Only axial attack is possible with cyclohexenes

These conformations of six-membered rings with more than one trigonal carbon are quite plainly not chairs, and are much less stable than chairs. Anything which allows them to become a chair is likely to be highly favoured, and the stereoselectivity of a reaction is likely to be driven by the need for the transition state and product to have a chair rather than a boat conformation. This can override the preference for substituents to go into equatorial positions. The choice of axial attack controls the stereoselectivity of reactions of cyclohexenes (and, as you will see, their epoxides), six-membered cyclic enolates, and six-membered cyclic enones.

● The number of trigonal carbon atoms in the ring decides which factors control stereoselectivity

 • Six-membered rings with one trigonal (sp2) carbon atom are already chairs and can undergo axial or equatorial attack.

 • Six-membered rings with two or more trigonal carbon atoms are not chairs and undergo axial attack in order to form chairs rather than boats. The final product may end up with axial or equatorial substitution, but this is not a consideration in the reaction itself.

Alkylations of enolates, enamines, and silyl enol ethers of cyclohexanone usually show substantial preference for axial attack. The enamine of 4-t-butylcyclohexanone, which has a fixed conformation because of the t-butyl group, gives 90% axial alkylation and only 10% equatorial alkylation with n-PrI.

To get at the reason for this result we need to look at the conformation of the enamine inter mediate. At this point we shall generalize a bit more and write a structure that represents any enol derivative where X may be OH, O−, OSiMe3, NR₂, and so on. The double bond (2 × sp² centres) in the ring means the conformation is a partially flattened chair, as described above. We place the t-butyl group in an equatorial position because, as with cyclohexanes, it is so bulky it cannot go axial. This means that there is only one conformation to consider—the one shown in the margin. Now, the electrophile must attack the π system of this conformation, and to do so it has to attack from more or less directly above or below because only then can it interact with one of the lobes of the p orbital at the enol position shown in orange. The need to interact with the π system is the reason cyclohexenes and related compounds react in an axial direction. The top of the molecule looks to be more open to attack so we shall try that approach first.

As the electrophile forms a bond to the trigonal carbon atom, that atom must become tetra hedral and it does so by forming a vertical bond upwards. The result is shown in the diagram—the ring turns into a twist-boat conformation. Now, of course, after the reaction is over, the ring can flip into a chair conformation and the new substituent will then be equatorial, but that information is not present in the transition state for the reaction. We could say that, at the time of reaction, the molecule doesn’t ‘know’ it can later be better off and get the substituent equatorial: all it sees is the formation of an unstable twist boat with a high-energy transition state leading to it. Attack from the apparently more hindered bottom face makes the trigonal carbon atom turn tetrahedral in the opposite sense by forming a vertical bond to the electrophile down wards. The ring goes directly to a chair form with the electrophile in the axial position.

When the carbonyl group is restored by hydrolysis (if necessary—with an enolate X is already O) the ring need not flip: it’s already a chair with the t-butyl equatorial, and the new substituent is axial on the chair. This is the observed product of the reaction. It’s important that you understand what is going on here. The reagent has to attack from an axial direction to interact with the p orbital. If it attacks from above, the new substituent is axial on an unstable twist boat. If it attacks from below, the new substituent is axial on a chair— granted, this is not as good as equatorial on a chair, but that’s not an option—it has to be axial on something, and a chair is better than a twist boat. So this is the product that forms. It’s just hard luck for the substituent that it can’t know that if it did weather it out on the twist boat it could later get equatorial—it plumps for life on the chair and so has to be content with ending up axial. Here is an example with an unsaturated carbonyl compound as an electrophile: the reaction is a Michael addition. The ketone here is slightly different—it has the t-butyl group in the 3- rather than the 4-position, and the reacting centre becomes quaternary during the Michael reaction. But the result is still axial attack.

This result is more impressive because the large electrophile ends up on the same side of the ring as the t-butyl group, so the stereoselectivity cannot be based on any simple idea of reaction on the less hindered side of the ring. It is genuine axial attack, as the conformational diagram of the product confirms. Cyclohexenones are even flatter than cyclohexenes, but it is convenient to draw them in a similar conformation. Conjugate addition to the substituted cyclohexenone in the margin gives the trans product. This is also axial addition to form a chair directly (rather than a twist boat) with the nucleophile approaching from the bottom. We must draw the ring as a flattened chair.

The 5-alkyl cyclohexenone that we have chosen as our example gives the best results. The mechanism suggests that the enolate intermediate is protonated on the top face (axial addition again), although we cannot tell this because the product has no stereogenic centre there. But, if we carry out a tandem reaction with the enolate trapped by a different electrophile, it becomes clear that the product is again that of axial attack.

We shall end this section on conformational control in six-membered rings with the preparation of a useful chiral molecule, 8-phenylmenthol, from the natural product (R)-(+) pulegone. The fi rst step is a copper-promoted conjugate addition to an exocyclic alkene. A new stereogenic centre is formed by protonation of the enolate intermediate but with virtually no stereoselectivity.

Now thermodynamic control can be brought into play. The position next to the ketone can be epimerized via the enolate to give the more stable isomer with both substituents equatorial. This improves the ratio of diastereoisomers from 55:45 to 87:13.

Now the ketone can be reduced with a small reagent, Na in i-PrOH works well— to put the hydroxyl group equatorial. This means that all the product has OH trans to the large group next to the ketone, although it is still an 87:13 mixture of diastereoisomers with respect to the relative configuration at the centre bearing Me.

These alcohols can be separated (they are, of course, diastereoisomers and not enantiomers) and the major, all-equatorial, one is the useful one. This is an impressive example of conformational control by thermodynamic and by kinetic means originating only from a distant methyl group in a six-membered ring.

اخر الاخبار

اخبار العتبة العباسية المقدسة

العتبة العباسية المقدسة تحيي ذكرى شهادة الإمام السجاد (عليه السلام)

العتبة العباسية المقدسة تنشر لافتات خاصة بذكرى شهادة الإمام زين العابدين (عليه السلام)

قسم شؤون المعارف ينظّم دورة مختصة بتحقيق المخطوطات لطلبة الحوزة العلمية النجف الأشرف

قسم التطوير ينظم دورات وورشا تدريبية لطلبة أكاديمية التطوير الإداري

المزيد

الآخبار الصحية

دراسة علمية تكشف مفاجأة حول الأسباب الحقيقية للسمنة

دراسة: الأطباء يتجاهلون "سببا شائعا" لارتفاع ضغط الدم

نظامك الغذائي غني بالبروتين؟.. احذر هذه الآثار الجانبية

لا تتجاهلها.. أعراض تنذرك بأنك مهدد بالإصابة بالسكري

المزيد

الآخبار التكنلوجية

ISOFIX: معيار الأمان الذهبي لمقاعد الأطفال في السيارات

هل المحرك الأكبر دائمًا الأفضل للسيارة؟

اختبارات ناجحة لمحرك "VK-800" الروسي وتطويره لطائرة بايكال الخفيفة

رئيس إنفيديا: الذكاء الاصطناعي الصيني "محفز للتقدم العالمي"

المزيد

مواضيع ذات صلة

Reactions of cis-decalins

cis-Fused rings

Reactions that break open bridged molecules can preserve stereochemistry

Bridged bicyclic rings

Regard five-membered rings with two or more sp3 carbons as flat

Five-membered ketones are flexible

Axial or equatorial attack is possible on a cyclohexanone

Diastereotopic protons in acyclic compounds

Spotting diastereotopic protons in the NMR spectrum

How to tell if protons are homotopic, enantiotopic, or diastereotopic

The size of the geminal coupling constant

Geminal (2J) coupling