1st-yr-lec. 5
29
O Ph O Ts O Ts N H KOH H 2 S OH Ph S N + (a) (b) Q. Predict the stereochemistry of these products. Are they single diastereomers, enantiomerically pure, or racemic, or something else ?
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Transcript of 1st-yr-lec. 5
O
Ph
OTs OTs
NH
KOH
H2S
OH
Ph
S
N+(a)
(b)
Q. Predict the stereochemistry of these products. Are they single diastereomers, enantiomerically pure, or racemic, or something else ?
O
Ph
+NH
N
OH
Ph
(a)
(b)
OTs OTsKOH
H2SS
SH OTs
HS SN2
S OTsS
X
R
REtOEtO
In presence of high concentration of EtO-
Tends to occur when “R” is bulky enough to reduce markedly the rate of direct SN2 displacement.
Cl
D
OCH3
HNaOMe NaOMe
Cl
D
Cl
D
D
D
OCH3
H3CO
H
H
SN2'
O R
O
H
But
HN
N
H
But
+
R=Cl2C6H3-
Example:
Examples of
Mechanism
SNi/ reaction
H3CCH CHCH2OHSOCl2
CH CH2
HCH3C
OH
SOCl2
CH CH2CH3C
Cl
H
CH
CH2ClCHH3C
Ether
(only)
Ether(only)
ClS
O
CH2
H3C
O
SO2
H3CCH CHCH2 O S Cl
O
CH CH2CH
H3C
Cl
. .
. .
. .
+
Payne rearrangement
Ph OOH
OS
NaOH
Ph OS
OH
OH
Ph OOH
OPh O
O
O
Ph O
O
OPh O
OH
O
H2OS
Ph OS
OH
OH
Neighbouring group participation
Q.
OH H2N
OH
CO2H
HNO2
OO
H
CO2H
S S
OH N2
OH
C
O
O HS O
OH
O
O
H
HR
Q. When I undergoes SN1 solvolysis, it reacts more rapidly than isobutyl chloride II.Explain.
H3C CH
CH2Cl H3C CH
CH2
CH3
Cl
I II
δHH
H3C Cl
H H
H3CTS
HCl
H
H
H3C
Sol OH
HH
+ Cl
Solvolysis products
phenonium ion
Q. Which compound solvolyses faster in HOAc containing NaOAc (I or II)?
The product is the same from either I or II. What is the structure of the product?
I
S
Cl
H
II
S
H
Cl
S
OAc
H
Q. Which compound solvolyses faster in HOAc? (I or II). Give the structure of the product from I.
OTs OTs
I II
Participation of the π electrons of the double bond gives the ion III, which would be stabilized by delocalization of the positive charge
I
OTs
HOAc
III
OAc
Q. Suggest a mechanism for the following reaction
PhN
Ph
O
O
Cl H2OPh N
H
O
O
O
Ph
CH3CN, heat
O
NPh
O
Ph
OH
O
NPh
O
Ph
Ph NH
O
O
O
Ph
N
O
Ph
O
Ph
Cl
Q. Hydrolysis of PhSCH2CH2Cl is considerably slower than that of EtSCH2CH2Cl. Explain.
Q. Hydrolysis of EtSCH2CHMeCl produces two products: EtSCH2CH(Me)OH & EtSCHMeCH2OH. Explain.
R X NaCN+ R CNsolvent ?
R X NaCN+ R CNCH2Cl2, H2O
X
R4N HSO4 trace amt. (cat.)
CH2Cl2, H2OR X NaCN+ R CN
fast
NaCN, an ionic compound, is soluble only waterRX preferred non-polar organic solvent and those are immiscible.
PHASE TRANSFER CATALYST (PTC)
Phase transfer catalysis
Phase- transfer catalysis of the SN2 reaction between NaCN and an alkyl halide
Na+ CN -
RX
CH2Cl2
Na+ CN -
RCN
RX
RX
Na+ X-
CH2Cl2
Q + X -
Q + CN -
Q + CN -Q + X -
aq. phase
org. phase
aq. phase
org. phaseQX = R4N + X -
such as (CH3CH2CH2 CH2)4 N+ X-
add Q + X -
Here no reaction takes place
because the nucleophile, CN -,
cannot enter the org. phase to
react with RX
Here the PTC transports the cyanide ion
(as Q + CN -) into the organic phase where
the reaction
RCN + X -
takes place rapidly
+
+
+
+
CN -+
Other types of reactions with PTC
Bu4 NBrCH3(CH2)7CNCH3(CH2)7Cl (in dioxane)
aq. NaCN, 105 0C (95 %)
Example
H3C(H2C)5 HC CH2 (benzene)R4 N X CH3 (CH2)5COOH
aq. KMnO4, 35 0C
99 %
Crown ethers
C6H5 CH2Cl
O
O
O
O
O
O
RCH2X
KFCH3CN
K +
RCH2CN
C6H5 CH2F
K
O
O
O
O
O
O
18 - Crown - 6
K + CN -+
18-C-6
benzene+ K+ X -
18-C-6+ + K+ Cl -
100 %
+
..
:
::
O O
O
O
O
O O
O
O
ONa+
[15]-crown-5cavity diameter = 1.7-2.2 A°
ionic diameter of Na+ is 1.80 A°
OO
O O
[12]-crown-4cavity diameter = 1.2-1.5 A°
ionic diameter of Li+ is 1.20 A°
OO
O O
Li+
inclusion compound
Crown ethers are named [X]-crown-Y, where X is the total number atoms in the ring and Y is the number of oxygen atoms in the ring
Host-guest relationship• The hole has diameter 2.7 Aº• Diameter of K+ = 2.66 Aº
O O O
O
O O O
O
O
O
O
O
Nonactin an antibiotic
An ionophorous antibiotic
An ionophore is a compound that transport metal ions by binding them tightly.
By disrubting carefully maintained electrolyte balance between inside and outside
The toxicity of mustard gas is due to nucleophiles of cell components becoming alkylated
S
Cl Cl
S
Cl Cl
Nu
ClS
Nu
. .. .
mustard gas
Mustard gas – a war gas that produces blisters all over the body surface
Biological Nucleophilic Substitution
Biological methylation for an organic chemist
CH3 INu-
+ CH3Nu + I -. .
For nucleophile in a cell, MeI cannot be used, because alkyl halides are insoluble in water
In biological systems, you have got predominantly aqueous environment
Let’s take the case of methylation in the cells of plants and animals:
Choline : important in the transmission of nerve impulsesAdrenaline : causes blood pressure to increaseNicotine : makes smoking tobacco addictive
Here it involves the transfer of a methyl group from an amino acid (methionine)
NH3
O2C CHCH2CH2 S CH3
H3C N
CH3
CH3
CH2CH2OH
HO
HO
CH CH2NH CH3
OH
N
N
CH3
adrenaline
choline
nicotine
+
+
N
NN
N
NH2
CH2
O P O P O
OH
O
P OH
OH
OO
OH
CHCH2CH2SCH3
NH3
O2C
O
OH OH
Adenine
H H
ATP
O
OH OH
AdenineCH2S
CH3
O2CCHCH2CH2
H3N H H PO
OH
O
O P O P
OH
O
OH
OH
O
+
Triphosphate ion
Adenine =
triphosphate group
leaving group
nucleophile..
CH3
N
CH3HO O
OH OH
AdenineCH2S
CH3
O2CCHCH2CH2
H3N
H H
H H
H3C N
CH3
OH
CH3
O
OH OH
AdenineCH2SO2CCHCH2CH2
H3N
H H
H H
+
S-Adenosylmethionine (SAM)
+
choline
. Nature makes use of high nucleophilicity of sulfur
. Weakly basic group (eg. triphosphate of ATP) functions as LG
. Attack at the less hindered CH3- rather at one of the more
hindered -CH2- groups
..
Q.
• Which compound solvolyses in HOAc faster ?• Predict the stereochemistry in each case• If I is optically active, will the solvolysed product be racemic ?
OTs
O
O
CH3
OTs
O
O
CH3
III
OAc
OAc
R OAc
OAc
HOAc
O
O
O
O
AcOH
AcOH
R
OTs
O
O
OAc
OAc
(+). .
(+)
s
s
OO
O
I II III
Transannular participation of ether oxygen
. Unfavorable polar effect of the C-O bond
.III is more favorable than either I or II
XO
XO
X
O
X
Relative rate 1.0 0.014 0.14 4.85 x 10 4
Q.
Explain
• SN1 reaction may be substantially retarded by substitution of deuterium atoms for hydrogen at one or more β-carbons
(CD3)2CCD2CH3
Cl
(CH3)2CCD2CH3
Cl
0.43k Dk H
0.71
Stretching of the β-C-H bonds in the activated complex
Since β-C-D bonds are somewhat “tighter” bonds than β-C-H bonds, substitution for β-hydrogens lower the extent of stabilization by hyperconjugation in the activated complex, boost the energy of activation and thus retard the reaction.
C
H
C X C C X
H
stabilization by hyperconjugation
extra stabilization fromσ donation into empty p orbital of planar carbocation
extra stabilization fromσ donation into empty p orbital of planar carbocation
no stabilization: no electronsto donate into empty p orbitalThe C-H bonds are at 90 º to the empty p orbital and cannot interact with it
H3C CH3
Hempty p orbital
H2C
H
CH2
CH2
H
H
H2C
H3C
CH2
CH2
CH3
H HH
CH3
A C-C bond is just as good as the C-H bond in donating electrons into an empty p orbital and a C-Si bond is even better.
Q.
Where do you expect D-effect should be considerably less?
Ph C
D
CH2Cl
D
H C
D
D
C
Me
Me
Cl
HCOOH HCOOH
ProductProduct
NN
I II
....
Q. Which one reacts with MeI more rapidly ?
Steric acceleration
Cl
Cl
+
+
H2O
H2O
OH
OH
+
+
HCl
HCl
(1)
(2)
Q. Which reaction takes place more rapidly (I or 2) ?
