Mechanisms of organic reactions

mirka.rovenska@lfmotol.cuni.cz
Types of organic reactions
Substitution an atom (group) of the molecule is replaced by another
atom (group)

Addition -bond of a compound serves to create two new covalent
bonds that join the two reactants together

Elimination two atoms (groups) are removed from a molecule which is
thus cleft into two products

Rearrangement atoms and bonds are rearranged within the molecule;
thus, isomeric compound is formed
Mechanism
A reaction can proceed by:

homolytic mechanism each fragment possesses one of the bonding
electrons; thus, radicals are formed:

AB A + B

heterolytic mechanism one of the fragments retains both the bonding
electrons; thus, ions are formed:

AB A
+
+ :B

Agents
Radical possess an unpaired electron (Cl

)

Ionic:
A) nucleophilic possess an electron pair that can be introduced
into an electron-deficient substrate:
i) anions (H

, OH

)
ii) neutral molecules (NH
3
, HOH)

B) electrophilic electron-deficient bind to substrate centres with
a higher electron density:
i) cations (Br
+
)
ii) neutral molecules (for example Lewis acids: AlCl
3
)

Lewis acids and bases
Lewis base: acts as an electron-pair donor; e.g. ammonia: NH
3

Lewis acid: can accept a pair of electrons; e.g.: AlCl
3
, FeCl
3
, ZnCl
2
. These
compounds important catalysts: generate ions that can initiate a reaction:

CH
3
Cl + AlCl
3
CH
3
+
+ AlCl
4
-




Radical substitution
1. Initiation formation of radicals: H
2
O OH + H
2. Propagation radicals attack neutral molecules generating new molecules
and new radicals:

CH
3
CH
2
R + OH CH
3
CHR CH
3
COO




3. Termination radicals react with each other, forming stable products;
thus, the reaction is terminated (by depletion of radicals)

H
CH
3
CH
2
R
- here: lipid peroxidation:
H
2
O
O
2
CH
3
COOH

R
H R
CH
3
CHR +
fatty acid
Electrophilic substitution
An electron-deficient agent reacts with an electron-rich substrate; the
substrate retains the bonding electron pair, a cation (proton) is
removed:

RX + E
+
RE + X
+


Typical of aromatic hydrocarbons:

chlorination
nitration etc.
Aromatic electrophilic substitution using
Lewis acids

Halogenation:


Very often, electrophilic substitution is used
to attach an alkyl to the benzene ring
(Friedel-Crafts alkylation):
benzene carbocation bromobenzene
Inductive effect
Permanent shift of -bond electrons in the molecule composed of atoms
with different electronegativity:
I effect is caused by atoms/groups with high electronegativity that
withdraw electrons from the neighbouring atoms: Cl, C=O, NO
2
:



+I effect is caused by atoms/groups with low electronegativity that
increase electron density in their vicinity: metals, alkyls:

C H
+
-
H
+
H
+
C
CH
3
CH
3
CH
3
CH
3
CH
2
CH
2
Cl
+ < + < + -
Mesomeric effects
Permanent shift of electron density along the -bonds (i.e. in compounds
with unsaturated bonds, most often in aromatic hydrocarbons)

Positive mesomeric effect (+M) is caused by atoms/groups with lone
electron pair(s) that donate electrons to the system: NH
2
, OH,
halogens




Negative mesomeric effect (M) is caused by atoms/groups that
withdraw electrons from the system: NO
2
, SO
3
H, C=O
Activating/deactivating groups
If inductive and mesomeric effects are contradictory, then the stronger
one predominates

Consequently, the group bound to the aromatic ring is:
activating donates electrons to the aromatic ring, thus facilitating
the electrophilic substitution:
a) +M > I OH, NH
2

b) only +Ialkyls

deactivating withdraws electrons from the aromatic ring, thus
making the electrophilic substitution slower:
a) M and I C=O, NO
2

b) I > +Mhalogens
Electrophilic substitution & M, I-effects
Substituents exhibiting the +M or +I effect (activating groups, halogens)
attached to the benzene ring direct next substituent to the ortho, para
positions:




Substituents exhibiting the M and I effect (CHO, NO
2
) direct the
next substituent to the meta position:
Nucleophilic substitution
Electron-rich nucleophile introduces an electron pair into the substrate;
the leaving atom/group retains the originally bonding electron pair:

|Nu

+ RY NuR + |Y

This reaction is typical of haloalkanes:





Nucleophiles: HS

, HO

, Cl

+
alcohol is produced
Radical addition
Again: initiation (creation of radicals), propagation (radicals attack neutral
molecules, producing more and more radicals), termination (radicals react
with each other, forming a stable product; the chain reaction is terminated)
E.g.: polymerization of ethylene using dibenzoyl peroxide as an initiator:
Electrophilic addition
An electrophile forms a covalent bond by attacking an electron-rich
unsaturated C=C bond
Typical of alkenes and alkynes
Markovnikovs rule: the more positive part of the agent (hydrogen in the
example below) becomes attached to the carbon atom (of the double
bond) with the greatest number of hydrogens:




Nucleophilic addition
In compounds with polar unsaturated bonds, such as C=O:



Nucleophiles water, alcohols, carbanions form a covalent bond with
the carbon atom of the carbonyl group:

used for synthesis
of alcohols
carbon atom carries +
aldehyde/ketone
Hemiacetals
Addition of alcohol to the carbonyl group yields hemiacetal:




As to biochemistry, hemiacetals are formed by monosaccharides:

glucose
hemiacetals
hemiacetal
Elimination
In most cases, the two atoms/groups are removed from the neighbouring
carbon atoms and a double bond is formed (-elimination)

Elimination of water = dehydration used to prepare alkenes:




In biochemistry e.g. in glycolysis:
2-phospho-
glycerate
phosphoenol-
pyruvate
H
2
O
Rearrangement
In biochemistry: often migration of a hydrogen atom, changing the
position of the double bond
Keto-enol tautomerism of carbonyl compounds: equilibrium between a
keto form and an enol form:




E.g.: isomerisation of monosaccharides occurs via enol form:
glucose
(keto form)
enol form fructose
dihydroxyaceton-
phosphate
glyceraldehyd-
3-phosphate
enol form