BITS Pilani

Pilani Campus

CHEM F111 : General Chemistry

Semester I: AY 2017-18
Lecture 37 (15-11-2017)
BITS Pilani, Pilani Campus
 Summary of Lecture 36
H H
H H
C C C C C C
Cl Cl
CH3 CH3

Resolution of Enantiomers:
Resolution: Separating enantiomers by
• Two methods:
– Chemical resolution
make environment chiral so that
– Chromatographic resolution enantiomers have different properties.

Relative and absolute configurations

CH3 CH2 C H 2C l
Cl Cl
C l2
H Cl H H Cl
C 2H 5 C 2H 5 C 2H 5
(S)-2-chlorobutane Same relative configuration (R)-1,2-dichlorobutane
2 BITSPilani, Pilani Campus
Nucleophilic Substitution Reactions

X = Cl, Br, I, OTs etc.

sp3

X is more electronegative than carbon Prone to undergo

Nucleophilic Substitution (SN)
C-X is attached to:
sp2
sp2
X X 1 carbon 2 carbons 3 carbons
undergo SNAr reactions H H R H
sp R R
C C
X R Cl C
R Br R I
do not undergo SN reactions 1o chloride 2o bromide 3o iodide
(R = carbon chain)
3 BITSPilani, Pilani Campus
Nucleophilic Substitution Reactions

d+ d-
Nu + C X Nu C + X
(leaving
group)
(nucleophile)(substrate) (product)
Nu: donates e- pair new covalent bond
Good leaving groups:
alkyl halides tosylates alcohols
R Cl O +
R O S CH3 R OH R O H
R Br
O H
R I
R O Ts Alcohols require acid
alkyl p-toluenesulfonate and then H2O leaves
Alcohols can also be converted to a good leaving group by making its
tosylate or through protonation.
4 BITSPilani, Pilani Campus
The Leaving group
 In comparing two leaving groups the better leaving group is
the weaker base. For example, H2O is a better leaving group
than HO¯ because H2O is a weaker base.
 There are periodic trends in leaving group ability:
Left to right across a row, basicity decreases so leaving group
ability increases.
 Down a column of the periodic table, basicity decreases so
leaving group ability increases.

5 BITSPilani, Pilani Campus

The Nucleophile
A nucleophile may be any molecule with an unshared electron pair.
Nucleophiles in general are anions ( -CN-, -I-, -SH- etc.) or neutral
molecules (H2O, ROH, NH3 etc.).
Although nucleophilicity and basicity are interrelated, they are
fundamentally different.
Basicity is a measure of how readily an atom donates its electron
pair to a proton.
It is characterized by an equilibrium constant, Ka in an acid-base
reaction, making it a thermodynamic property.
Nucleophilicity is a measure of how readily an atom donates its
electron pair to other atoms.
It is characterized by a rate constant, k, making it a kinetic property.

6 BITSPilani, Pilani Campus

The Nucleophile
For two nucleophiles with the same nucleophilic atom,
nucleophilicity parallels basicity, i.e. the stronger base is
the stronger nucleophile.
The relative nucleophilicity of HO¯ and CH3COO¯, two
oxygen nucleophiles, is determined by comparing the pKa
values of their conjugate acids (H2O = 15.7, and
CH3COOH = 4.8). HO¯ is a stronger base and stronger
nucleophile than CH3COO¯.
A negatively charged nucleophile is always a stronger
nucleophile than its conjugate acid.
HO¯ is a stronger base and stronger nucleophile than H2O.

7 BITSPilani, Pilani Campus

The Nucleophile
 Nucleophilicity does not parallel basicity when steric
hindrance becomes important.
 Steric hindrance decreases nucleophilicity but not basicity.
Sterically hindered bases that are poor nucleophiles are
called non nucleophilic bases.

Ethoxide (Stronger nucleophile)

tert-Butoxide (Stronger base)
8 BITSPilani, Pilani Campus
Types of Substitution Reactions
SN2 and SN1 mechanisms:
1st type: SN2 (concerted mechanism)
R
R d+ d- d- d- R
HO +
C Br HO C Br HO C + Br
H H
H HH H
transition state (T.S.)

The rate (speed) of reaction is directly proportional to the

concentration of either reactant. When the concentration of
either reactant is doubled, the rate of reaction doubles.

Rate dependent on [CH2RBr][OH-]

Rate = k[CH2RBr][OH-]
9 BITSPilani, Pilani Campus
SN2 Reaction
Mechanism of SN2 is very well supported by three
evidences.
(1) Kinetics second order reaction - bimolecular
(2) Stereochemistry and
(3) Reactivity of substrates.
Stereochemistry
All SN2 reactions results in inversion of
configuration at a stereogenic center.

H3C (R) CH3

H S
(S)
Br C + Br
HS + C
H
H
CH2CH3
CH2CH3
(inversion)
10 BITSPilani, Pilani Campus
SN2 Reaction

Nu⊖ attacks from the BACK face.

+ N N N + Br
Br H
H N3

Nu⊖ attacks from the TOP face.

H H
H3C I + C N
O

11 BITSPilani, Pilani Campus

SN2 Reaction
When a substrate contains more than
one stereocenter, inversion takes place
only at the stereocenter being attacked
by the nucleophile.
Reactivity of substrates: As the number of substituents attached
to the carbon bearing the halogen is increased, the reactivity
toward SN2 substitution decreases.

Methyl 10 20 Neopentyl 30
Relative Rates (30) (1) (0.03) (0.00001) (~0)
12 BITSPilani, Pilani Campus
2nd type: SN1 (stepwise mechanism)

Step (1): R
C Br
R slow
R
Carbocation
Step (2) R
R C + H2O
fast
R

Step (3) R
H
R C O + H2O
H fast
R
13 BITSPilani, Pilani Campus
SN1 Reaction
The rate of SN1 reactions depends only on [alkyl halide]
Rate = k[RX], first-order reaction
unimolecular nucleophilic substitution
The Structure of Carbocations:
Carbocations are trigonal planar
The central carbon of carbocation is
electron deficient; 6 valence shell e⊖
Empty p orbital is e(-) pair acceptor
SP2 SP3 s bond
50:50 chance of attack from both side
resulted racemic mixture
14 BITSPilani, Pilani Campus
Rearrangements in SN1 Reactions
 Carbocations can rearrange to form a more stable carbocation.
Hydride shift (~H): The movement of hydrogen with its bonding
pair of electrons.
Methyl shift (~CH3): CH3 moves from adjacent carbon if no H’s are
available.

15 BITSPilani, Pilani Campus

Rearrangements in SN1 Reactions
 Increasing the stability of carbocation intermediates is not the
only factor that leads to molecular rearrangement. If angle
strain, torsional strain or steric crowding in the reactant
structure is relieved by an alkyl or aryl shift to a carbocation
site, such a rearrangement is commonly observed.

Although a 3º-carbocation is initially formed, the angle and torsional

strain of the four-membered ring is reduced by a methylene group shift
resulting in ring expansion to a 2º-carbocation.
16 BITSPilani, Pilani Campus
Factors Affecting the Rates of SN1 and SN2 Rxs
• The structure of the substrate
• Reactivity of the nucleophile
• Nature of the solvent
• The nature of the leaving group Bridged C-does not
participate in SN
Reactivity of Substrates towards SN2 Rxn

Reactivity of Substrates towards SN1 Rxn

17 BITSPilani, Pilani Campus

Relative strength of a Nucleophile

R-X Me, 1o, 2o, 3o

SN2
strong
strong SN2
bases SN2 +

SN2
moderate
nucleopilicity

S N2 SN1 +

weak

18 BITSPilani, Pilani Campus

Classification of solvents

Polar protic solvents

(e.g. H2O, MeOH, CH3CO2H)

Non-polar solvents Polar

(e.g. hexane, C6H6)
Solvents solvents
O O
CH3
C H N
CH3 CH3
CH3
CH3 C N Polar aprotic solvents
(acetone) (DMF) (Acetonitrile) (e.g. DMSO, HMPA)
O O
S P NMe
CH3 CH3 Me2N NMe2 2
(DMSO) (HMPA)
19 BITSPilani, Pilani Campus
Polar APROTIC solvents solvate cations
Best solvents for SN2 rxs are
Polar Aprotic solvents
F- - strong dipoles
- and no OH or NH groups
Na+ CH3Br + NaI CH3I + NaBr

Na+ Solvent Relative Rxn Rate

Na+ MeOH 1
DMF 106

“naked” anion - F e’s “free” of Na+

20 BITSPilani, Pilani Campus
Polar protic solvents solvate cations & anions
Solvation of nucleophile by Polar protic
solvents, decreases its nucelophilicity. So
they are not good solvent for SN2 rexn.
SN1 Reactions: Solvent effects are due
to stabilization of the transition state.
F- Polar Protic solvents stabilize ionization
in transition state
Na +
Solvation lowers the Protic solvents can
potential energy of the form hydrogen
nucleophile making it bonds and can
less reactive. solvate both
cations and anions.
Solvation energy is inversely proportional to the size of anion. Thus,
smaller anion such as F- are solvated more than I- and thus are weaker
nulcleophile in protic solvent.
21 BITSPilani, Pilani Campus
Nucleophilic Aromatic Substitution (SNAr)
Nucleophilic Aromatic Substitution (SNAr)
Nucleophilic Aromatic Substitution (SNAr)