Reaction Mechanisms

Organic Chemistry

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Bond Making

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Bond Breaking

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Ionic Reactions

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 The sited examples illustrate the basic rules for
mechanism and the use of curly arrows.

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 Ionic Reactions
Nitrogen:
• Has three (3) bonding electrons and a lone pair
• (valency = 3) hence, can bond to three atoms
• Can also bond to four (4) atoms by donating its lone pair
(where it carries a positive charge)

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Oxygen:
• Has two (2) bonding electrons and two (2) lone pairs
• Can bond to two other atoms; usually divalent
• Can also bond to one (1) atom in a negatively charged
form; or three (3) atoms in a positively charged form

Carries a lone pair but

(these electrons) do not
participate in bond
formation as it would
necessitate an
unfavorable double-
charged oxygen 10
Bond Making & Bond Breaking

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Bond Making & Bond Breaking

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 Hydrogen:
• Has one (1) bonding electron and can bond to one (1)
other atom
• monovalent
• Electrons can be donated to hydrogen resulting in
hydride anion

Or can be donated
to the other atom,
generating a proton
Typical mechanisms where lone pairs, apart from those
involved in subsequent bonding, are omitted:

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 Bond Polarity
Partial charges

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Nucleophiles and Electrophiles

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Leaving Groups

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Radical Reactions

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Type of Reactions

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Type of Reactions

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 Nucleophilic Reactions:
Nucleophilic Substitution (SN)

Nucleophilic substitution:
-> reagent is nucleophile
-> nucleophile replaces leaving group
-> competing reaction: (elimination +
rearrangements)

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 Nucleophilic Reactions:
Nucleophilic Substitution (SN)

leaving
group
nucleophilic
substitution -
Nu -
+ C X C Nu + X
Nucleophile

• in the following general reaction, substitution

takes place on an sp3 hybridized (tetrahedral)
carbon 28
 Nucleophilic Substitution
• Some nucleophilic substitution reactions

-
Reactio n: Nu + CH3 X CH3 Nu + X-

HO - CH3 -OH An alcoh ol

-
RO CH3 -OR An eth er
-
HS CH3 -SH A thiol (a mercap tan)
-
RS CH3 -SR A su lfid e (a th ioeth er)

I - CH3 -I An alk yl iodide

NH3 CH3 -NH3 + An alk ylammoniu m ion

+
HOH CH3 -O-H An alcoh ol (after p roton tran sfer)
H 29
 Mechanism
• Chemists propose two limiting mechanisms for
nucleophilic displacement
– a fundamental difference between them is the timing
of bond breaking and bond forming steps

• At one extreme, the two processes take place

simultaneously; designated SN2
 S = substitution
 N = nucleophilic
 2 = bimolecular (two species are involved in the rate-
determining step)
 rate = k [haloalkane] [nucleophile]
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 Mechanism
• In the other limiting mechanism, bond breaking
between carbon and the leaving group is entirely
completed before bond forming with the
nucleophile begins. This mechanism is
designated SN1 where
 S = substitution
 N = nucleophilic
 1 = unimolecular (only one species is
involved in the rate-determining step)
 rate = k[haloalkane]
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SN2 Reaction: Bimolecular Nucleophilic Substitution

– both reactants are involved in the transition

state of the rate-determining step
– the nucleophile attacks the reactive center from
the side opposite the leaving group
H
H - - H
HO + C Br HO C Br HO C + Br
-

H
H H
HH H

Transition state with

simultaneous bond breaking
and bond forming
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 SN2
• An energy diagram for an SN 2 reaction
– there is one transition state and no reactive
intermediate

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SN1 Reaction: Unimolecular Nucleophilic Substitution

• SN1 is illustrated by the solvolysis of tert-butyl bromide

– Step 1: ionization of the C-X bond gives a carbocation
intermediate

H 3C slow , rate CH3

d etermining
C Br C+ + Br
H3 C
H3 C H 3 C CH3
A carbocation intermediate;
carbon is trigonal p lanar
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 SN1
– Step 2: reaction of the carbocation (an
electrophile) with methanol (a nucleophile)
gives an oxonium ion
CH3 H3 C CH3 H3 C CH3
f ast
CH3 O + C+ + OCH3 O C + C O
CH 3 H3 C
H H3 C CH3 H H CH3 H3 C H

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 SN1
– Step 3: proton transfer completes the reaction

H3 C H3 C CH3 H
CH3 H
+ + fas t +
C O O C O + H O
H3 C CH3 H3 C
H H3 C CH3
H3 C

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 SN1
• An energy diagram for an SN1 reaction

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 SN1
• For an SN1 reaction at a stereocenter, the product is a
racemic mixture
• the nucleophile attacks with equal probability from either
face of the planar carbocation intermediate
C6 H 5 C 6 H5
C6 H5 C6 H5
- +
-Cl CH3 OH CH 3 O C C OCH3
C Cl C+ + H H
-H
H H

Cl Cl
Cl (S)-Enantiomer (R)-Enantiomer
Cl
(R)-Enantiomer Planar carbocation
A racemic mixture
(achiral) 38
Effect of variables on SN Reactions

– the nature of substituents bonded to the

atom attacked by nucleophile

– the nature of the nucleophile

– the nature of the leaving group

– the solvent effect

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Effect of Substituents on SN2

Effect of structure on rates of SN2 reactions

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Effect of substituents on SN2

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Effect of Structure on Rates of SN1

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Effect of Structure on Rates of SN1

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 Effect of substituents on SN reactions
• SN1 reactions
– governed by electronic factors, namely the
relative stabilities of carbocation intermediates
– relative rates: 3° > 2° > 1° > methyl

• SN2 reactions
– governed by steric factors, namely the
relative ease of approach of the nucleophile to
the site of reaction
– relative rates: methyl > 1° > 2° > 3°
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 Effect of substituents on SN reactions
• Effect of electronic and steric factors in
competition between SN1 and SN2 reactions

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 Nucleophilicity

• Nucleophilicity: a kinetic property measured by

the rate at which a Nu attacks a reference
compound under a standard set of experimental
conditions
– for example, the rate at which a set of
nucleophiles displaces bromide ion from
bromoethane
+ -
CH3 CH2 Br + NH3 CH3 CH2 NH3 + Br

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 Nucleophilicity

Two important features:

- An anion is a better nucleophile than
a uncharged conjugated acid
- strong bases are good nucleophiles

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 Nucleophilicity

Ef fectiv eness N ucl eoph ile

Br-, I -
g oo d CH3 S- , RS-
HO-, CH3 O-, RO-
O O
CH3 CO-, RCO-
mo derate
CH3 SH, RSH, R2 S
NH3 , RNH2 , R2 NH, R3 N
H2 O
CH3 OH, ROH
po or O O
CH3 COH, RCOH
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Nucleophilicity & basicicty with N and O Nucleophiles

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Nucleophilicity

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Leaving Group

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Leaving Group

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Leaving Groups and Acidity of Conjugate Acid

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 The Leaving Group
– the best leaving groups in this series are the halogens
I-, Br-, and Cl-
– OH-, RO-, and NH2- are such poor leaving groups that
they are rarely if ever displaced in nucleophilic
substitution reactions
Rarely act as leavi ng gro ups
in nucleo phil ic substi tutio n
G reater abi lity as leavi ng gro up and -el imin atio n reaction s
O
I- > Br- > Cl- >> F- > CH3 CO- > HO- > CH3 O- > NH2 -

Greater stabi li ty o f ani on; greater stren gth o f co njug ate acid

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 Solvent Effect
• Protic solvent: a solvent that contains an -OH group
– these solvents favor SN1 reactions; the greater the
polarity of the solvent, the easier it is to form
carbocations in it

Protic Polarity
Solven t Structure of Solvent
Water H2 O
Formic acid HCOOH
Methanol CH3 OH
Ethan ol CH3 CH2 OH
Acetic acid CH3 COOH

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 Solvent Effect
• Aprotic solvent: does not contain an -OH group
– it is more difficult to form carbocations in aprotic
solvents
– aprotic solvents favor SN2 reactions
Aprotic Polarity of
Solvent Stru cture Solvent
O
Dimethyl su lfoxide CH3 SCH3
(D MS O)
O
Acetone CH3 CCH3
Dichloromethane CH2 Cl2
Dieth yl eth er (CH3 CH2 ) 2 O
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 Summary of SN1 and SN2
Type of
Haloalkane SN 2 SN 1
Methyl SN 2 is favored . SN 1 does not occur. The methyl
CH3 X cation is s o u nstab le th at it is
never ob served in solution .
Primary SN 2 is favored . SN 1 does not occur. Primary
RCH2 X carbocations are so un stable that
they are never observed in s olution.
Secon dary SN 2 is favored in aprotic SN 1 is favored in protic solven ts
R2 CHX solvents w ith good w ith poor n ucleoph iles .
nu cleophiles.
Tertiary SN 2 does not occur because SN 1 is favored becau se of th e ease of
R3 CX of s teric h indrance around formation of tertiary carbocation s.
the s ubstitu tion center.
Su bstitution Invers ion of configu ration. Racemization. Th e carbocation
at a The n ucleophile attacks intermediate is plan ar, and attack b y
stereocenter the s tereocenter from the the n ucleophile occurs w ith equ al
sid e op pos ite the leavin g probability from either sid e.
group . 57
 Competing Reaction: Elimination
Elimination: removal of atoms or groups of
atoms from adjacent carbons to form a carbon-
carbon double bond

+ CH CH O- Na+
C C 3 2
CH3 CH
Example: Dehydrohalogenation (the elimination OH β-
of2HX);
H X
elimination Base
An alkyl
halide
 
C C + CH3 CH2 O- Na+ + CH CH OH + Na+ X -
CH CH OH C C 3 2
3 2
H X
Bas e
An alkyl An alkene
halide
C C + CH3 CH2 OH + Na+ X -

An alken e
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 β-Elimination
There are two limiting mechanisms for β-
elimination reactions:
• E1 mechanism: at one extreme, breaking of the
C-X bond is complete before reaction with base
breaks the C-H bond
– only R-X is involved in the rate-determining
step
• E2 mechanism: at the other extreme, breaking
of the C-X and C-H bonds is concerted
– both R-X and base are involved in the rate-
determining step
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 E2 Mechanism
• A one-step mechanism; all bond-breaking and
bond-forming steps are concerted

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 E1 Mechanism

– Step 1: ionization of C-X gives a

carbocation intermediate

CH3 s low , rate CH3

determin ing –
CH 2 -C- CH 3 CH 3 -C- CH 3 + Br
+
Br (A carb ocation
in term ediate)

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 E1 Mechanism

– Step 2: proton transfer from the carbocation

intermediate to a base (in this case, the solvent) gives
the alkene
Nucleophile
-> acting as a CH3 CH3
strong base
H fas t H +
O + H-CH2 -C-CH3 O H + CH2 =C-CH3
H3 C + H3 C

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 Elimination
• Saytzeff rule: the major product of a elimination is
the more stable (the more highly substituted) alkene

Br CH3 CH2 O-Na+ +

CH3 CH2 OH
2-Bromo-2- 2-Meth yl-2-bu tene 2-Meth yl-1-
methylbutan e (major p roduct) b utene

Br CH3 O-Na+
+
CH3 OH
1-Bromo-1-methyl- 1-Methyl- Methylene-
cyclopentane cyclopen tene cyclop entane
(major product) 63
 Elimination Reactions

• Summary of E1 versus E2 Reactions for Haloalkanes

Haloalkane E1 E2
Primary E1 d oes not occur. E2 is favored.
RCH2 X Primary carbocations are
so un stable that th ey are
never ob served in solution .
Secon dary Main reaction w ith w eak Main reaction w ith s trong
R2 CHX bas es su ch as H 2 O and ROH. bas es su ch as OH - an d OR-.

Tertiary Main reaction w ith w eak Main reaction w ith s trong

R3 CX bas es su ch as H 2 O and ROH. bas es su ch as OH - an d OR-.

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 Substitution vs Elimination
• Many nucleophiles are also strong bases (OH- and RO-)
and SN and E reactions often compete
– the ratio of SN/E products depends on the relative
rates of the two reactions

nucleop hilic
sub stitution H C C Nu + X-
H C C X + N u-
-elimination C C + H-Nu + X-

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 Substitution vs Elimination

What favors Elimination reactions:

- attacking nucleophile is a strong and
large base
- steric crowding in the substrate
- High temperatures and low polarity of
solvent

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 SN1 versus E1
• Reactions of 2° and 3° haloalkanes in polar protic
solvents give mixtures of substitution and elimination
products
CH3
E1
CH2 C + H+
CH3 CH3
CH3 C I
-I- CH3 CH3
CH3 SN 1
CH3 C+ CH3 C OH + H+
H2 O
CH3 -Cl- CH3 CH3
CH3 C Cl CH3
CH3 SN 1
CH3 C OCH3 + H+
CH3 OH
CH3
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 SN2 versus E2
• It is considerably easier to predict the ratio of
SN2 to E2 products

Attack of base on a -hydrogen by

E2 is only sligh tly affected by R R
branching at the -carbon; alkene H C
formation is accelerated
C leavin g group
SN 2 attack of a nucleop hile is R
impeded by branching at the R
- and -carbons

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 Summary of S vs E for Haloalkanes

– for methyl and 1°haloalkanes

Methyl SN2 The only sub stitution reactions observed
CH3 X SN1 SN 1 reactions of methyl halid es are n ever observed.
The meth yl cation is so uns table that it is never
formed in solution .
Primary SN2 The main reaction w ith strong bases such as OH - an d
RCH2 X EtO -. Als o, th e main reaction w ith good
nu cleophiles/w eak bas es, su ch as I- and CH 3 COO -.

E2 The main reaction with stron g, bu lky bases , such as

potas sium t ert-butoxide.
SN 1 / E1 Primary cation s are n ever formed in s olution; th erefore,
S N 1 and E1 reaction s of p rimary h alid es are never obs erved.

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 Summary of S vs E for Haloalkanes

– for 2° and 3° haloalkanes

Secondary SN 2 The main reaction w ith w eak b ases/good nu cleophiles,

R2 CHX such as I- and CH 3COO -.
E2 Th e main reaction w ith s trong bases /good nucleoph iles
su ch as OH - an d CH 3CH 2O -.
SN1 / E1 Common in reactions w ith w eak nucleop hiles in p olar
protic s olvents, s uch as w ater, methan ol, an d ethanol.

Tertiary SN 2 SN 2 reactions of tertiary halides are n ever observed

R3 CX because of th e extreme crow ding aroun d the 3° carbon.
E2 Main reaction w ith strong bas es, su ch as HO - an d RO -.
SN1 / E1 Main reactions w ith poor nu cleophiles/w eak b ases.

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 Summary of S vs E for Haloalkanes
– Examples: predict the major product and the mechanism for
each reaction

Cl 80°C
1. + NaOH Elimination, strong base, high temp.
H2 O

30°C SN2, weak base, good

2. + ( C2 H5 ) 3 N nucleophile
Br CH2 Cl2

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 Summary of S vs E for Haloalkanes

Br SN1+Elimination),
- + strong base, good
3. + CH3 O Na
meth anol nucleophile, protic
solvent

Cl No reaction,
+ - I is a weak base
4. + Na I (SN2)
acetone
I better leaving
group than Cl

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 Carbocation Rearrangements

Also 1,3- and other

shifts are possible

The driving force of rearrangements is to form a

more stable carbocation !!!
Happens often with secondary carbocations -> more
stable tertiary carbocation
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Carbocation Rearrangements in SN + E reactions

Rearrangement

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 Carbocation Rearrangements in SN + E reactions
(Wagner – Meerwein Rearrangements)

Rearrangement of a secondary carbocations -> more stable tertiary carbocation

Plays an important role in biosynthesis of molecules, i.e. Cholesterol -> 75
(Biochemistry)
 Carbocation Rearrangements in Electrophilic Addition Reactions
Formation of secondary
carbocation favored

Formation of primary
carbocation unfavorable
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