Aromatic Chemistry Flashcards
Criteria for Aromaticity
- Cyclic
- Planar
- Conjugated (alternating single and double bonds)
- 4n+2 Pi Electrons
Criteria for Anti-Aromaticity
- Cyclic
- Planar
- Conjugated (alternating single and double bonds)
- 4n Pi Electrons
Benzene
- Discovered in 1825 by Michael Faraday as a liquid out of gas lamps.
- Found by physical chemistry techniques to have the formula C6H6.
- All 6 positions were equivalent so mono substituted benzene has only one isomeric form.
- Disubstituted benzene has only three isomeric forms (ortho, meta, para)
Stability of Benzene
- Thermodynamically, benzene is 150 kJ mol-1 more stable that would be expected based on it’s formula alone. This is explained by Hückel’s Rule.
Hückel’s Rule
Hückel’s Rule states that a planar cyclic fully conjugated compound with 4n+2 pi electrons benefits from a special stability as a result of the electron delocalisation and is described as ‘aromatic”.
Anti-Aromatic Compounds
For planar, cyclic, conjugated molecules with 4n pi electrons delocalisation of electrons would be destabilising resulting in an “anti-aromatic” structure which normally distorts to be non-planar to avoid delocalisation and to remain “non-aromatic”.
Ionic Molecules and Aromaticity
Ionic molecules can also benefit from aromaticity. Some examples are the cyclopentadienide and cycleheptatrienium ions.
NMR Effects - Aromatic Systems
The delocalisation of electrons in an aromatic system can be picked up in chemical shift measurements. The external magnetic field applied during NMR measurements causes the electrons in the molecule to circulate in a diamagnetic ring current and set up a secondary magnetic field which enhances the external one outside the ring and opposes it inside the ring.
NMR Effects - Anti Aromatic Systems
The delocalisation of electrons in a anti-aromatic system can be picked up in chemical shift measurements. The external magnetic field applied during NMR measurements causes the electrons in the molecule to circulate to give a paramagnetic ring current which sets up a secondary magnetic field which will then enhance the external one when the electrons are inside the ring and oppose it when they are outside the ring.
Heterocyclic Compounds - Cyclopentadienide Anion
By replacing the C- of the cyclopentadienide anion with a heteroatom such as O, N or S we also get a 6 pi aromatic system. Note the lone pair of the heteroatom is needed since the 4 carbons can only contribute 4 electrons.
Heterocyclic Compounds - Benzene
If we replace one or more benzene ring atoms with a heteroatom, the molecule remains aromatic. The heteroatom only contributes one electron from its lone pair to the conjugated system in order to fulfil the criteria for aromaticity.
Naphthalene
Naphthalene is a white solid found in coal tar with a pungent smell used for “mothballs”. It could be regarded as a 10 pi system, or, more accurately, as two 6 pi systems. It is aromatic but the stabilisation energy is slightly lower than that of twice benzenes stabilisation energy. The bonds lengths are all equal, as is consistent with the resonance forms.
Azulene
- first prepared in 1936, it is an isomer of naphthalene, C10H8.
- As well as the two uncharged resonance forms which are [10]-annulenes, there is an especially favourable form which combines a delocalised cyclopentadienide anion and a cycloheptatrienium cation, two 6 pi systems. This results is azulene having a small dipole moment of 0.8 Debye.
There is also small charge transfer band in the visible region which explains its very intense blue colour.
It has a stabilisation energy of 180 kJ mol-1.
Reactivity of Aromatics
Because of the aromatic stabilisation, it is not favourable for reactions to take place that result in the permanent loss of the 6-pi system. Benzene undergoes aromatic substitution but as the intermediate is not necessarily aromatic, these reactions can have a high activation energy and are often associated with a catalyst.
Treatment of benzene with chlorine
Treatment of benzene with chlorine results in substitution to give chlorobenzene and HCl.
Electrophilic Aromatic Substitution
This is important as it provides a way to functionalist aromatics. In substitution reactions, the positive charge can be delocalised over three positions (o- and p- to the electrophile).
Nitration of Benzene
Reaction with nitric acid and concentrated sulphuric acid converts benzene to nitrobenzene. The linear electrophile is formed by protonation of HNO3 followed by loss of water. Sulfuric acid is acting as a catalyst.
Sulfonation
Treatment of benzene with concentrated sulfuric acid under severe conditions or with a solution of SO3 in H2SO4 under milder conditions gives benzene sulfonic acid. If the product is treated with more dilute sulphuric acid the processed is reversed to regenerate the benzene.
Halogenation
Elemental halogens react to give halobenzenes. However this is only common for Cl and Br. I2 is too unreactive while F2 is too dangerous and aryl fluorides can be made other better ways. A Lewis acid is required, AlCl3 for chlorination and FeBr3 for bromination.
Friedel Crafts Alkylation
Reaction of benzene with an alkyl in the present of a Lewis acid such as AlCl3 leads to substitution. However, there may be complications with rearrangement of the alkyl group. Adding one alkyl group activates the system towards further reaction so there may be multiple alkylations. The reaction can work well with groups that cannot rearrange (e.g. methyl or text-butyl halides), however, in general the reaction is problematic.
Friedel Crafts Acylation
Reaction of benzene with an acyl halide in the presence of a Lewis acid such as AlCl3 leads to substitution. Adding an acyl group deactivates the compound, meaning it stops at mono substitution and thus the reaction works well with no isomerism. Since there are convenient ways to get from RC=O to RCH2, this also provides a way to monoalkylate benzene- first acylate it and then reduce the ketone to get to the target.
Inductive Effects
Inductive effects are electron withdrawing (-I) or electron donating (+I) effects purely due to the electronegativity of the substituting and are transmitted via the single Ar-X bond.
Mesomeric Effects
Mesomeric effects are electron withdrawing (-M) or electron donating (+M) effects via resonance and involving at some stage a double bond between Ar and X.
Substituent Effects: NH2,NHR, NR2
Electronic Effects: +M>-I
Directing: o-/p-
Reactivity: Activating
Substituent Effects: OH, OR
Electronic Effects: +M>-I
Directing: o-/p-
Reactivity: Activating
Substituent Effects: NHCOR, OCOR
Electronic Effects: +M>-I
Directing: o-/p-
Reactivity: Activating
Substituent Effects: Ph, -CH=CH2
Electronic Effects: +M>-I
Directing: o-/p-
Reactivity: Activating
Substituent Effects: R
Electronic Effects: +I
Directing: o-/p-
Reactivity: Activating
Substituent Effects: H
Electronic Effects: -
Directing: -
Reactivity: -
Substituent Effects: Cl, Br, I
Electronic Effects: -I>+M
Directing: o-/p-
Reactivity: Deactivating
Substituent Effects: CHO, COR
Electronic Effects: -I>-M
Directing: m-
Reactivity: Deactivating
Substituent Effects: CO2H, CO2R, CN
Electronic Effects: -I>-M
Directing: m-
Reactivity: Deactivating
Substituent Effects: SO3H
Electronic Effects: -I>-M
Directing: m-
Reactivity: Deactivating
Substituent Effects: NO2
Electronic Effects: -I>-M
Directing: m-
Reactivity: Deactivating
Strongly Activating Groups
Both phenol and aniline contain strongly activating groups and therefore undergo direct tri-substitution with many reagents. They both reaction with bromine at RT (no catalyst) to get the trisubstituted product. To get mono substitution, the reactivity can be reduced by acetylation to give acetanilide which is then well behaved.
Nitration Conditions
Nitration of highly activating compounds such as o-dimethoxybenzene can be done using dilute nitric acid alone at RT while an electron withdrawing substituent needs stronger acids and formation of polynitroarenes needs both stronger acids and severe conditions.
Ortho vs. Para Selectivity
Mixtures of isomers are commonly found from o-/p- directing groups. Where the existing substituent or the electrophile are large, para substituent may be favoured due to steric hinderance, however even with large groups both isomers are still formed - the selectivity is never complete. The isomeric product often differ markedly in their properties and can usually be easily seperated by distillation or recrystallisation.
Combination of substituent effects
In cases where the directing effects are conflicting the most strongly activating group dominates and determines where substitution occurs.
Use of removable directing groups
Sulfonation is reversible with oleum or strong sulfuric acid causing the forward reaction, but more dilute sulfuric acid causing the reverse. This gives a way of directing substitution exclusively to the ORTHO position.
Electrophilic Substitution on Naphthalene
There are two possibilities for substitution onto naphthalene both of which offer five possible resonance forms, however the ones which maintain a complete benzene ring are favourable. 1-Substitution (near join of two rings) offers two resonance forms in which a complete benzene ring is maintained, whereas 2-substitution (further from join of two rings) offers only one resonance form in which a complete benzene ring is present and for this reason 1-substitution dominates.
Sulfonation of Naphthalene
As expected, naphthalene-1-sulfonic acid is formed under normal conditions, however this is the kinetic product and at higher temperatures naphthalene-2-sulfonic acid can be produced. This is more stable since it avoids the 1,8 peri interactions.
Effect of Substituents on Naphthalene Substitution
Substitution follows the expected trends, however, the activating/deactivating effect will control which RING reacts. In the case of a deactivating group, substitution occurs at the other ring in the two alpha positions regardless of where on the other ring the substituent is. If an activating group is present, substitution occurs on the same ring in the 2- and 4- positions when a 1-substituent is present but almost exclusively in the 1- position in the case of a 2-substituent.
Nucleophilic Aromatic Substitution
This is less common than electrophilic substitution and only occurs in a few special cases. The first is where a halo benzene has one or more powerfully electron-withdrawing (usually nitro) groups in the o-/p- positions.
The substitution occurs by an addition/elimination mechanism and the intermediate is stabilised by delocalisation of the negative charge by the nitro groups. In many cases the intermediates, “Meisenheimer Complexes” are stable enough to be isolated.
The initial nucleophilic attack is the rate determining step and this explains the trend of reactivity among the halogens (more electronegative gives faster reaction as it favours attack by the anion).
Sangers Reagent
1-Fluro-2,4-dinitrobenzene (FDNB) formed the bases of an important early method for determining the N-terminal residue of peptides. Treatment of an unknown peptide with the reagent results in a nucleophilic aromatic substitution by the N-terminal NH2 group giving the N-2,4-dinitrophenyl derivative. Hydrolysis of the whole peptide then gave a mixture of amino acids with only the terminal one as the dinitrophenyl derivative. It could then be easily identified by chromatographic comparison with an authentic sample. This played a decisive role in the determination of the structure of insulin.
Benzyne and other Arynes
Reaction of aryl halides with strongly basic nucleophiles such as NaNH2, sodium amide, leads to apparent nucleophilic substitution. However, this occurs in a unusual way as easily shown by having another substituent present. In an early experiment 14C labelling was used to show the new nucleophile is not necessarily on the same carbon as the leaving group had been.
The formation of isomeric products arises from the addition of the nucleophile to the symmetrical neutral intermediate “benzene” so this is an elimination-addition mechanism.
If there is an additional substituent present, the resulting unsymmetrical aryne reacts selectively to give the m-product to avoid steric hinderance and due to the stabilisation of the intermediate negative charge by the -I effect of the substituent.
Biphenylene
Biphenylene is a stable solid which exists mainly as two resonance forms which have complete benzene rings separated by an elongated rectangular cyclobutadiene ring. This benefits from the benzene ring aromaticity but avoids the instability of anti-aromatic cyclobutadiene. (No hint of any contribution from the form with a cyclobutadiene but not complete benzene rings).
Diazonium Salts
Readily formed from aromatic amines and allow replacement of the original amino acid group by a wide variety of nucleophiles: F, Cl, Br, I, CN, OH or H. In addition coupling to phenols or aromatic amines gives the ado dyes of great industrial importance.
Formation of diazonium salts
They are formed by reaction of an aniline with sodium nitrate and an acid. This process is call “diazotisation”. They are rather unstable and are formed and used in dilute aqueous solution taking care to keep the temperature just above 0°C. In the pure state, most diazonium salts are dangerously explosive so they are never isolated but rather used in situ for the next reaction.
Diazonium Salt - reaction with loss of N2
Heating the aqueous solution or suspension of a diazonium salt carefully with a suitable nucleophile leads to loss of nitrogen gas and interception of Ar+ in an overall nucleophilic substitution. In the absence of any added nucleophile water reacts to give the phenol. However, where the phenol is the desired product it is best to use sulfuric acid for the diazotisation otherwise with hydrochloric acid some chlorobenzene can be formed. The new group ends up where the NH2 started.
Diazo Coupling - a reaction with retention of N2
Treatment of a diazonium salt with tin(II) chloride or sodium sulfite results in reduction to the phenyl hydrazine. However, the diazonium group can also behave as an electrophile and cause electrophilic aromatic substitution on an added aromatic compound. It is weakly electrophilic so this reaction works best with highly activating groups as in anilines and phenols. For steric reasons the p-directing effect predominates and we get mainly the azo compounds shown. 2-Naphthol is also an important diazo coupling agent and couples at the 1-position.
Uses of Azo Compounds
The azo function absorbs in the visible region and azo dyes and pigments are among the most important synthetic colouring agents. Some pH indicators are azo dyes such as methyl red.
Benzidine Rearrangement
Benzidine is a dangerous carcinogen formerly used in the dye industry. The reaction is intramolecular and second order in [H+]. The remarkable mechanism involves homiletic fission of the N-N bond in the deprotonated form.
Five-membered Heterocyles
Replacement of a CH=CH unit of benzene by a heteroatom gives a five metered heterocycle. These are aromatic and isoelectronic with cyclopentadienide anion. The three most important ones are thiophene (S), pyrrole (NH) and furan (O).
Properties of five-membered heterocyles
The properties of these compounds are dominate by the fact that the heteroatom’s lone pair is needed for the 6-pi system. This means the heteroatom has lost full control of it’s electrons and becomes relatively electron poor, while the four carbon atoms enjoy a share of 6-pi electrons in a five atom ring and therefore relatively electron rich. For this reason these systems are described as pi-excessive heterocycles. The extra electron density results in shielding in NMR giving lower than expected chemical shifts for an aromatic compound.
Basicity/Acidity of Pyrrole
Because of it’s lone pair being required for the 6-pi system, it is not available to act as a base and pyrrole is not at all basic although it might seem to have a secondary amine structure. The NH is however significantly acidic and can be removedly a strong base to give an anion isoelectronic with cyclopentadiene anion which still retains it’s aromaticity.
Five-mebered heterocycles - electrophilic aromatic substitution
The higher electron density favours attack of E+ and these compounds are observed to undergo substitution very readily. Rate enhancement can be spectacular and pyrrole in particular is “super reactive” with bromination even under mild conditions proceeding immediately to the tetrabromo.
Acid Sensitivity of Pyrrole
Treatment of pyrrole with concentrated nitric acid results in oxidative degradation, nitration has to be carried out using milder conditions.
Five-mebered heterocycles - substitution position
As not all position are equivalent we have to consider directing effects. Substitution tends to occur on the 2- and 5- positions on these compounds but on 3- and 4- positions is also possible. This can be rationalised by the greater number of resonance forms for the intermediate in the former case.
Benzo fuesd five-mebered heterocycles
Indoles are particularly important as there are many biologically active indole compounds including indole alkaloids, the amino acid tryptophan and the neurotransmitter serotonin.
Indole Properties
As with pyrrole, indole is acidic and deprotonation and N-alkylation are possible. Again indole is completely non-basic since the lone pair is required for aromaticity and it not available.
Benzo fuesd five-mebered heterocycles - electrophilic aromatic substitution
Substitution occurs exclusively on the activated pi-excessive heterocyclic ring rather than the benzene ring. The directing effect means that substitution occurs mainly at the 3-position. We again need to consider the possible resonance forms but discount any that do not include a complete benzene ring (as these are unstable). These compounds do not undergo nucleophilic aromatic substitution.
Six membered ring heterocycles
If we replace =CH- by a heteroatom we get the six membered ring heterocycle pyridine (can’t use O or S or ring would be charged). The resulting compound is aromatic but importantly the lone pair of N is not needed for the 6-pi system meaning that compared to benzene the N atom is electron rich while the C atoms are relatively electron poor, for this reason pyridine is referred to as a pi-defficient heterocycle.
Pyridine Properties
As it’s lone pair is not involved in the pi-system, pyridine is basic (pka 5.2) and readily forms salts with acid or other electrophiles.
Pyridine - electrophilic aromatic substitution
Because of the pi-deficient character, electrophilic aromatic substitution occurs very reluctantly or not at all, with the alternative possibility of addition to the N atom instead of attack at C. To get around this, we can use pyridine N-odixe (which uses up the lone pair on N in bonding to oxygen) which has stable resonance forms with C- on the ring meaning electrophilic substitution goes readily (exclusively on the 4-position). The compound can then be deoxygenated.
Pyridine - nucleophilic aromatic substitution
Nucleophilic aromatic substitution occurs readily is there is a suitable leaving group such as a halogen and it is placed so that the negative charge in the intermediate can be stabilised by being on the N. This means the halogen must be on the 2- or 4-position.
Rings with two nitrogens
Replacing two C atom by N atoms gives further aromatic compounds:
- pyridazine (N directly beside each other)
- pyrimidine (N meta to each other)
- pyrazine (N para to each other)
In al cases the N lone pairs are not required for the 6-pi system and these are pi deficient systems behaving like pyridine.
Benzo-fused six membered heterocycles
We can fuse benzene onto pyridine in two ways to get to isomer compounds quinoline (N in 1-position) and isoquinoline (N in 2-position). These are both well known, biologically active alkaloids.
Benzo-fused six membered heterocycles - electrophilic aromatic substitution
Substitution occurs exclusively on the benzene ring rather than the strongly deactivated pyridine ring. The two rings behave essentially independently so the substitution is positioned neared the ring junction (5- and 8-position) rather than further from the ring (6- and 7-) for the same reasons we saw in naphthalene.
Imidazole
Imidazole is a benzene with one CH=CH unit and one =C atom replaced by N. This compounds is a stable solid and behaves more like pyridine than pyrrole. It undergoes electrophilic substitution quite reluctantly and is strongly basic, even more so than expected. The main reason for this is that protonation gives a symmetrical resonance stabilised cation.
