So, what happens when a cyclohexanone is attacked by a nucleophile? For cyclohexanone itself, the reaction below gives a product which can adopt either of the two conformations shown, with Nu axial or equatorial, depending on the relative size of Nu and OH. This reaction does not tell us much about the attack on the C=O group itself—we can’t tell, for exam ple, whether Nu− attacked the axial or the equatorial face of the C=O group.

Now think of a nucleophile attacking 4-t-butylcyclohexanone. Since the t-butyl group locks the ring (t-Bu can never be axial), whether Nu is axial or equatorial will depend only on which face of the C=O group it attacks. Attack on the same face as the t-butyl group leaves the nucleophile axial and the hydroxyl group equatorial; attack on the opposite face leaves the nucleophile equatorial and the hydroxyl group axial. The nucleophile is said to attack either in an axial or equatorial manner, depending on where it ends up. It’s easier to see this in a diagram.

Now for an observation—we’ll try and explain it shortly. In general, large nucleophiles attack equatorially and small nucleophiles attack axially. For example, reduction of 4-t-butyl cyclohexanone with lithium aluminium hydride in Et2O gives 90% of the trans alcohol: 90% of the hydride has added axially. AlH4 − is quite small as nucleophiles go: to make more of the cis alcohol we need a larger nucleophile—lithium tri-sec-butylborohydride, for example, sold under the name of L-selectride. This is so large that it attacks only equatorially, yielding typi cally 95% of the cis alcohol.

Carbon-centred nucleophiles follow the same trend—the table shows that, as size increases from the slender ethynyl anion through primary and secondary organometallics to t-BuMgBr, the axial selectivity drops off correspondingly. PhLi behaves as though it were quite small because it is flat.

Now the difficult part—why? This is a question to which the answer really is not known for certain. It’s certainly true that the direction of approach for axial attack is more hindered than for equatorial attack, and this is certainly the reason large nucleophiles prefer to attack equatorially. But if this is the case, why do small ones actually prefer to attack axially? There must be another factor that favours axial attack for those nucleophiles small enough to avoid the bad interactions with the other axial hydrogens. At the transition state, the forming –O− oxygen substituent is moving in either an axial or an equatorial direction. Just as the axial substituent is less favourable than an equatorial one, so is the transition state leading there, and the route leading to the equatorial hydroxyl group is favoured. When chemists made the drug alphaprodine using the reaction shown below, they found that the combination of the equatorial preference of a methyl group adjacent to C=O and an equatorial preference for attack on the C=O group were enough to favour the formation of one diastereoisomer. Here is the reaction, with the starting material and product represented as a conformational diagram.

We can also represent the reaction in configurational terms. This is less good for explaining the stereoselectivity, but you should always be prepared to turn conformational diagrams into standard configurational ones.

In the next reaction, stereoselectivity is not so good. Zeneca (now AstraZeneca) announced the manufacture of a drug by the addition of a lithiated thiophene to another heterocyclic ketone, which initially gave a mixture of diastereoisomers.

Such a mixture is no good for manufacture of a pure drug, but the compound can be equilibrated in dilute acid by repeated SN1 formation of a tertiary cation and recapture by water so that the required product (which is more stable as it has both Me and the thiophene equatorial) dominates by 92:8 and can be purified by crystallization. The unwanted isomer can be recycled in the next batch.

In these reactions the molecule has a free choice whether to place a substituent in an axial or equatorial position and this is the only consideration because the starting materials in the reactions—ketones or carbocations—have six-membered rings that are already in the chair conformation even though they have one trigonal (sp²) atom in the 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

Only axial attack is possible with cyclohexenes

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