Five-membered rings with two or more nitrogen atoms Imidazole

we imagined adding more nitrogen atoms to the pyrrole ring and noticed then that there were two compounds with two nitrogen atoms: pyrazole and imidazole.

Only one nitrogen atom in a five-membered ring can contribute two electrons to the aromatic sextet. The other replaces a CH group, has no hydrogen, and is like the nitrogen atom in pyridine. The black nitrogens are the pyrrole-like nitrogens; the green ones are pyridine-like. The lone pairs on the black nitrogens are delocalized round the ring; those on the green nitrogens are localized in sp² orbitals on nitrogen. We can expect these compounds to have properties intermediate between those of pyrrole and pyridine. Imidazole is a stronger base than either pyrrole or pyridine—the imidazolium ion has a pKa of almost exactly 7, meaning that it is 50% protonated in neutral water. Imidazole is also more acidic than pyrrole, with a pKa of 14.5.

These curious results are a consequence of the 1,3 relationship between the two nitrogen atoms. Both the (protonated) cation and the (deprotonated) anion share the charge equally between the two nitrogen atoms—they are perfectly symmetrical and unusually stable. Another way to look at the basicity of imidazole would be to say that both nitrogen atoms can act at once on the proton being attacked. It has to be the pyridine-like nitrogen that actually captures the proton but the pyrrole nitrogen can help by using its delocalized electrons like this:

Nature makes use of this property by having imidazole groups attached to proteins in the form of the amino acid histidine and using them as nucleophilic, basic, and acidic catalytic groups in enzyme reactions. We use this property in the same way when we add a silyl group to an alcohol. Imidazole is a popular catalyst for these reactions.

A weakly basic catalyst is needed here because we want to discriminate between the primary and secondary alcohols in the diol. Imidazole is too weak a base to remove protons from an alcohol (pKa ~ 16) but it can remove a proton after the OH group has attacked the silicon atom.

In fact, the imidazole is also a nucleophilic catalyst of this reaction, and the fi rst step is substitution of Cl by imidazole—that is why the leaving group in the last scheme was shown as ‘X’. The reaction starts off like this:

The same idea leads to the use of carbonyl diimidazole (CDI) as a double electrophile when we want to link two nucleophiles together by a carbonyl group. Phosgene (COCl₂) has been used for this but it is appallingly toxic (it was used in the First World War as a poison gas with dreadful effects). CDI is safer and more controlled. In these reactions imidazole acts (twice) as a leaving group.

The amino group probably attacks fi rst to displace one imidazole anion, which returns to deprotonate the ammonium salt. The alcohol can then attack intramolecularly, displacing the second imidazole anion, which deprotonates the OH group in its turn. The other product is just two molecules of imidazole.

The relationship between the delocalized imidazole anion and imidazole itself is rather like that between an enolate anion and an enol. It will come as no surprise therefore that, like an enol, imidazole tautomerizes rapidly at room temperature in solution. For the parent compound the two tautomers are the same, but with unsymmetrical imidazoles the taut omerism is more interesting. We will explore this question alongside electrophilic aromatic substitution of imidazoles. Imidazoles with a substituent between the two nitrogen atoms (position 2) can be nitrated with the usual reagents and the product consists of a mixture of tautomers.

The initial nitration may occur at either of the remaining sites on the ring with the electrons coming from the pyrrole-like nitrogen atom. Tautomerism after nitration gives the mix ture. Tautomerism is rapid and the tautomers cannot be separated.

The tautomerism can be stopped by alkylation at one of the nitrogen atoms. If this is done in basic solution, the anion is an intermediate and the alkyl group adds to the nitrogen atom next to the nitro group. Again, it does not matter from which tautomer the anion is derived— there is only one anion delocalized over both nitrogen atoms and the nitro group. One reason for the formation of this isomer is that it has the linear conjugated system between the pyrrole-like nitrogen and the nitro group .

Important medicinal compounds are made in this way. The antiparasitic metronidazole comes from 2-methyl imidazole by nitration and alkylation with an epoxide in base.

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

Benzo-fused heterocycles-Indoles are benzo-fused pyrroles

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