Reactions of saturated heterocycles

Saturated nitrogen heterocycles: amines, but more nucleophilic In many reactions the simple saturated nitrogen heterocycles—piperidine, pyrrolidine, piperazine, and morpholine—behave simply as secondary amines that happen to be cyclic.

They do the sorts of things that other amines do, acting as nucleophiles in addition and substitution reactions. Morpholine, for example, is acylated by 3,4,5-trimethoxybenzoyl chloride to form the tranquillizer and muscle relaxant trimetozine, and N-methylpiperazine can be alkylated in an SN1 reaction with diphenylmethyl chloride to give the travel sickness drug cyclizine.

The addition of pyrrolidine to aldehydes and ketones is a particularly important reaction because it leads to enamines, the valuable enol.

Enamines formed from pyrrolidine and piperidine are particularly stable because pyrrolidine and piperidine are rather more nucleophilic than comparable acylic amines such as diethylamine. This is a general feature of cyclic amines (and cyclic ethers, too, as you will see shortly), and is a steric effect. The alkyl substituents, being tied back into a ring, are held clear of the nucleophilic lone pair, allowing it to approach an electrophile without hindrance. This effect is well illustrated by comparing the rates of reaction of methyl iodide with three amines—tertiary this time. The two cyclic compounds are bridged—quinuclidine is a bridged piperidine while the diamine known as DABCO (1,4-diazabicyclo[2.2.2] octane) is a bridged piperazine. The table below shows the relative rates, along with pKa values, for triethylamine, quinuclidine, and DABCO.

Quinuclidine and DABCO are 40–60 times more reactive than triethylamine. This is again due to the way the ring structures keep the nitrogen’s substituents away from interfering with the lone pair as it attacks the electrophile. You should contrast the effect that the cyclic structure has on the basicity of the amines: none! Triethylamine and quinuclidine are equally basic and, as you can see in the margin, so (more or less) are diethylamine, dibutyl amine, and piperidine. A proton is so small that it cares very little whether the alkyl groups are tied back or not. Much more important in determining pKa is how electron-rich the nitrogen is, and this is the cause of the glaring discrepancy between the basicity of quinuclidine and that of DABCO, or between the basicities of piperidine (pKa 11.2) and morpholine (pKa 9.8) or pip erazine (pKa 8.4). The extra heteroatom, through an inductive effect, withdraws electron density from the nitrogen atom, making it less nucleophilic and less basic. In this sense, morpholine can be a very useful base, less basic than triethylamine but somewhat more so than pyridine (pKa 5.2). Notice how much lower is the second pKa (that is, the pKa for proton ation of the second nitrogen) of the diamines DABCO and piperazine: the protonated nitrogen of the monoprotonated amine withdraws electrons very effectively from the unprotonated one.

The exposed nature of the nitrogen atom in cyclic amines means that nitrogen heterocycles are very frequently encountered in drug molecules, particularly those operating on the central nervous system (cocaine, heroin, and morphine all contain nitrogen heterocycles, as do codeine and many tranquillizers, such as Valium). But the ring can also be used as a support for adding substituents that hinder the nitrogen’s lone pair. Just as the nitrogen atom of piperidine is permanently exposed, the nitrogen atom of 2,2,6,6-tetramethylpiperidine (TMP) nestles deep in a bed of methyl groups. The lithium salt of TMP (LiTMP) is an analogue of LDA—a base that experiences enormous steric hindrance that can be used in situations where the selectivity even of LDA fails.

اخر الاخبار

اخبار العتبة العباسية المقدسة

قسم الشعائر يواصل تحضيراته لتنظيم عمل المواكب الحسينية في زيارة الأربعين

قسم شؤون المعارف يناقش تحضيرات المؤتمر العلمي الأول لمركز تراث البصرة

قسم الشؤون الفكرية يقيم دورة تطويرية لملاكات هيأة المساءلة والعدالة في الأرشفة الإلكترونية

المجمع العلمي ينظم مجلس عزاء في قضاء الهندية

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

Aziridine: ring strain promotes ring opening

More heteroatoms in fused rings mean more choice in synthesis

Quinolones also come from anilines by cyclization to an ortho position

Quinolines and isoquinolines

Pyrimidines can be made from 1,3-dicarbonyl compounds and amidines

Pyrazoles and pyridazines from hydrazine and dicarbonyl compounds

Thermodynamics is on our side

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

Five-membered rings with two or more nitrogen atoms Imidazole