The Ritter reaction and the Beckmann fragmentation

Another collection of related intermediates occurs in the Ritter reaction and the Beckmann fragmentation. The Ritter reaction involves the combination of a tertiary alcohol and a nitrile in acid solution and the proposed mechanism involves a series of intermediates.

The Beckmann fragmentation also occurs in acid solution on the fragmentation of an oxime with a tertiary alkyl group anti to the OH of the oxime. The fragmentation step gives the same cation and the same nitrile together with a molecule of water and these three combine in the same way to give the same amide. We need evidence that the carbocation and the nitrilium ion are genuine intermediates and that the same sequence is found in both reactions.

Evidence that the two reactions are intimately related comes from the formation of the same amide from two different starting materials: a tertiary alcohol and an oxime, both based on the decalin skeleton. The oxime has its OH group anti to the ring junction to minimize steric hindrance as oxime formation is under thermodynamic control.

The experiments also provide stereochemical evidence that a carbocation is an inter mediate in both reactions. Both starting materials are cis-decalins but the product is a trans decalin. The carbocation intermediate has no stereochemistry and can react with the nitrile from either face: since axial attack is preferred the product is the more stable trans-decalin. Here’s the mechanism for the Beckmann fragmentation:

It is also possible to trap the carbocation in other ways. The Beckmann fragmentation of this oxime of an aryl seven-membered ring ketone gives a tertiary carbocation that might be expected to cyclize to give an amide. However, this reaction would give an unfavourable eight membered ring and does not happen. Instead, the chain twists round the other way and forms a much more stable six-membered ring by intramolecular Friedel–Crafts alkylation.

In the Ritter reaction a rather different kind of evidence for the cation is the fact that families of isomeric alcohols all give the same product. In all these cases, rearrangements of the fi rst-formed carbocation can easily account for the products. An example in the decalin series is this Ritter reaction with KCN as the nitrile in acidic solution so that HCN is the reagent. The starting material is a spirocyclic tertiary alcohol but the product is a trans-decalin formed by rearrangement.

Trapping the nitrilium cation is also possible. A famous example is the heterocycle produced by intramolecular capture of the nitrilium ion with a hydroxyl group. Note that the tertiary alcohol reacts to give the cation while the secondary alcohol acts as the nucleophilic trap.

An important example in which the diastereoisomer produced was critical in determining the mechanism is the synthesis of cis-aminoindanol, a part of Merck’s anti-HIV drug Crixivan (indinavir). The reaction involves treatment of indene epoxide with acetonitrile (MeCN) in acidic solution. The product is a cis fused heterocycle. It is easy to see which atoms have come from the nitrile (green) but the substitution of nitrogen for oxygen at one end of the epoxide has occurred with retention of configuration as the cis-epoxide has given the cis product. Clearly, we have some sort of Ritter reaction and the nitrilium ion has been trapped with an OH group.

What about the regioselectivity? The obvious explanation is that a cation is formed from the epoxide by a specifi c acid-catalysed ring opening. But why should the nitrile attack the bottom face of the cation? We should expect it to attack the top face preferentially as the hydroxyl group partly blocks the bottom face.

A reasonable suggestion is that the nitrile adds reversibly to the cation. Every time it adds to the top face, it drops off again as the OH group cannot reach round to form the heterocycle. But every time it adds to the bottom face (which may well be less often), it is quickly captured by the OH group because 5,5 fused rings are favourable when the ring junction is cis. Eventually, all the compound is converted to the heterocycle.

The mechanism of this reaction is of great importance because it is the foundation stone of the synthesis of Crixivan (indinavir)—an anti-HIV drug that has saved thousands of lives.

اخر الاخبار

اخبار العتبة العباسية المقدسة

شعبة متابعة الأداء تنظم محاضرة تربوية لمتطوعات مجمع العلقمي استعدادًا لزيارة الأربعين

شعبة الحرم الشريف تكثف استعداداتها لتقديم خدمات متنوعة لزائري الأربعين

قسم الشؤون الفكرية يفتتح محطتين ثقافيتين في ذي قار لخدمة زائري الأربعين

العتبة العباسية المقدسة تعقد ملتقى خاصًا لمنتسبيها العاملين في مراكز إرشاد التائهين خلال زيارة الأربعين

المزيد

الآخبار الصحية

علامات فارقة بين النوبة أو السكتة القلبية.. ماهي؟

الفلفل الأحمر.. سعرات حرارية منخفضة وفوائد صحية عديدة

8 أعراض إذا شعرت بها.. اذهب للطوارئ فورا !

تعرف على أكثر 8 أماكن اتساخا في المنزل

المزيد

الآخبار التكنلوجية

إنتاج الهيدروجين الأخضر في البحر.. هذه أحدث الدراسات

"ناسا" تخطط لبناء مفاعل نووي على سطح القمر !

ابتكار ومواهب وأموال.. مارك زوكربيرغ يعلن الحرب على أبل

عودة التعاون الفضائي بين روسيا وأميركا.. وبحث ملفات "هامة"

المزيد

مواضيع ذات صلة

Bonding and reactions in transition metal complexes

Ligands can be attached in many different ways

The 18-electron rule

Transition metals extend the range of organic reactions

Specific base catalysis

Specific acid catalysis

Entropy of activation

The kinetic isotope effect

Non-linear Hammett plots

A complete picture of the transition state from Hammett plots

Using the Hammett ρ values to uncover mechanisms

Reactions with small Hammett ρ values