1. Tues. 9/ 11/ 1433 H. Pharmaceutical Organic Chemistry. Classes and ... 1-
Homolytic cleavage: each atom involved in the covalent bond receives.
LEC. 1 Tues. 9/ 11/ 1433 H Pharmaceutical Organic Chemistry Classes and Mechanisms of Organic reactions
Textbooks:
R. Fessenden and J. Fessenden, Organic Chemistry, PWS Publishers, Latest edition.
Organic Chemistry defined as the chemistry of carbon compounds Organic Reaction Process in which two or more than two compounds react together to form new compound(s) AB + CD
AD + CB
reactants
products
Mechansim of the Reaction the detailed description of how a reaction occurs, i.e. how bonds dissociated (cleaved) and formed
Bond Cleavage (Dissociation) by two ways:
1- Homolytic cleavage: each atom involved in the covalent bond receives one electron, resulting in formation of free radical
2- Heterolytic cleavage: both bonding electrons are retained by one of the atoms, resulting in formation of ionic species
or
Electronegativity Is the ability of atom to pull (withdraw) electrons order F > O > Cl > N > Br > C > H F > Cl >Br > I Ionic Species Ions are charged particles (atoms e.g. H+, or groups e.g. OH-) Nucleophile [ nucleus lover] … attracted to +ve center, Nu- or Nu..
some neutral polar molecules can act as Nue.g. H2O, CH3OH and CH3NH2 Electrophile [ electron lover]… attracted to –ve center, E+
ORGANIC REACTIONS The most common types of organic reactions include: 1.
Substitution reactions
2. Addition reactions 3. Elimination reactions 4. Rearrangement reactions
SUBSTITUTION
REACTIONS
A reaction in which one atom, ion or group is substituted for another
This type of organic reactions is divided into: 1. Nucleophilic Substitution e.g. the hydrolysis of an alkyl bromide, R-Br + OH− → R-OH + Br− 2. Electrophilic Substitution
e.g. The reaction between benzene and chlorine in the presence of either aluminium chloride or iron gives chlorobenzene. C6H6 + Cl2
C6H5Cl + HCl
NUCLEOPHILIC SUBSTITUTION A reaction in which Nu is substituted by another Nu
can occur by an:
a. SN1 path b. SN2 path
Most common reaction of alkyl halides (RX) and alcohols (ROH)
NUCLEOPHILIC SUBSTITUTION REACTION OF ALKYL HALIDE SN1 reaction
unimolecular nucleophilic substitution, two-step mechanism Step1: ionization and formation of R+
R
X
slow
R+
+
X-
Carbonium ion Step2: combination of R+
R+
+ Nu:
fast
RNu:
Cont. SN1 reaction
The rate of chemical reaction is a measure of how fast the reaction proceed, It dose not depend on the conc. Of Nu-, depend on only conc. Of RX It follow first order kinetic, depend only on reactant conc.(RX) It is unimolecular reaction [ because only one particle (RX) is involved in the transition state of rate determining step
R
X
R----------X transition state from one particle
R+
+
X-
Cont. SN1 reaction
R
X
R----------X
R+
+
X-
transition state from one particle The rate-determinig step in SN1 reaction involves the formation of R+,
So, increasing the stability of R+ will increase the rate of the reaction
C6H5CH2+, CH2=CHCH2+, (CH3)3C+, (CH3)2CH+, CH3CH2+, CH3+ Decreasing the stability of R+, decreasing SN1 rate of RX * Only benzylic, allylic and 3°R+ undergo SN1
Cont. SN1 reaction
Q1: List the following carbocation in order of increasing stability
1.
2.
CH2
3.
C(CH3)2
Q2: Which of the following compounds is more reactive toward SN1 reaction. Explain why
1. C6H5CH2Br
2. CH3Br
3. CH2=CHCH2Br
Cont. SN1 reaction When weak Nu such as H2O or ROH is used the rate of SN1 reaction Is in the following order
C6H5CH2X
>
CH2=CHCH2X
>
3° RX
When a strong Nu as CN- is used, 3° RX undergo SN1 reaction exclusively, whereas
C6H5CH2X or CH2=CHCH2X
SN1 H2O or ROH
C6H5CH2OH or CH2=CHCH2OH
SN2 CN-
C6H5CH2CN or CH2=CHCH2CN
NUCLEOPHILIC SUBSTITUTION REACTION OF ALKYL HALIDE
SN2 reaction
bimolecular nucleophilic substitution, one-step mechanism, which involves a transition state. Nu attacks from back-side.
Bimolecular reaction, because both Nu and RX are involved in the transition state.
Transition state
Cont. SN2 reaction
The rate of second order, because it is proportional to conc. Of both Nu & RX Increase the steric hindrance around the halogenated carbon …. Decreases the rate of SN2 reaction.
3° RX are too hindered to undergo SN2 reaction. CH3X
RCH2X
R2CHX
increasing steric hindrance , decreasing SN2 rate
CH3X…… most reactive 2 ° [R2CHX ]…… react slowly 3 ° [R3X ] …….no react by SN2
When strong Nu as CN- is used, the SN2 rate in the following order benzylic halide > Allylic halide > Methyl halide
** CH3X and RCH2X (1° RX) undergo SN2 exclusively, irrespective of the strength of Nu-
Q: Outline all steps in the mechansim of each of the following reaction: 1. C6H5CH2Br + NaCN
2.
C6H5CH2Br + H2O
3. (CH3)3CCl
+ CH3O-Na+
C6H5CH2CN + NaBr
C6H5CH2OH + HBr
(CH3)3COCH3 + NaCl
NUCLEOPHILIC SUBSTITUTION REACTION OF ALCOHOL ROH In acidic solution, alcohols can undergo substitution reactions CH3CH2CH2OH
+ HBr
CH3CH2CH(CH3)OH (CH3)3COH
+ HCl
H2SO4
ZnCl2
CH3CH2CH2Br
+
CH3CH2CH(CH3)Cl + H2O
+ HCl
(CH3)3CCl
+
H2O
** unlike RX, ROH do not undergo substitution in neutral or alkaline solution
(CH3)3COH
H2O
+ Br-
No reaction
WHY ?
R
OH
+
H
- X-
X
R
X-
OH2
RX + H2O
oxonium ion
SN1 or SN2 SN2 R
H+
OH
R
OH2
X-
X
R = CH3 methyl alcohol
R
OH2
R
X
+
SN2 transition state
R = CH3CH2 primary alcohol
SN1
(CH3)2CHOH
+
H+
(H3C)2HC
OH2
-H2O
(CH3)2CH+
carbocation intermediate
X-
(CH3)2CHX
H2O
SN1 MECHANISM FOR REACTION OF ALCOHOLS WITH HBr Step 1: An acid/base reaction. Protonation of the alcoholic oxygen to make a better leaving group. This step is very fast and reversible. The lone pairs on the oxygen make it a Lewis base.
Step 2: Cleavage of the C-O bond allows the loss of the good leaving group, a neutral water molecule, to give a carbocation intermediate. This is the rate determining step (bond breaking is endothermic)
Step 3: Attack of the nucleophilic bromide ion on the electrophilic carbocation creates the alkyl bromide.
SN2 MECHANISM FOR REACTION OF ALCOHOLS WITH HBr Step 1: An acid/base reaction. Protonation of the alcoholic oxygen to make a better leaving group. This step is very fast and reversible. The lone pairs on the oxygen make it a Lewis base.
Step 2: Simultaneous formation of C-Br bond and cleavage of the C-O bond allows the loss of the good leaving group, a neutral water molecule, to give a the alkyl bromide. This is the rate determining step.
ELECTROPHILIC SUBSTITUTION REACTIONS
An electrophile E+ is substituted by another E+. Most common reaction of benzene (C6H6), which is known as electrophilic aromatic substitution (EAS)
THE NITRATION OF BENZENE Benzene is treated with a mixture of concentrated nitric acid and concentrated sulphuric acid at a temperature not exceeding 50°C. As temperature increases there is a greater chance of getting more than one nitro group, NO2, substituted onto the ring. Nitrobenzene is formed. H2SO4 heat
or:
THE HALOGENATION OF BENZENE Benzene reacts with chlorine or bromine in an electrophilic substitution reaction, but only in the presence of a catalyst. The catalyst is either aluminium ferric chloride (or aluminium (ferric) bromide if you are reacting benzene with bromine) or iron.
FeCl3
FeBr3
FRIEDEL-CRAFTS ACYLATION OF BENZENE
Named after Friedel and Crafts who discovered the reaction. Reagent : normally the acyl halide (e.g. usually RCOCl) with aluminum trichloride, AlCl3, a Lewis acid catalyst. The AlCl3 enhances the electrophilicity of the acyl halide by complexing with the halide. Electrophilic species : the acyl cation or acylium ion (i.e. RCO + ) formed by the "removal" of the halide by the Lewis acid catalyst, which is stabilised by resonance as shown below.
Other sources of acylium can also be used such as acid anhydrides with AlCl3
MECHANISM FOR THE FRIEDEL-CRAFTS ACYLATION OF BENZENE Step 1: The acyl halide reacts with the Lewis acid to form a complex. Loss of the halide to the Lewis acid forms the electrophilic acylium ion. Step 2: The p electrons of the aromatic C=C act as a nucleophile, attacking the electrophilic C+. This step destroys the aromaticity giving the cyclohexadienyl cation intermediate.
Step 3: Removal of the proton from the sp3 C bearing the acylgroup reforms the C=C and the aromatic system, generating HCl and regenerating the active catalyst.
FRIEDEL-CRAFTS ALKYLATION OF BENZENE
Named after Friedel and Crafts who discovered the reaction in 1877. Reagent : normally the alkyl halide (e.g. R-Br or R-Cl)
with aluminum trichloride, AlCl3, a Lewis acid catalyst The AlCl3 enhances the electrophilicity of the alkyl halide by complexing with the halide
Electrophilic species : the carbocation (i.e. R +) formed by the "removal" of the halide by the Lewis acid catalyst, Other Lewis acids such as BF3, FeCl3 or ZnCl2 can also be used
MECHANISM FOR THE FRIEDEL-CRAFTS ALKYLATION OF BENZENE Step 1: The alkyl halide reacts with the Lewis acid to form a more electrophilic C, a carbocation Step 2: The p electrons of the aromatic C=C act as a nucleophile, attacking the electrophilic C+. This step destroys the aromaticity giving the cyclohexadienyl cation intermediate. Step 3: Removal of the proton from the sp3 C bearing the alkyl- group reforms the C=C and the aromatic system, generating HCl and regenerating the active catalyst.
