Five-membered aromatic heterocycles are good at electrophilic substitution

Just about everything is the other way round with pyrrole. Electrophilic substitution is much easier than it is with benzene—almost too easy in fact—while nucleophilic substitution is more difficult. Pyrrole is not a base nor can it be converted to an N-oxide. We need to find out why this is. The big difference is that the nitrogen lone pair is delocalized round the ring. The NMR spectrum suggests that all the positions in the ring are about equally electron-rich with chemical shifts about 1 ppm smaller than those of benzene. The ring is flat and the bond lengths are very similar, although the bond opposite the nitrogen atom is a bit longer than the others.

The delocalization of the lone pair can be drawn equally well to any ring atom because of the fi ve-membered ring and we shall soon see the consequences of this. All the delocalization pushes electrons from the nitrogen atom into the ring and we expect the ring to be electron rich at the expense of the nitrogen atom. The HOMO should go up in energy and the ring become more nucleophilic. An obvious consequence of this delocalization is the decreased basicity of the nitrogen atom and the increased acidity of the NH group. In fact, the pKa of pyrrole acting as a base is about –4, and protonation occurs at carbon below pH –4. By contrast, the NH proton (pKa 16.5) can be removed by much weaker bases than those that can remove protons on normal secondary amines. The nucleophilic nature of the ring means that pyrrole is attacked readily by electrophiles. Reaction with bromine requires no Lewis acid and leads to substitution (con firming the aromaticity of pyrrole) at all four free positions. Contrast pyridine’s reactivity with bromine : it reacts just once, at nitrogen.

This is a fi ne reaction in its way, but we don’t usually want four bromine atoms in a molecule so one problem with pyrrole is to control the reaction to give only monosubstitution. Another problem is that strong acids cannot be used. Although protonation does not occur at nitrogen, it does occur at carbon and the protonated pyrrole then adds another molecule like this.

●Pyrrole polymerizes! Strong acids, those such as H2SO4 with a pKa of less than –4, cannot be used without polymerization of pyrrole.

 Some reactions can be controlled to give good yields of monosubstituted products. One is the Vilsmeier reaction, in which a combination of an N,N-dimethylamide and POCl3 is used to make a carbon electrophile in the absence of strong acid or Lewis acid. It is a substitute for the Friedel–Crafts acylation, and works with aromatic compounds at the more reactive end of the scale (where pyrrole is).

In the fi rst step, the amide reacts with POCl₃, which makes off with the amide oxygen atom and replaces it with chlorine. This process would be very unfavourable but for the formation of the strong P–O bond, and is the direct analogy of the chloropyridine-forming reaction you have just seen.

The product from this fi rst step is an iminium cation that reacts with pyrrole to give a more stable iminium salt. The extra stability comes from the conjugation between the pyrrole nitrogen and the iminium group. The work-up with aqueous Na2CO3 hydrolyses the imine salt and removes any acid formed. This method is particularly useful because it works well with Me2NCHO (DMF) to add a formyl (CHO) group. This is difficult to do with a conventional Friedel–Crafts reaction.

You may have noticed that the reaction occurred only at the 2-position on pyrrole. Although all positions react with reagents like bromine, most reagents go for the 2- (or 5-) position and attack the 3- (or 4-) position only if the 2- and 5-positions are blocked. A good example is the Mannich reaction. In these two examples N-methylpyrrole reacts cleanly at the 2-position while the other pyrrole with both 2- and 5-positions blocked by methyl groups reacts cleanly at the 3-position. These reactions are used in the manufacture of the non-steroidal anti-inflammatory compounds tolmetin and clopirac.

Now we need an explanation. The mechanisms for both 2- and 3-substitutions look good and we will draw both, using a generalized E+ as the electrophile. Both mechanisms can occur very readily. Reaction in the 2-position is somewhat better than in the 3-position but the difference is small. Substitution is favoured at all positions. Calculations show that the HOMO of pyrrole does indeed have a larger coefficient in the 2-position, and one way to explain this result is to look at the structure of the intermediates. The intermediate from attack at the 2-position has a linear conjugated system. In both intermediates the two double bonds are, of course, conjugated with each other, but only in the fi rst intermediate are both double bonds conjugated with N+. The second intermediate is ‘cross-conjugated’, while the first has a more stable linear conjugated system.

Since electrophilic substitution on pyrroles occurs so easily, it can be useful to block substitution with a removable substituent. This is usually done with an ester group. Hydrolysis of the ester (this is particularly easy with t-butyl esters) releases the carboxylic acid, which decarboxylates on heating. There is no doubt that the final electrophilic substitu tion must occur at C2.

The decarboxylation is a general reaction of pyrroles: it’s a kind of reverse Friedel–Crafts reaction in which the electrophile is a proton (provided by the carboxylic acid itself) and the leaving group is carbon dioxide. The protonation may occur anywhere but it leads to reaction only if it occurs where there is a CO₂H group.

اخر الاخبار

اخبار العتبة العباسية المقدسة

قسم الشؤون الفكرية يختتم المرحلة الثالثة من مشروع استعادة مكتبة جامعة الموصل

جامعة الكفيل تنظّم دورة حول نظام (كوها) العالمي لإدارة المكتبات الجامعية في النجف

مجموعة مشاتل الكفيل: إضافة نحو 70 نوعًا جديدًا من المغروسات تتناسب مع الظروف المناخية المحلية

المجمَع العلمي يطلق الدورة التطويرية الخامسة لمعلمي التربية الإسلامية ومدرسيها في النجف الأشرف

المزيد

الآخبار الصحية

اختراق علمي.. دواء يؤخر ظهور السكري من النوع الأول لسنوات

هذا ما يحدث لجسمك إن أهملت نظافة فراشك

لماذا تعتبر النساء أكثر عرضة للإصابة بألزهايمر من الرجال؟

لماذا يحذر الخبراء من الإفراط في تناول الفراولة؟

المزيد

الآخبار التكنلوجية

السيارات الكهربائية أنظف بنسبة 73% من سيارات الوقود

سيارة لوسِد الكهربائية تدخل "غينيس" بأطول مدى في العالم

نظرية جديدة تنسف كل ما نعرفه عن تشكل أول قارة في الأرض

منذ 37 ألف عام.. دراسة تكشف "أقدم أمراض" أصابت البشر

المزيد

مواضيع ذات صلة

Furan and thiophene are oxygen and sulfur analogues of pyrrole

Pyridine as a catalyst and reagent

Pyridine N-oxides are reactive towards both electrophilic and nucleophilic substitution

Pyridones are good substrates for nucleophilic substitution

Nucleophilic substitution is easy with pyridines

Pyridine is bad at electrophilic aromatic substitution

Pyridine is a very unreactive aromatic imine

Aromaticity survives when parts of benzene’s ring are replaced by nitrogen atoms

The Claisen ester disconnection: a 1,3-diO relationship needing two carbonyl groups

Aldol-style disconnections with N and O in a 1,3-relationship: I

Look out for concealed functional group relationships

Donor and acceptor synthons