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Pavel Koovsk
E-mail: P.Kocovsky@chem.gla.ac.uk Office: A4-08 Introduction 1. Aromatic Compounds and the Structure of Benzene [Bruice: Ch. 6; McM: Ch. 15] 1.1. Comparison of Alkenes and Aromatic Compounds 1.2. Structure of Benzene 1.3. Aromaticity When is a compound aromatic? Hckel rule. Antiaromaticity. 2. Reactivity of Aromatic Compounds 2.1. Electrophilic Aromatic Substitution [Bruice: Ch. 14; McM: Ch. 16] (a) Bromination/Chlorination (b) Nitration (c) Sulfonation (d) Friedel-Crafts Alkylation (e) Friedel-Crafts Acylation 2.2. Substituent Effects in Electrophilic Aromatic Substitution (a) The effects on reactivity (inductive and resonance effects) (b) The effects on orientation (o/p- and m-directing groups) 2.3. Nucleophilic Aromatic Substitution (a) Mechanism (b) Applications in herbicide chemistry (c) Applications in heterocyclic chemistry 3. Synthesis of Substituted Benzene Derivatives 3.1. Synthetic Strategy 3.2. Electrophilic Substitution of Disubstituted Benzenes 3.3. Modifying Reactivity of Substituted Benzenes 3.4. Aromatic Amines and their Use in Synthesis (a) Amine synthesis (b) Diazonium salts (generatin, reaction with Nucl, Sandmeyer)
Introduction
Aromatic: Originally, aromatic came from aroma of some natural products. Later: aromatic = derivative of benzene Current: aromatic = compound with one or more benzene or benzene-like rings
Examples OH CH3 O2N OH CH3 Benzene Phenol (antiseptic) CH3 NO2 TNT HO Estrone O O O O Piperine (major constituent of black peper) CH3CO2 Heroin N CH3CO2 C2H5O HN CH3 NO2 O O Ecstasy NH2 O
CH3 N N CH2CH2CH3
O NCH3 O S O N N
CH3
Viagra
Benzene is 150 kJ/mol more stable than the calculated value for 'cyclohexatriene'; this is known as the delocalisation energy - its source can be seen from consideration of the molecular orbital diagram for benzene.
6 antibonding 4 5
Energy
bonding
The 150 KJ/mol stabilisation comes from all electrons being in molecular orbitals of lower energy than the p atomic orbitals. The delocalisation energy can be measured by determining the heat of hydrogenation (i.e., how much energy is required to convert benzene into cyclohexane). This delocalisation means benzene is thermodynamically more stable than the hypothetical cyclohexatriene. It is often more convenient to use the Kekul representation:
This is only a representation - benzene is neither of the structures shown above but a single substance in between these two extremes with extensive p-electron delocalisation. The actual structure of benzene is a resonance hybrid of these two canonical forms.
1.3. Aromaticity
When is a compound aromatic? (a) Experimentally: the molecular formula suggests a high degree of unsaturation (double bonds etc.) but the compound does NOT undergo addition reactions (b) Theoretically: the molecule has a flat, cyclic structure with uninterrupted clouds of delocalised electrons above and below the plane. There must be 4n+2 electrons in the delocalised clouds where n is any integer (0,1,2,3.... AND NOT the number of rings) - in other words there must be 2,6,10,14..... electrons (Hckel's Rule). Compounds with 4n electrons CANNOT be aromatic but may be cyclic and conjugated.
Examples benzene 6 electrons 4n + 2 (where n = 1), therefore aromatic planar
pyrrole
N H cyclooctatetraene
..
4 electrons + 2 electrons of the lone pair 4n + 2 (where n = 1), therefore aromatic planar 8 electrons 4n (where n = 2), therefore not aromatic non-planar
cyclobutadiene
. . .
. . .
1 Benzene
5
Q: Which of the following structures are aromatic?
H H
H H
H H O S N N H
+ Br2 bp 80 oC
FeBr3
Mechanism of bromination FeBr3 is a Lewis acid and it complexes with a bromine molecule to increase its electrophilicity. + Polarised bromine is the source of "Br ". (You may consider it as displacement of FeBr 4
from Br2FeBr3 complex by two electrons of the benzene ring). + Br (or its equivalent) forms a new bond to the ring using two of the electrons of the benzene ring. FeBr4- then acts as a base by abstracting a proton from the -complex. The two electrons from the C-H bond go back in to the ring and regenerate the delocalised -system.
Br Br ..
..
NB: Addition of Br- to the -complex is not favoured because the electron delocalisation (aromaticity) would be lost.
Generalisation and stereochemical view of aromatic electrophilic substitution (E = Electrophile, B = Base) E+ E H H H H B
..
FeBr 3
Br Br H H
Br [FeBr4]
slow
H H
H -complex
E H
+ HB
Br
Br TS2 Br Br
-complex (intermediate)
G o Br + HBr
+ Br2
Transition State 1: The C-Br is forming as the aromaticity within the ring is being lost. Intermediate -complex: The C-Br bond is now fully formed and the carbon with H and Br 3 2 attached is sp -hybridised; the positive charge is delocalised over the remaining five sp carbon atoms, wich stabilises the intermediate. + Transition State 2: The C-H bond begins to break as H is lost from the intermediate, which results in the formations of the aromatic product (restoring aromaticity). The alternative addition of bromine in the second step (the blue pathway) does not restore aromaticity (the product would be much higher in energy).
Notes: G is the activation energy; it is reduced when an activating substituent is present and increased when a deactivating substituent is present. Compare the G for benzene with that of an alkene. (b) Chlorination and Iodination Use Cl2/FeCl3 or Cl2/AlCl3 for chlorination and I2/CuI2 or I2/CuCl2 for iodination - analogous to bromination. Chlorination is used in the synthesis of a number of pharmaceutical agents, including the tranquilizer diazepam (Valium).
CH3 N Cl N O
NO2
O
+
N+ O
HNO3 + 2 H2SO4 H
+
N O
SO3H
Mechanism O O S
+
O H2SO4 O - HSO4 O OH S
+
S+ O
OH
+
H
+
O OH - H2O
SO3H
S O
OH
p-cresol (a phenol)
CH2CH3 Cl
CH2CH3 AlCl 4 H
AlCl 4
CH2CH3
Other options H3C H3C H3C H3C H3C or OH H+ H+ CH2 + H2SO4 C(CH3)3
9
Appliaction C6H6 HF Linear alkene (available from petroleum industry) 1. H2SO4 / SO3 (sulfonation) 2. NaOH (neutralisation) SO3Na+
detergent
Problems: One akylation makes the benzene ring more reactive to Friedel-Crafts alkylation; hence, mixtures of multiply-alkylated products are often formed. Use of primary halides often results in the formation of product mixtures owing to the o o o rearrangement to a more stable cation (remember the stability: 3 > 2 > 1 ). (f) Friedel-Crafts Acylation Acyl group = RCOO O + CH3 Cl AlCl 3 CH3 + HCl
Mechanism O R Cl AlCl 3
+ + .. R C O ..
R C O .. H
AlCl 4 O
10 As a result, when benzene is subjected to nitration, only one mono-substituted product (nitrobenzene) is formed (nitrobenzene is not further nitrated under mild conditions). By contrast, when toluene (methylbenzene) is nitrated, we can expect formation of mono-, di- and even tri-nitro products. Substituents also effect the position of substitution:
CH3 HNO3 H2SO4 20 oC CH3 NO2 + NO2 ortho Statistically expected: Experimentally found: NO2 HNO3 H2SO4 90 oC 40 62 NO2 NO2 + NO2 ortho Experimentally found:
+
CH3 +
CH3
meta 40 5 NO2 +
meta 93.2
6.5
Methyl group - directs the electrophile (NO2 ) mainly to the ortho and para positions Nitro group - directs mainly to meta position Reactivity and orientation are connected - both are a matter of relative reaction rates. Thus, CH3 makes the ring react slightly faster than benzene at all 5 positions but makes ortho and para positions on the ring react faster than meta. - therefore ortho and para products predominate (energy of TS and intermediate lower than for benzene). Nitro group makes ring react significantly slower than benzene at all 5 positions but the reaction at ortho and para positions is slower than meta position - therefore meta product predominates (energy of TS and intermediate higher than for benzene) Reaction rate is determined by rate of the slowest step, i.e., attack of electrophile on ring. If substituent X can release electrons into the ring this will help to stablise the positive charge developing in the ring. The energy of the intermediate will be lower, so that less activation energy will be required the reaction will be faster. If substituent that withdraws electrons from the ring this will destabilise the positively charged intermediate and hence make the activation energy higher and therefore the reaction slower.
11
Reactivity NH2 OCH3 CH3 F Br CH=O CO2H SO3H NO2
OH
NHCOCH3 C6H5 H
Cl I
CO2CH3
N+R3
Resonance effect
.. H O
..
.. H O
.. H O
.. H O or
+ .. H O o- / p
.. Cl
+Cl
..
+ Cl
..
+ Cl
..
.. + Cl or
..
.. ..
..
..
..
o- / p-
+ or +
+ m-
Examples OH Br2 Br OH Br or Br Compare with: CH3 Br2 FeBr3 Br CH3 Br + NH2 Br2 Br NH2 Br
Br CH3
12
Cl
benzyl chloride
chlorobenzene
Nu O - X NO2 NO2
2,3,7,8-Tetrachlorodioxin (toxic!)
A mixture of 2,4,5-Trichlorophenoxyacetic acid (2,4,5-T) and 2,4-dichlorophenoxyacetic acid (2,4D) was used as a large-scale defoliant (Agent Orange) in the Vietnam war. (c) Applications in Heterocyclic Chemistry
Nu N Cl
_ _
Cl Nu
Cl
Nu
13
Example 1: Chloronitrobenzenes
p-Nitrochlorobenzene Cl C-N Cl C-Cl Note: Cl is o- / p-directing, hence the plan is good
NO2 Compare:
Cl C-Cl Note: NO2 is m-directing, hence the plan is bad NO2 NO2
m-Nitrochlorobenzene Cl C-Cl NO2 Compare: Cl C-N NO2 Actual synthesis Cl Cl2 FeCl3 NO2 HNO3 H2SO4 HNO3 H2SO4 Cl NO2 + 30% Cl2 FeCl3 heat NO2 NO2 60% Cl NO2 Note: Cl is o- / p-directing, hence the plan is bad NO2 C-N Note: NO2 is m-directing, hence the plan is good
Cl
14
ortho
15
Br cannot be isolated
Br
Solution: Moderating the activity of NH2 O NH2 CH3 O O O CH3 HN CH3 Br2 HN O CH3 OH heat Br The activating influence of NH2has been reduced due to competing withdrawal of N-lone pair by carbonyl group: .. HN O CH3 Br
+
NH2
O HN CH3
Chemical reduction is carried out in an acidic medium. The amine product is basic and + therefore the salt is actually formed (C6H5NH3 Cl ). The free amine can be obtained by neutralising the salt with alkali.
16
NH2
N Cl
N HSO4
N KI O2N I
CH3
Replacement with Cl, Br, CN (Sandmeyer Reaction) NaNO2 HBr (dil.) Cl NH2 Cl NaNO2 HCl (dil.) N
+
Cl
N Br N Cl CuCN 60 oC N
N CuBr 60 oC CuCl 60 oC Cl Cl Cl Br
Cl
NaBH4
Cl
H3O+ heat
Cl
CO2H