a is correct
• Why?

83
2?Williamson ???

84
2?Williamson ???

• Sulfonate esters can be used in the Williamson
  ether synthesis

85
3?????????

• ?????????????????

86
3?????????

• This reaction illustrateds a problem common to
  many organic reactions a product is often
  capable of entering into reaction with one or
  more of the starting materials.

87
3?????????

• The ability to obtain B in high yield depends on
  the relative rates k1 and k2
• When k1 gt k2, B can be obtained in good yield
  through control of the reaction time
• When k1 lt k2, the yield of B is low
• In the above reaction, the rate of reaction of RX
  with - SH will be higher than that with - SR by
  using an excess of NaSH

88
3?????????

• An alternative method for the formation of thiol
  is the reaction of the anion of thiolacetic acid
  with alkyl halides to form thiol ester.
• Hydrolysis of the thiol ester, the designed
  product thiol can be obtained in good yield

89
4??????????

• ?????????????????

90
4?????Gabriel???

• ????????????

91
4????????????
92
5?????

• ????????????????
• ??????????????

93
????????????

• The difference between carbon nucleophile and
  heteroatom nucleophile
• 1. Carbon nucleophiles enter into relatively few
  SN2 reactions with sp3-hybridized carbon.
• This is, in part, because they are much stronger
  bases and bring about competing elimination
  reactions.

94
????????????

• They are sufficiently basic to abstract not only
  relatively acidic protons, such as those attached
  to heteroatoms, but also the much less acidic
  protons attached to carbon.
• So,the more characteristic reactions of carbon
  nucleophiles are nucleophilic addition to
  sp2-hybridized carbon.

95
????????????

• 2. Most of the carbon nucleophiles are highly
  reactive substances that are stable only in the
  absence of air and water.
• Therefore, their use depends on the availability
  of more sophisticated laboratory techniques than
  are required for the manipulation of heteroatoms
  nucleophiles.

96
????????????

• -CN ????????????
• ???????????????????????????????
• ????????????,??????????
• ????????????????

97
????????????

• 1????? Procaine
• ??????
• ??????????????????????(1884?)?????????????????????
  ??(Cocaine)??????,???,??????,???????,?????????????

98
????????????

• ??????????????,?????????????????????????????

99
????????????

• ??????????????,???????,????????????,?????????????,
  ?????????????????????,???1904?????????????????

100
????????????

• ???
• ????????????????

101
????????????

• 2?????????????
• Trifluperidol Hydrochloride

102
????????????

• 3?????????? Phenobarbital

103
????????????

• 4??????????
• ( Sodium Valproate)
• ?????????????

104
????????????

• The difference between carbon nucleophile and
  heteroatom nucleophile
• 1. ???????????,???????????????????,??????????sp2-?
  ?????,??????sp3-???????
• 2. ???????????????,??????????????

105
????????????

• -CN ????????????
• ???????????????????????????????
• ????????????,??????????
• ????????????????

106
????????????

• ????????????
• 1?sp-?????- CN, RCC -
• ???????????
• ?????????????????????????(??6.6?)

107
????????????

• 2? sp2 ?sp3??????? ???????? (?????)
• ??????????
• ??,???????????????????????????????????-??????,????
  ???????????????????
• ??????????????????????????(????)?

108
????????????

• 3?sp2 ?sp3???????
• ??????? (Organometallic Compounds)
• ????????????????????,????????????
• ????????????????,??????
• ??,??????????????

109
Organometallic Compounds

• Formation of Organolithium and Organomagnesium
  Compounds
• Organometallic compounds are formed by treatment
  of an alkyl halide or aryl halide with a
  zero-valent metal, usually lithium or magnesium.

110
Organometallic Compounds
111
Organometallic Compounds

• The metal atoms in both organolithium and
  organomagnesium compounds coordinate particularly
  well with the oxygen atoms of ethers.
• Therefore, ether such as THF or ethyl ether are
  commonly used as solvents for both the formation
  of organometallic reagents and their subsequent
  reactions.

112
Organometallic Compounds

• Organomagnesium compounds are commonly called
  Grignard Reagents in recognition of the French
  chemist Francois Victor Grignard, who was honored
  in 1912 with the Nobel prize for his discovery of
  this class of compounds.

113
Organometallic Compounds

• Note
• The overall process of formation of Grignard
  reagent results in insertion of magnesium between
  the carbon atom and the bromine atom to which the
  carbon was originally attached.
• Thus, the reaction in this way is often called as
  insertion reaction.

114
Organometallic Compounds

• Reactions of Organolithium and Organomagnesium
  Compounds
• They are generally poor nucleophiles with respect
  to alkyl halides and alkyl sulfonate esters,
  sp3-hybridized electrophile carbon species.
• In addition, they are very strong bases and
  promote elimination reaction.

115
Organometallic Compounds

• 1. With Epoxides ---- SN2 reaction
• It is a good path way to obtain the increasing
  two carbon atoms alcohol
• The C-O bonds of an epoxide are weaker than those
  of other ethers (why?). And they are weakened by
  the complexation betwwen the metal acting as a
  Lewis acid and the oxygen acting as a Lewis base.

116
Organometallic Compounds
117
Organometallic Compounds

• 2. With compounds containing active-proton
  group(OH, NH, COOH)
• ( ???????????,???????????? )
• Reduction of Alkyl Halides
• Isotopic Labeling

118
Organometallic Compounds

• 3. Grignard Reagents reacting with CO2
• ---- an good alternative method for obtaining
  carboxylic acid
• ---- this is an addition reaction

119
Organometallic Compounds

• 4. Lithium Dialkylcuprates
• Unlike the organolithium reagents, lithium
  dialkylcuprates are excellent nucleophiles in
  reactions with alkyl halides and alkyl sulfonate
  esters.
• Aryl halides and vinyl halides also react with
  them form C-C bonds. (not SN2)

120
Organometallic Compounds
121
Basic Skill Check

• 1. Can I predict the product (including
  stereochemistry and regiochemistry), when given
  the reactants?
• 2. Do I know the reagent(s) and conditions
  necessary to convert the given functional group
  into the product?

122
Basic Skill Check

• 3. For a desired product formed by a given
  reaction path, can I correctly choose an
  appropriate starting materials?
• 4. Given the reactants, conditions, and products,
  can I write a detailed reaction mechanism showing
  the specific electron flow that describes how the
  reaction proceeds?

123
??? ??????

• ??????
• 1. ????
• 1)?????
• ????gt??gt??gtCH4
• ???????????????????????????

124
2). ??????-H???
125
???????,???N-??????(??NBS)
???????????HBr?Br2?????
126
??
127
(No Transcript)
128
2.???????(?)

• 3.?????????(?)
• ??????
• ???????HX?PX3?PX5?????(???????SOCl2)

129
1.??????
????????NaX?????????
2.??????
130
3.???????

????????
131
Reading Assignment

• ??
• ??? ??????
• ??? ?????(????)

132
Homework Assignment

• P2522 4(125)5-1820
• 212326