Benzo-fused heterocycles

Indoles are benzo-fused pyrroles

Indomethacin and its tetrazole analogue contain pyrrole rings with benzene rings fused to the side. Such bicyclic heterocyclic structures are called indoles and are our next topic. Indole itself has a benzene ring and a pyrrole ring sharing one double bond, or, if you prefer to look at it this way, it is an aromatic system with 10 electrons—eight from four double bonds and the lone pair from the nitrogen atom.

Indole is an important heterocyclic system because it is built into proteins in the form of the amino acid tryptophan because it is the basis of important drugs such as indomethacin, and because it provides the skeleton of the indole alkaloids—biologically active compounds from plants including strychnine and LSD . In many ways the chemistry of indole is that of a reactive pyrrole ring with a relatively unreactive benzene ring standing on one side—electrophilic substitution almost always occurs on the pyrrole ring, for example. But indole and pyrrole differ in one important respect. In indole, electrophilic substitution is preferred in the 3-position with almost all reagents whereas it occurs in the 2-position with pyrrole. Halogenation, nitration, sulfonation, Friedel–Crafts acylation, and alkylation all occur cleanly at that position.

This is, of course, the reverse of what happens with pyrrole. Why should this be? A simple explanation is that reaction at the 3-position simply involves the rather isolated enamine system in the fi ve-membered ring and does not disturb the aromaticity of the benzene ring. The positive charge in the intermediate is, of course, delocalized round the benzene ring, but it gets its main stabilization from the nitrogen atom. It is not possible to get reaction in the 2-position without seriously disturbing the aromaticity of the benzene ring.

● Electrophilic substitution on pyrrole and indole Pyrrole reacts with electrophiles at all positions but prefers the 2- and 5-positions, while indole much prefers the 3-position.

A simple example of electrophilic substitution is the Vilsmeier formylation with DMF and POCl3, showing that indole has similar reactivity, if different regioselectivity, to pyrrole. If the 3-position is blocked, reaction occurs at the 2-position and this at fi rst seems to suggest that it is all right after all to take the electrons the ‘wrong way’ round the five-membered ring. This intramolecular Friedel–Crafts alkylation is an example.

An ingenious experiment showed that this cyclization is not as simple as it seems. If the starting material is labelled with tritium (radioactive 3H) next to the ring, the product shows exactly 50% of the label where it is expected and 50% where it is not.

To give this result, the reaction must have a symmetrical intermediate and the obvious candidate arises from attack at the 3-position. The product is formed from the intermediate spiro compound, which has the five-membered ring at right angles to the indole ring—each CH₂ group has an exactly equal chance of migrating.

It is now thought that most substitutions in the 2-position go by this migration route but that some go by direct attack with disruption of the benzene ring. A good example of indole’s 3-position preference is the Mannich reaction, which works as well with indole as it does with pyrrole or furan.

The electron-donating power of the indole and pyrrole nitrogens is never better demon strated than in the use to which these Mannich bases (the products of the reaction) are put. You may remember that normal Mannich bases can be converted to other compounds by alkylation and elimination. No alkylation is needed here as the indole nitrogen can even expel the Me₂N group when NaCN is around as a base and nucleophile. The reaction is slow and the yield not wonderful but it is amazing that it happens at all. The reaction is even easier with pyrrole derivatives.

All of the five-membered rings we have looked at have their benzo-derivatives but we will concentrate on just one, 1-hydroxybenzotriazole, both because it is an important compound and because we have said little about simple 1,2,3-triazoles.

اخر الاخبار

اخبار العتبة العباسية المقدسة

أهالي كربلاء يحيون اليوم السابع لذكرى شهادة الإمام الحسين (عليه السلام)

مشروع أمير القراء الوطني يشهد مشاركة أكثر من 100 طالبٍ في مرحلته الثالثة

قسم الشؤون الفكرية يصدر دليلًا يوثّق القصص الفائزة في مسابقة فتوى الدفاع المقدسة

قسم الشؤون الفكرية يعلن عن توفير عددٍ من المكتبات الإلكترونية المتخصّصة للمؤسّسات الدينية والمكتبات العامّة

المزيد

الآخبار الصحية

نصائح عملية للحد من التعرق المفرط في الصيف

أطباء يحذرون: مكمل غذائي شائع قد يدمر الجهاز العصبي

تحذير طبي من تأثير جانبي "غير متوقع" لحقن التخسيس

حمامات الثلج قد تكون خطيرة وأحيانا مميتة.. ما السبب؟

المزيد

الآخبار التكنلوجية

أكبر جدارية شمسية في العالم تدخل موسوعة غينيس.. مشروع ضخم

تسارع دوران الأرض يثير القلق.. وتحذيرات من "كوارث محتملة" ؟

"سوذبيز" تطرح أكبر قطعة من المريخ على الأرض في مزاد علني

أوبن أيه آي تعتزم إطلاق متصفح إنترنت يعمل بالذكاء الاصطناعي

المزيد

مواضيع ذات صلة

There are thousands more heterocycles out there

Fusing rings to pyridines: quinolines and isoquinolines

Putting more nitrogen atoms in a six-membered ring

Five-membered rings with two or more nitrogen atoms Imidazole

Nitrogen anions can be easily made from pyrrole

Five-membered heterocycles act as dienes in Diels–Alder reactions

Electrophilic addition may be preferred to substitution with furan

Furan and thiophene are oxygen and sulfur analogues of pyrrole

Five-membered aromatic heterocycles are good at electrophilic substitution

Pyridine as a catalyst and reagent

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

Pyridones are good substrates for nucleophilic substitution