Making heterocycles: ring-closing reactions

We have talked about the structure of saturated heterocycles, particularly with regard to stereoelectronic control over conformation, and before that we looked at some of their reactions. We will now look at how to make them. By far the most important way of making them is by ring-closing reactions because we can usually use the heteroatom as the nucleophile in an intramolecular substitution or addition reaction. Ring-closing reactions are, of course, just the opposite of the ring-opening reactions we talked about earlier in the chapter, and we can start with a reaction that works well in both directions: ring closure to form an epoxide. You know well that epoxides can be formed using m-CPBA and an alkene, but you have already seen examples where they form by an intramolecular substitution reaction such as this.

The same method can also be used to generate larger cyclic ethers. Oxetane, for example, is conveniently made by adding 3-chloropropyl acetate to hot potassium hydroxide. The fi rst step in this reaction is the hydrolysis of the ester. The alkoxide produced then undergoes an intramolecular substitution reaction to yield oxetane.

Tetrahydropyran was prepared as early as 1890 by a ring closure that occurs when a mixture of 1,5-pentanediol with sulfuric acid is heated.

These are all SN2 reactions, so you will not be surprised that nitrogen heterocycles can be prepared in the same way. Aziridine itself, for example, was fi rst prepared in 1888 from 2-chloroethylamine. Related reactions can be used to form three-, five-, and six-membered nitrogen heterocycles, but fail to form four-membered rings. In fact, four-membered rings are generally among the hardest of all to form.

To illustrate this, the green columns of the table below show the rates (relative to six membered ring formation = 1) at which bromoamines of various chain lengths cyclize to saturated nitrogen heterocycles of three to seven members.

At fi rst sight it may seem that these rates have been produced by a random number genera tor! There seems to be no rhyme or reason to them, and no consistent trend. To convince you that these numbers mean something, the table also shows, in the orange columns, the relative rates for another ring-closing reaction, this time forming four- to seven-membered rings that are not even heterocycles by intramolecular alkylation of a substituted malonate. Although the numbers are quite different in the two cases, the ups and downs are the same, and the final column summarizes the relative rates. Put another way, a rough guide (only rough—it doesn’t work in all cases) to the rate of ring formation is this.

● Rough guide to the rate of formation of saturated rings Fastest 5 > 6 > 3 > 7 > 4 > 8–10 slowest

We show the numbers in colour to highlight the fact that this seemingly illogical ordering of numbers actually conceals two superimposed trends. Once you get to five-membered rings, the rate of formation drops consistently as the ring size moves from ‘normal’ (5 and 6) to ‘medium’ (8 to 13) sized rings. ‘Small’ (3 and 4) rings insert into the sequence after 6. The reason for the two superimposed trends is two opposing factors. Firstly, small rings form slowly because forming them introduces ring strain. This ring strain is there even at the transition state, raising its energy and slowing down the reaction. The activation energy for forming

a three-membered ring is very high, due to strain, but decreases as the ring gets larger. This explains why three- and four-membered rings don’t fi t straightforwardly into the sequence. But if the reaction rate simply depended on the strain of the product, the slowest reaction would be the formation of the three-membered ring, and six-membered rings (which are essentially strain-free) would form fastest. Yet the data shows that four-membered rings form more slowly than three-membered ones, and five-membered ones faster than six-membered ones.

The activation energy barriers ΔG‡ of our reactions are made up of two parts: an enthalpy of activation ΔH‡, which tells us about the energy required to bring atoms together against the strain and repulsive forces they usually have, and an entropy of activation ΔS‡, which tells us about how easy it is to form an ordered transition state from a wriggling and randomly rotating molecule. ΔG‡ for three- and four-membered ring formation is large because ΔH‡ is large: energy is needed to bend the molecule into the strained small-ring conformation. ΔH‡ for five-, six-, and seven-membered rings is smaller: this is the quantifiable representation of the ‘ring strain’ fac tor we have just introduced. The second factor is one that depends on ΔS‡: how much order must be imposed on the molecule to get it to react. Think of it this way: a long chain has a lot of disorder, and to get its ends to meet up and react means it has to give up a lot of freedom. So, for the formation of medium and large rings, ΔS‡ is large and negative, contributing to a large ΔG‡ and slow reactions. For three-membered rings, on the other hand, the reacting atoms are already very close together and almost no order needs to be imposed on the molecule to get it to cyclize: rotation about just one bond is all that is needed to ensure that the amine group is in the perfect position to attack the σ* of the C–Br bond in our example above. ΔS‡ is very small for three-membered rings so, while ΔH‡ is large, there is little additional contribution from the TΔS‡ term and cyclization is relatively fast. Four-membered rings suffer the worst of both worlds: forming a four-membered ring introduces ring strain (ΔH‡) and requires order (ΔS‡) to be imposed on the molecule. They form very slowly as a result.

اخر الاخبار

اخبار العتبة العباسية المقدسة

قسم الشؤون الفكرية ينظم ندوة عن الأبعاد الفكرية والعقدية لثورة الإمام الحسين (عليه السلام)

المجمع العلمي يواصل برامجه ودوراته القرآنية في عدد من المحافظات العراقية

لليوم الرابع.. قسم العلاقات العامة يواصل إقامة فعاليات مخيّم البذرة الواعدة

العتبة العباسية المقدسة تطلق التشغيل التجريبي لمعمل غسيل السجاد والأغطية

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

Baldwin’s rules and ring opening

Combatting ΔS‡—the Thorpe–Ingold effect

Thermodynamic control over ring size

Related effects in other types of compounds

Some substituents of saturated heterocycles prefer to be axial: the anomeric effect

Determining stereochemistry when coupling constants are no help: the nuclear Overhauser effect

Oxygen heterocycles

Aziridine: ring strain promotes ring opening

Reactions of saturated heterocycles

More heteroatoms in fused rings mean more choice in synthesis

Quinolones also come from anilines by cyclization to an ortho position

Quinolines and isoquinolines