Combatting ΔS‡—the Thorpe–Ingold effect

The rate of ring formation is affected not just by ring size but by substituents on the ring being formed. Compare the following relative rates (krel) for epoxide-forming cyclization reactions. The second looks as though it suffers more steric hindrance but nonetheless it is tens of thousands of times faster!

Adding substituents to other ring-forming reactions makes them go faster too: in the next two examples the products are oxetanes and pyrrolidines.

This effect is quite general, and is known as the Thorpe–Ingold effect after the fi rst chemists to note its existence, in 1915.

●The Thorpe–Ingold effect The Thorpe–Ingold effect is the way in which substituents on the ring increase the rate, or equilibrium constant, for ring-forming reactions.

 As the box says, it’s not only rate that can be affected by additional substitution. Here are the relative equilibrium constants for the formation of an anhydride from a 1,4-dicarboxylic acid (the unsubstituted acid is called succinic acid, and the values are scaled so that Krel for the formation of succinic anhydride is 1). More substituents mean more cyclized product at equilibrium. The Thorpe–Ingold effect is both a kinetic and a thermodynamic phenomenon.

Now we need to explain why this is. The explanation comes in two parts, one of which may be more important than the other, depending on the ring being formed. The fi rst part is more applicable to the formation of small rings, such as the fi rst example we gave you. If you measure the bond angles of chains of carbon atoms, you expect them to be close to the tetrahedral angle, 109.5°. The crystal structure of the 1,3-dicarboxylic acid in the margin, for example, shows a C–C–C bond angle of 110°. Now imagine adding substituents to the chain. They will repel the carbon atoms already there, and force them a little closer than they were, making the bond angle slightly less. X-ray crystallography tells us that adding two methyl groups to our 1,3-dicarboxylic acid decreases the bond angle by about 4°. We can assume that the same is true in the alcohol starting materials for the epoxide-form ing reactions on p. 808 (we can’t measure the angle directly because the compounds aren’t crystalline). Now consider what happens when both of these alcohols form an epoxide. The bond angle has to become about 60°, which involves about 50° of strain for the fi rst diacid, but only 46° for the second. By distorting the starting material, the methyl groups have made it slightly easier to form a ring. This part of the argument works only for small rings. For larger rings, we need another explanation, and it involves entropy. We’ll use the pyrrolidine-forming reaction as an example. We have explained the effect of ΔS‡ (entropy of activation) on the rate of ring formation: as larger rings form, they have to lose more entropy at the transition state, and this contributes to a less favourable ΔG‡.

But, when the starting material has more substituents, it starts off with less entropy anyway. More substituents mean that some conformations are no longer accessible to the starting material—the green arcs on the structures on the right above show how the methyl groups hinder rotation of the N and CH₂Br substituents into that region of space. Of those fewer con formations, many approximate to the conformation in the transition state, and moving from starting material to transition state involves a smaller loss of entropy: ΔS‡ is less negative so ΔG‡ (= ΔH‡ – TΔS‡) is more negative and the ring forms faster. The same arguments apply to ΔS for the reaction as a whole (the difference in entropy between starting material and products), so increased substitution favours ring closure even under thermodynamic control.

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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

Thermodynamic control over ring size

Making heterocycles: ring-closing reactions

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