Lecture 8 Saturday January 23 2016 10 55 AM pyridine pyrrole How to count electrons in heteroaromatics In pyridine the nitrogen is formally sp2 hybridized there is an explicit double bond to nitrogen So the lone pair of the nitrogen is in an sp2 hybride orbital which is in the plane of the ring As a result this lone pair is perpendicular to pi system of the ring I added those orbitals to the image below and it does not contribute to it In pyrrole the nitrogen is formally sp3 hybridized So the structure is shown below However if the nitrogen atom adopts sp2 hybridization the lower structure then the lone pair becomes parallel to the other p atomic orbitals in the ring and the system becomes fully conjugated pi system with now 6 electrons in it The change in hybridization leads to aromaticity Because of the fact that in pyrrole the lone pair is part of the aromatic pi system and in pyridine it is not pyrrole is much less basic Its lone pair is much less available This is reflected in the pKa s of conjugated acids for the two molecules For export Page 1 Lecture 8 Saturday January 23 2016 10 55 AM electrophilic aromatic substitution Unlike alkenes arenes undergo substitution reaction in the presence of electrophiles not addition From the mechanism it is clear why the difference After the reaction of the arene with the electrophile and the formation of the sigma complex there are two paths available Y can add to the sigma complex to give the product of the addition same as in alkenes This path path a leads to a non aromatic compound Loosing aromaticity costs 40 kcal mol and it does not happen Instead we go down path b in which Y abstracts a proton from the sigma complex to restore the aromaticity As you can see from the typical energy diagram for electrophilic aromatic substitution the first step formation of the sigma complex is really hard and that is the slow step of the reaction the second step is fast The formation of the sigma complex requires a lot of energy because we go from aromatic neutral compound to a non aromatic cation So we need a very reactive electrophile or a high temperature Deprotonation is easy because it leads to a neutral aromatic compound For export Page 2 Lecture 8 Saturday January 23 2016 10 55 AM Nitration reaction strong electrophile confirms that deprotonation is fast and happens after the rate determining step Sulfonation With just H2SO4 the reaction is fully reversible with equilibrium constant that barely favors the products To accomplish the reaction we need to remove water from the mixture In the presence of the SO3 reaction is faster and products are favored even though the reaction is still reversible Bromination Unlike alkene arenes do not react with bromine Bromine is just not electrophilic enough For export Page 3 Lecture 8 Saturday January 23 2016 10 55 AM To accomplish the reaction we need a catalyst FeBr3 acts as a Lweis acid and takes electron density from one of the Brs That polarizes Br2 and makes it more electrophilic Notice that FeBr3 is recovered at the end of the reaction So we can use a very small amount of it at the beginning of the reaction and it will get the job done Friedel Crafts alkylation Alkyl halides are not good enough electrophiles but carbocations formed by the reaction of alkyl halides with a strong Lewis acid are WE can also form cations from secondary alkyl halides Methyl and ethyl halides do not form carbocation intermediates The reactive electrophiles are complexes of alkyl halide and the Lewis acid For export Page 4 Lecture 8 Saturday January 23 2016 10 55 AM Other primary carbocations will undergo rearrangement prior to the reaction The rearrangement can also occur with secondary cations and we can get a mixture of products That is why the reaction works the best with tertiary alkyl halides Think about the possible products from the following two reactions Other sources of cations The carbocation intermediate can also be formed by the reaction of the alkenes with acids and the reaction of alcohols with acids Friedel Crafts acylation reaction Unlike alkyl cations acyl cation does not undergo rearrangements So what we put in that s what we get out For export Page 5 Lecture 8 Saturday January 23 2016 10 55 AM Synthesis of acyl halides Other electrophiles Anhydrides work as well We just need a good leaving group circeled to make the acyl cation Use of Fridel Crafts acylation to accomplish alkylation Reduction of hydroacylation products Clemmensen reduction Wolff Kishner reduction Note that the Clemmensen reductiuon will also reduce NO2 group to NH2 while Wolf Kishner will not Other functional groups not reduced under either set of conditions So using this approach we can make and because of the rearrangement of the primary carbocation we could not do this using Friedel Crafts alkylation For export Page 6 no rearrangement to worry about