Lecture 1 - Introduction To Organic Reactions

Pharmaceutical Chemistry 126
PHARMACEUTICAL ORGANIC CHEMISTRY 2

Department of Pharmaceutical Chemistry
University of the Philippines ManilaCollege of Pharmacy
INTRODUCTION
What is a REACTION MECHANISM?
It provides insight into electron movement and bonding
that takes place during a chemical transformation.
It provides a useful means of predicting the product(s) of
chemical reactions.
It provides unequivocal proof of the given pathway (in
terms of electron movement and binding) that a
reaction follows.
ORGANIC REACTIONS (Review)
ADDITION
SUBSTITUTION
ELIMINATION
Electrophilic
Nucleophilic
Electrophilic
Nucleophilic
EW
C C
R
R R
R
C
O R
1
R
2
C C R
R R
X H
R
ELECTROPHILES
electron-poor species those that possess:

formal positive charges, e.g., carbocations,
nitronium ions, sulfonates, acylium ions

incomplete octets, e.g., free radicals, carbenes

greatly reduced electron density, e.g., BF
3
, AlCl-
3

NUCLEOPHILES
electron-rich species which may have:

excess negative charges;
fractional negative charges; or
lone pairs of electrons that can readily be used for
formation of bonding molecular orbitals
e.g., carbanions, hydroxides, alkoxides, sulfides,
halides, cyanides, carboxylates, phenoxides and
azides
ADDITION ELECTROPHILIC REACTIONS
ADDITION NUCLEOPHILIC REACTIONS
ADDITION NUCLEOPHILIC REACTIONS (continued)
SUBSTITUTION ELECTROPHILIC REACTIONS
SUBSTITUTION ELECTROPHILIC REACTIONS
(continued)
SUBSTITUTION NUCLEOPHILIC REACTIONS
C X
+ -
+
Nu
-
C Nu
+
X
-

OH SH NH
2
CN
OR SR NHR CCR
Nu
-
=
NR
2

X = Cl Br I
A substitution reaction in which a nucleophile (Nu
-
)
replaces a leaving group (L)
(continued)
Nu
-
C X C X Nu
-
X
-
C Nu
-

Nu
-

X
-

C
Nu
-

C X
+
C Nu
C Nu
S
N
2
S
N
1
Rate = k [RX][Nu
-
]
Substitution Nucleophilic
Bimolecular (S
N
2)
C
C
6
H
13

CH
3

Br H C
C
6
H
13

CH
3

H HO
NaOH
S
N
2
()-2-Bromooctane
[] = 39.6
0
100% OP
(+)-2-Octanol
[] = +10.3
0
100% OP
k
1

k
2
k
2

Rate = k
1
[RX]
Substitution Nucleophilic
Unimolecular (S
N
1)
S
N
2 S
N
1
Second-order kinetics First-order kinetics
Rate = k [RX][Nu
-
] Rate = k
1
[RX]
Complete stereochemical
inversion
Racemization (and inversion)
Absence of rearrangement Rearrangement
CH
3
W > 1
0
> 2
0
> 3
0
3
0
> 2
0
> 1
0
> CH
3
W
Factors Affecting Mechanism
1. Nature of leaving group
2. Nature of alkyl group of the substrate
3. Nature of nucleophile
4. Concentration of nucleophile
5. Nature of solvent
Reactivity of Leaving Group Rate of Both S
N
2 and S
N
1
1. Nature of leaving group
2. Nature of alkyl group of the substrate
SN1 Reactivity Increases
SN2 Reactivity Increases
Steric Hindrance
Carbocation Stability
S
t
r
e
n
g
t
h

o
f

N
u
c
l
e
o
p
h
i
l
e

Charge
Electronegativity
Delocalization
Strong nucleophile favors S
N
2.
Weak nucleophile favors S
N
1.
An increase in [Nu
-
] speeds up the
second-order reaction but has no
effect on the first-order reaction.
4. Concentration of the nucleophile
A decrease in [Nu
-
] slows down the
second-order reaction but has no
effect on the first-order reaction.
[Nu
-
] S
N
2
S
N
2 [Nu
-
]
indirectly favors the S
N
1

favors the S
N
2

5. Nature of solvent
Polar Aprotic Solvent S
N
2
Polarity
Polar protic Solvent S
N
1
C
H
C
+
C
R
C
+
C
H
C C
+
C
H
C
R
C C C
R
+
+
+
Rearrangement (1,2-Shift)
- takes place to yield a more stable carbocation
C H
3
CH
2
CH
2
+
C H
3
CH
+
CH
3
C H
3
C CH
2
+
CH
3
H
C H
3
C
+
CH
3
CH
3
C H
3
C CH
2
+
CH
3
CH
3
C H
3
C
+
CH
2
CH
3
CH
3
C H
3
C CH
2
CH
3
CH
3
Br
C
2
H
5
O
-
?
C H
3
C CH
2
CH
3
CH
3
Br
C
2
H
5
OH
?
ADDITION-SUBSTITUTION REACTIONS
- involving the carbonyl center
AROMATIC NUCLEOPHILIC SUBSTITUTION
Cl
N
+
N
+
O
-
O
O
-
O
+
Nu
-
Nu
N
+
N
+
O
-
O
O
-
O
+
Cl
-
Cl
+
Nu
-
Nu
+
Cl
-
H
+
, H
2
O

ELIMINATION REACTIONS
Rate = k
1
[RX]
Rate = k [RX][B
-
]
Factors Affecting Mechanism (S
N
vs E)
1. Stability of alkene product
Elimination Increases
Substitution Increases
C H
2
CH
2
C CH
2
R
H
C CH
2
R
R
C C
H
R R
H
C C
R
R R
H
C C
R
R R
R
1. Stability of alkene
2. Nature of Nucleophile
weakly basic nucleophile substitution
(I
-
, Br
-
, RS
-
, N
3
-
, RCOO
-
)

strongly basic nucleophile and highly branched
elimination
/sbmSS2011-2012

Lecture 1 - Introduction To Organic Reactions

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Lecture 1 - Introduction To Organic Reactions

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Pharmaceutical Chemistry 126

PHARMACEUTICAL ORGANIC CHEMISTRY 2

Department of Pharmaceutical Chemistry

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