Ultimate Guide to the Felkin-Anh Model - Organic Chemistry

The Felkin-Anh model in Organic Chemistry explained using a combination of steric factors and molecular orbital interactions (stereoelectronic effects). High diastereoselectivity is achieved for the addition of nucleophiles to aldehydes and ketones that have alpha stereocentres when reactions are performed under kinetic control, with nucleophiles attacking under irreversible reaction conditions.
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Reference:
Total Synthesis of (-)-Preswinholide A; I Paterson, et al.
J. Am. Chem. Soc. 1994, 116, 6, 2615-2616
doi.org/10.102...
The Felkin-Anh model is perhaps the most reliable model as a predictive tool for the observed diastereoselectivity for the addition of nucleophiles to aldehydes and ketones that have a single adjacent (alpha) stereocentre that is composed of three distinct groups - one large, one medium, and one small in size. (Other models to explain diastereoselectivity in such reactions do exist, e.g. the Cornforth model, but are not the subject of this video as over time they have generally proven to be less predictive in general, although really good in specific circumstances.) The most populated conformations of these types of aldehydes/ketones are the ones which orientate the large group perpendicular to the plane of the carbonyl bond. This conformational preference is predominantly controlled by steric effects. When the substrate is in this conformation, one side of the carbonyl is also more blocked by steric effects and so an attacking nucleophile with stereoselectively prefer to react opposite to the large group. Attack of a nucleophile on to a carbonyl occurs via the Burgi-Dunitz trajectory, which is perpendicular to the plane of the sp2 carbonyl carbon atom, in a plane aligned to the C=O bond, and at a 107 degree angle relative to the C=O bond from the oxygen. This Burgi-Dunitz trajectory is a compromise between maximising HOMO-LUMO overlap of molecular orbitals of the nucleophile with the C=O pi star antibonding molecular orbital and minimising electrostatic repulsion with the filled C=O pi bonding molecular orbital. The most populated conformations project their medium and small groups on the other side the carbonyl. One of these conformers will project the medium group along the direction of the Burgi-Dunitz trajectory and the other populated conformer will have the small group in that position. Therefore the attacking nucleophile will prefer to attack the carbonyl antibonding LUMO on the flight-path that passes over the small group as a preference as a steric effect. This will lead to the formation of a new stereocentre with good diastereoselectively, often with a diastereomeric ratio of 4:1-10:1 for reasonably simple substrates, often better with particularly reactive nucleophiles as the reaction can be conducted at lower temperatures and the kinetic control is emphasised. These reactions show the highest levels of diastereoselectivity when there is very good differentiation on sterics between the three groups on the alpha stereocentre to the carbonyl.
When there is an electronegative atom directly attached to the alpha stereocentre, however, there is another stereoelectronic effect that tends to override the above purely sterically based diastereoselectivity. The Felkin-Anh model instructs the user to treat the electronegative atom as the large group in the above setup, regardless of the steric size of the group compared to the others present. For the purposes of this discussion, I will use a C-OMe group, where the C is the alpha carbon to the carbonyl being attacked. As oxygen is much more electronegative than the carbon, the C-OMe sigma bond is both polarised with electron density being towards the oxygen and also the sigma star antibonding molecular orbital has both a large coefficient on the alpha carbon atom and is relatively low in energy for a carbon-based sigma star MO, by which I mean quite close in energy to the unbonded carbon atom energy. This means that when the C-OMe sigma star antibonding molecular orbital is arranged perpendicular to the C=O carbonyl bond, it is in fact aligned with the C=O pi star LUMO. Therefore, in this conformations, the two antibonding empty molecular orbitals will combine as they have a similar size and energy match. The combination of these two antibonding molecular orbital results in a new lower energy LUMO for the molecule. Hence in this conformation, the substrate is much more reactive (lower activation energy) than when it is in any other conformation, even if that conformer is not the most populated one.
One final observed effect on diastereoselectivity is observed if the electronegative atom on the alpha stereocentre has available lone pairs (sterically and size). In these cases a five-membered ring chelate can form if a reasonably strongly Lewis acidic metal cation happens to be present.
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[@theonearney205]

Going through some natural product synthesis in your style would be amazing!!

[@CasualChemistry]

Cool 😎 I definitely have plans for 2022 on this lines. I’m prepping topics with things like this video that I can refer to later when looking at big molecule syntheses.

[@asmakhurshid6333]

Very well explained starting from A with well clarity leading to Z! Awesome!

[@CasualChemistry]

Thanks 🙂

[@hennyschw]

i discovered your channel through this video and i am very happy about it. i am looking forward to many more videos and hope that your channel gets its deserved growth. greetings from germany.

[@CasualChemistry]

🙂 Thanks for the feedback and glad you enjoyed the video! I have my next few planned out but the day job has been getting in the way of me recording them recently - but definitely more on the way.

[@XavHD]

@@CasualChemistry Thank god :D. I thought you might stopped doing videos and was worried already. Currently going through your videos about asymmetric synthesis for my stereochemistry exam in a few days.

[@CasualChemistry]

This week is looking good for me getting on track with more content. Are there any asymmetric synthesis topics in particular that might be worthwhile me thinking about making a video on? It’s my PhD/PostDoc area so I’m flexible with ideas but have a few ideas in the pharmaceutical area coming soon

[@amitkumarde9239]

Pls come with lecture on 1,3 evans polar model and Reetz cyclic model with multiple stereocenters. Your lecture series is really awesome. 😊

[@CasualChemistry]

🙂 Thanks for the feedback. These topics are on my to-do list to think about interesting ways of presenting them. I probably will need to collect together a few more ideas on a cyclic stereocontrol for this but it is one of my favourite topics.

[@jacopogaronzi9666]

Outstanding explanation, concise and straight to the point, always explaining the reason for which something happens. Ive discovered this channel a few days ago and I can say already say its top notch Keep up the good work sir Could you make a video about chiral bisoxazolines ?

[@CasualChemistry]

🙂 Thanks - I spotted a gap I thought I could help fill to broaden out chemistry stuff online. I haven’t got one planned for BOX catalysts but I certainly want to do more asymmetric catalysis videos so I will have a think about a good way to present.

[@antozon5070]

Thank you for making this video! The explanations were quite clear and well presented.

[@CasualChemistry]

Many thanks for the feedback - much appreciated 🙂. This video’s been in the been in the back of my head for ages and I thought was going to be my first one. It’s really satisfying getting it done now that I’m more practised with my stylus and video making.

[@Andy-wc5xw]

Prepping for final year organic exams, I have the Felkin Ahn down pretty well but it's a joy to get a refresher of this quality

[@CasualChemistry]

Thanks for the feedback 🙂

[@dlvivlviv]

At 9:40, I think in conformational analysis you wrote enantiomers to the one on top in chain form.

[@CasualChemistry]

Do you mean the “EN atom” bit at this time stamp ? I meant that as an abbreviation for electronegative. I haven’t defined absolute stereochemistry in the chain form.

[@joshcantrell8397]

Well done!

[@CasualChemistry]

Thanks 🙂

[@You_know_me_son]

Thank you so much for this wonderful lecture

[@CasualChemistry]

🙂 No worries - glad you enjoyed

[@liviudruche452]

Very well explained

[@CasualChemistry]

Thanks 🙂

[@crabcrab2024]

Wonderful video with a fascinating ending. Unfortunately, I didn’t quite understand the interaction of MOs here. (

[@pablovignolo637]

This is excellent

[@CasualChemistry]

😀 Thanks

[@joshcantrell8397]

How do I know which transition state model to use?

[@CasualChemistry]

That’s going to totally depend on each individual molecule. So a way to approach is to first identify if your aldehyde is chiral, and then see if each of the assumptions of any model apply. For pure Felkin-Anh, the reaction must be irreversible, and there must be a stereocentre alpha to the aldehyde carbonyl with 3 very distinct groups - this can be on size but electronegative groups can also play the role of “big” groups. If none of these are true, try a different model. If none model available fits, it’s likely the reaction will not be very selective or not selective at all.

[@joshcantrell8397]

@ thank you.

[@kirakira592]

Thnx so much

[@CasualChemistry]

No worries 🙂

[@crabcrab2024]

Hi! How come Sigma * and pi* have the same symmetry? Is it even possible? Or did I get something wrong?

[@CasualChemistry]

Ah - now I think I know the bit you mean with the orbitals drawn out. I didn’t shade them the way I’d intended and it was beyond my editing skills to tweak - I decided it was fine to leave in as it is still correct. I would have flipped all the shading on the sigma star to make the lower combined MO the obvious addition, and the higher combined MO the subtraction. Whereas the diagram actually still holds for the ones I’ve drawn, just that the lower combined one is actually the subtraction instead and the higher one the addition (here the anti bonding combination is actually the addition of the orbital wavefunctions). Apologies for any confusion on this - that was unintended. If I’d done this with maths and the symbols, it would probably make it clearer exactly how to combine them but I thought that might be a bit much for the video.

[@crabcrab2024]

@@CasualChemistry Oh, now I think I see what was meant. Thank you very much for your explanation. I really appreciate it. 🙂