REAKSI ALKIL HALIDA:
SUBSTITUSI DAN ELIMINASI NUKLEOFILIK
Nukleofil dan gugus pergi:
Reaksi alkil halida dengan nukleofil



Alkil halida terpolarisasi pada ikatan karbonhalida, membuat karbon menjadi elektrofil.
Nukleofil mengganti halida pada ikatan C-X
(sebagai basa Lewis)
Nukleofil yang memeiliki basa Brønsted kuat
dapat menghasilkan produk eliminasi.
Nukleofil


Basa Lewis yang netral atau bermuatan negatif
Perubahan muatan pada reaksi nukleofil
 Nukleofil
netral menjadi bermuatan positif
 Nukleofil bermuatan negatif menjadi netral
Based on McMurry, Organic Chemistry,
6th edition, (c) 2003
4
Reaktifitas Relatif Nukleofil




Tergantung pada kondisi reaksi
Nukleofil dengan sifat basa lebih kuat bereaksi lebih
cepat untuk struktur yang sama.
Nukleofil yang baik terletak lebih bawah dalam SPU.
Anion biasanya lebih reaktif dari yang netral.
Based on McMurry, Organic Chemistry,
6th edition, (c) 2003
5
Based on McMurry, Organic Chemistry,
6th edition, (c) 2003
6
Gugus Pergi


A good leaving group reduces the barrier to a reaction
Stable anions that are weak bases are usually excellent
leaving groups and can delocalize charge
Based on McMurry, Organic Chemistry,
6th edition, (c) 2003
7
“Super” Leaving Groups
Based on McMurry, Organic Chemistry,
6th edition, (c) 2003
8
Poor Leaving Groups

If a group is very basic or very small, it is
prevents reaction
Based on McMurry, Organic Chemistry,
6th edition, (c) 2003
9
Reaction Kinetics


The study of rates of reactions is called kinetics
The order of a reaction is sum of the exponents
of the concentrations in the rate law – the first
example is first order, the second one second
order.
C H3
N aO H
+
C H3
C
C H3
Br
N aBr
+ C H3
C H3
+ C H 3B r
v = k [C H 3 B r][N a O H ]
OH
C H3
v = k [C 4 H 9 B r]
N aO H
C
N aBr
+ C H 3O H
The SN1 and SN2 Reactions


Follow first or second order reaction kinetics
Ingold nomenclature to describe characteristic
step:
 S=substitution
N
(subscript) = nucleophilic
 1 = substrate in characteristic step (unimolecular)
 2 = both nucleophile and substrate in
characteristic step (bimolecular)
Stereochemical Modes of
Substitution

Substitution with inversion:

Substitution with retention:

Substitution with racemization: 50% - 50%
SN2 Process

The reaction involves a transition state in which
both reactants are together
“Walden” Inversion
Keadaan Transisi SN2

Keadaan transisi reaksi SN2 adalah planar,
karbon mengikat tiga gugus.
Urutan Kereaktifan Reaksi SN2

Semakin banyak gugus alkil terikat reaksi
semakin lambat
Based on McMurry, Organic Chemistry,
6th edition, (c) 2003
16
Pengaruh sterik pada Reaksi SN2
The carbon atom in (a) bromomethane is readily accessible
resulting in a fast SN2 reaction. The carbon atoms in (b) bromoethane
(primary), (c) 2-bromopropane (secondary), and (d) 2-bromo-2-methylpropane
(tertiary) are successively more hindered, resulting in successively slower SN2
reactions.
Steric Hindrance Raises
Transition State Energy
Very hindered


Steric effects destabilize transition states
Severe steric effects can also destabilize
ground state
11.5 Characteristics of the SN2
Reaction






Sensitive to steric effects
Methyl halides are most reactive
Primary are next most reactive
Secondary might react
Tertiary are unreactive by this path
No reaction at C=C (vinyl halides)
The SN1 Reaction


Tertiary alkyl halides react rapidly in protic
solvents by a mechanism that involves departure
of the leaving group prior to addition of the
nucleophile
Called an SN1 reaction – occurs in two distinct
steps while SN2 occurs with both events in same
step
Stereochemistry of SN1
Reaction

The planar
intermediate
leads to loss of
chirality
A
free
carbocation is
achiral

Product is
racemic or has
some inversion
SN1dalam Kenyataannya
Karbokation cenderung bereaksi pada sisi
yang berlawanan dari gugus pergi lepas
 Suggests reaction occurs with carbocation
loosely associated with leaving group
during nucleophilic addition

Effects of Ion Pair Formation



If leaving group remains
associated, then
product has more
inversion than retention
Product is only partially
racemic with more
inversion than retention
Associated carbocation
and leaving group is an
ion pair
SN1 Energy Diagram
k1
k-1
k2
Step through highest energy
point is rate-limiting (k1 in
forward direction)
V = k[RX]

Rate-determining step
is formation of
carbocation
11.9 Characteristics of the SN1
Reaction
 Tertiary
alkyl halide is most reactive
by this mechanism
Controlled
by stability of carbocation
Delocalized Carbocations



Delocalization of cationic charge enhances
stability
Primary allyl is more stable than primary alkyl
Primary benzyl is more stable than allyl
Perbandingan : Mekanisme Substitusi

SN1
 Dua
tahap dengan hasil antara karbokation
 Terjadi pada 3°, allil, benzil

SN2
 Satu
tahap tanpa hasil antara
 Terjadi pada alkil halida primer dan sekunder
Effect of Leaving Group on SN1



Critically dependent on leaving group
 Reactivity: the larger halides ions are better leaving
groups
In acid, OH of an alcohol is protonated and leaving group
is H2O, which is still less reactive than halide
p-Toluensulfonate (TosO-) is excellent leaving group
Based on McMurry, Organic Chemistry,
6th edition, (c) 2003
28
Allylic and Benzylic Halides

Allylic and benzylic intermediates stabilized by
delocalization of charge (See Figure 11-13)
 Primary
allylic and benzylic are also more
reactive in the SN2 mechanism
Based on McMurry, Organic Chemistry,
6th edition, (c) 2003
29
Based on McMurry, Organic Chemistry,
6th edition, (c) 2003
30
The Solvent



Solvents that can donate hydrogen bonds (-OH or –NH)
slow SN2 reactions by associating with reactants
Energy is required to break interactions between
reactant and solvent
Polar aprotic solvents (no NH, OH, SH) form weaker
interactions with substrate and permit faster reaction
Based on McMurry, Organic Chemistry,
6th edition, (c) 2003
31
Based on McMurry, Organic Chemistry,
6th edition, (c) 2003
32
Polar Solvents Promote
Ionization


Polar, protic and unreactive Lewis base solvents
facilitate formation of R+
Solvent polarity is measured as dielectric
polarization (P)
Solvent Is Critical in SN1

Stabilizing carbocation also stabilizes
associated transition state and controls
rate
Solvation of a carbocation by
water
Effects of Solvent on Energies

Polar solvent stabilizes transition state and
intermediate more than reactant and product
Polar aprotic solvents


Form dipoles that have well localized
negative sides, poorly defined positive
sides.
Examples: DMSO, HMPA (shown here)
O
P
C H3 N
N C H3
N
C H3
C H3
C
H
C H3
3
+
+
+
Common polar aprotic solvents
O
S
C H3
C H3
d im e th y lsu lfo xid e (D M S O )
O
P
C H3
N
N C H3
N
C H3
C H3
C H3 C H3
h e xa m e th ylp h o s p h o ra m id e (H M P A )
O
H
C
N
C H3
N ,N -d im e th y lfo rm a m id e (D M F )
C H3
s u lfo la n e
S
O
O
Polar aprotic solvents solvate cations well, anions poorly
+ + +
-
-
+ + +
+ + +
+ + +
-
good fit!
Cl
bad fit!
-
Na
-
-
+ + +
-
+ + +
+
+ + +
+ + +
SN1: Carbocation not very
encumbered, but needs to be
solvated in rate determining step
(slow)
Polar protic solvents are good because they solvate both the leaving
group and the carbocation in the rate determining step k1!
The rate k2 is somewhat reduced if the nucleophile is highly solvated,
but this doesn’t matter since k2 is inherently fast and not rate
determining.
SN2: Things get tight if highly
solvated nucleophile tries to form
pentacoordiante transition state
Polar aprotic solvents favored! There is no carbocation to be solvated.
Nucleophiles in SN1

Since nucleophilic addition occurs after
formation of carbocation, reaction rate is
not affected normally affected by nature or
concentration of nucleophile
REAKSI ELIMINASI ALKIL HALIDA




Eliminasi merupakan salah satu jalan alternatif
dari suatu reaksi substitusi
Lawan dari reaksi adisi
Menghasilkan alkena
Menurunkan produk substitusi terutama SN1
Aturan Zaitsev’s untuk Reaksi Eliminasi (1875)

Pada eliminasi HX dari suatu alkil halida, produk
tersubstitusi lebih dominan
Mechanisms of Elimination
Reactions


Ingold nomenclature: E – “elimination”
E1: X- leaves first to generate a carbocation


a base abstracts a proton from the carbocation
E2: Concerted transfer of a proton to a base and
departure of leaving group
11.11 The E2 Reaction
Mechanism



A proton is transferred to base as leaving
group begins to depart
Transition state combines leaving of X and
transfer of H
Product alkene forms stereospecifically
Geometry of Elimination – E2

Antiperiplanar allows orbital overlap and
minimizes steric interactions
E2 Stereochemistry

Overlap of the developing  orbital in the
transition state requires periplanar geometry,
anti arrangement
Allows orbital overlap
Predicting Product



E2 is stereospecific
Meso-1,2-dibromo-1,2-diphenylethane with base
gives cis 1,2-diphenyl
RR or SS 1,2-dibromo-1,2-diphenylethane gives
trans 1,2-diphenyl
(E)-1bromo-1,2-diphenylethene
11.12 Elimination From
Cyclohexanes


Abstracted proton and leaving group should
align trans-diaxial to be anti periplanar (app) in
approaching transition state (see Figures 11-19
and 11-20)
Equatorial groups are not in proper alignment
11.14 The E1 Reaction


Competes with SN1 and E2 at 3° centers
V = k [RX]
Stereochemistry of E1
Reactions


E1 is not stereospecific and there is no
requirement for alignment
Product has Zaitsev orientation because step
that controls product is loss of proton after
formation of carbocation
Comparing E1 and E2



Strong base is needed for E2 but not for E1
E2 is stereospecifc, E1 is not
E1 gives Zaitsev orientation
11.15 Summary of Reactivity: SN1,
SN2, E1, E2


Alkyl halides undergo different reactions in
competition, depending on the reacting molecule
and the conditions
Based on patterns, we can predict likely
outcomes
Special cases, both SN1 and SN2
blocked (or exceedingly slow)
Br
Carbocation highly unstable, attack from behind blocked
Carbocation can’t flatten out as required by sp2
hybridization, attack from behind blocked
Also: elimination not possible, can’t place double
bond at bridgehead in small cages (“Bredt’s rule”)
Br
Carbocation highly unstable, attack from behind blocked
Br
C H3
C H2B r
C H3
C H3
Carbocation would be primary, attack from
behind difficult due to steric blockage
Kinetic Isotope Effect



Substitute deuterium for hydrogen at  position
Effect on rate is kinetic isotope effect (kH/kD =
deuterium isotope effect)
Rate is reduced in E2 reaction
 Heavier
isotope bond is slower to break
 Shows C-H bond is broken in or before ratelimiting step