Retrosynthesis 1 - Organic Chemistry Casual Chemistry 2026-09-18 | Retrosynthesis 1 - Organic Chemistry
A Retrosynthetic Analysis of Aspidophytine Casual Chemistry 2025-06-17 | A proposal for a disconnection approach to analysing this alkaloid natural product. The retrosynthesis is driven by key functional group relationships and minimising competition between electrophiles and nucleophiles. This retrosynthetic analysis identifies sensible starting materials as an indole and a cyclopentenone (ketone functionalised cyclopentene).This discussion was inspired by the Corey synthesis of apspidophytine: J. Am. Chem. Soc. 1999, 121, 28, 6771–6772pubs.acs.org/doi/10.1021/ja9915201Links to other mentioned videos:- CBS reduction: youtu.be/rv-dZ2qyAzM- Indole synthesis: youtu.be/v2lSd253nwU
Prevost Reaction in Organic Chemistry #ochem #chemistry #organicchemistry Casual Chemistry 2025-03-20 | Prevost dihydroxylation reaction is selective for converting an alkene to an anti diol, using an intermediate iodonium ion, SN2 substitution and neighbouring group participation.
Anti Aldol Reactions - Lactate Auxiliaries #chemistry #organicchemistry #ochem #chemistryeducation Casual Chemistry 2024-09-24 | ...
Solving Anti Aldol Reaction Issues Casual Chemistry 2024-09-12 | Using lactic acid derived auxiliary chemistry to perform highly diastereoselective anti aldol reactions (lactate aldols). A full explanation evolving a Zimmerman-Traxler Transition State into a chelated boat-like transition state where the configuration of an alpha (prime) stereocentre on the boron enolate can induce stereochemical control on the product. The reaction relies on a stabilising, non-classical hydrogen bond with the formyl hydrogen atom of the activated carbonyl group.Links to other videos referenced---------------------------------------------------Introduction Part 1: youtu.be/XZ30Fup3xyAIntroduction Part 2:youtu.be/qFe5T7WLHDYFelkin-Anh Model:youtu.be/JvF5NQ54-z4A simple boron-mediated aldol reaction:youtu.be/b9KWPWeVkZgA retrosynthesis using auxiliary chemistryyoutu.be/zlclJzdrtBIReferences from video------------------------------------Studies on Lactate Aldol Reactions:Tetrahedron Lett. 1994, 35, 9083-9086doi.org/10.1016/0040-4039(94)88434-XTetrahedron Lett. 1994, 35, 48, 9087-9090doi.org/10.1016/0040-4039(94)88435-8J. Org. Chem. 1992, 57, 19, 5173–5177doi.org/10.1021/jo00045a033
Barton-McCombie Deoxygenation #organicchemistry #chemistry #orgo Casual Chemistry 2024-08-18 | For removing a hydroxyl group using controlled radical chemistry. The overall transformation reduces an alcohol to an alkyl group.
Ellman Auxiliaries for Amine Synthesis #chemistry #organicchemistry Casual Chemistry 2024-04-08 | For asymmetric synthesis of primary amines. A stereocentre is formed by direct addition of a Grignard nucleophile to a sulfinimide (sulphinimide) with a stereogenic sulfur centre. The sulfinimide is formed by condensation of the enantiomerically enriched sulfoxide (sulphoxide) with a carbonyl, such as an aldehyde or ketone. The transition state is thought to be a chelated Zimmerman-Traxler type six-membered ring.
Eschenmoser Fragmentation #chemistry #organicchemistry Casual Chemistry 2024-04-07 | Eschenmoser fragmentation of an epoxy hydrazine. The epoxide has likely formed by conjugate addition to an alpha,beta-unsaturated ketone. The reaction is driven by base here but the fragmentation can also be started with acid. After releasing ring strain in the epoxide, a further fragmentation forms a new carbonyl and allows two really good leaving groups to leave - nitrogen gas and the tosyl anion. In this process an alkyne is formed with a triple carbon-carbon bond.
Payne Rearrangement #chemistry #organicchemistry Casual Chemistry 2024-04-02 | Mechanism for the isomerisation of epoxy alcohols to the terminal epoxide. It is likely that the initial epoxide was generated by oxidation of an allylic alcohol - perhaps by asymmetric catalysis using a Sharpless Asymmetric Epoxidation reaction. The terminal epoxide is favoured as it has less steric strain from eclipsing interactions.
Pummerer Rearrangement #chemistry #organicchemistry Casual Chemistry 2024-04-02 | Organic chemistry mechanism of a sulfoxide (sulphoxide) reacting with acetic anhydride to give a thiol-acetate via elimination
Skraup Synthesis #chemistry #organicchemistry Casual Chemistry 2024-04-01 | Synthesis of quinoline. Conjugate addition of aniline to the 1,4 position of acrolein. Mediated by acid. Cyclisation by electrophilic aromatic substitution on to an activated carbonyl group. After rearomatisation, water is eliminated likely by an E1 mechanism. The intermediate is then oxidised by a separate oxidising agent such as nitrobenzene.
Narasaka Reduction Mechanism #chemistry #organicchemistry Casual Chemistry 2024-04-01 | Narasaka reduction mechanism where a beta hydroxy-ketone is chelated first with a boron based bidentate Lewis acid. The chelated structure prefers to adopt a half-chair six-membered ring conformation. Attack of an external borohydride nucleophile is from the face of the carbonyl that leads to a chair-like transition state (rather than a twist boat) to the 1,3-syn diol product. The reaction is very diastereoselective.
Pinacol Rearrangement #chemistry #organicchemistry Casual Chemistry 2024-04-01 | Reaction mechanism for the Pinacol Rearrangement in Organic Chemistry and Synthesis. A reductive coupling using magnesium metal followed by an acid mediated migration to give a spiro centre.
CBS Reduction as Asymmetric Catalysis #chemistry #organicchemistry #ochem Casual Chemistry 2024-03-31 | Chiral sodium borohydride for reduction of ketones in organic chemistry. The proline based species can be used like this as a type of asymmetric catalysis to form one enantiomer of product in high enantiomeric excess (ee).
Sharpless Asymmetric Epoxidation #chemistry #organicchemistry #ochem Casual Chemistry 2024-03-31 | Named reaction in Organic Chemistry. Mechanism in longer video.
Evans Auxiliaries in Aldol Reaction Chemistry Casual Chemistry 2024-03-29 | Chiral auxiliary in Organic Chemistry #chemistry #organichemistry
Evans Auxiliaries and a Friend for Aldol Reactions Casual Chemistry 2024-03-26 | Using chiral auxiliaries for asymmetric synthesis - diastereoselective aldol reactions with chelating enolates and cyclic transition states. The transition states can be constructed using the Zimmerman-Traxler model.Motivation in my previous video:youtu.be/XZ30Fup3xyAFollowing selective enolisation, either by hard enolisation with strong bases such as LDA or by soft enolisation methods using a Lewis acid and a weak base, a stereodefined enolate can react with aldehydes in an aldol reaction. Both the nucleophile and electrophile are prochiral and so we form two new stereocentres from this reaction. The reaction is diastereoselective. The diastereoselectivity can be increased by using chelation into a six-membered ring transition state, in which big groups prefer to go equatorial.A chiral auxiliary can be used to select further for a particular combination of stereocentres that can be formed in this reaction. The chiral auxiliary adds another level of diastereoselectivity and the Evans auxiliary can lead to very high d.r. (diastereomeric ratio). When the aldol reaction is complete, the chiral auxiliary can be cleaved carefully, separate by chromatograhpy, and recycled.Another type of chiral auxiliary is the lactate auxiliary which uses a stereocentre derived from lactic acid. Both enantiomers of lactic acid are available in the chiral pool. There are similar types of diastereoselectivity observed with these chiral auxiliaries and this topic will be expanded upon in my next video. REFERENCESEvans Aldol Reaction:J. Am. Chem. Soc. 1981, 103, 8, 2127–2129doi.org/10.1021/ja00398a058Lactate Aldol Auxiliaries:Tet.Letters Vol. 35. No. 48, pp. 9083-9086. 1994doi.org/10.1016/0040-4039(94)88434-XFURTHER DETAILFelkin-Anh Model:youtu.be/JvF5NQ54-z4Boron aldol reaction:youtu.be/b9KWPWeVkZgAnother example of use of chiral auxiliaries:youtu.be/zlclJzdrtBI#chemistry #organicchemistry #education
Making a Synthesis Stereoselective Casual Chemistry 2024-02-09 | Introduction to stereoselective synthesis via retrosynthetic analysis. How to change reagents without changing disconnections in a retrosynthesis to introduce diastereoselectivity and enantioselectivity.Discussion based on this literature synthesis:doi.org/10.1002/anie.201310164Boron Enolates and Aldol Reactions:youtu.be/b9KWPWeVkZgUltimate Guide to the Felkin-Anh Model:youtu.be/JvF5NQ54-z4#chemistry #education #organicchemistry
Elemental Metals in Retrosynthetic Analysis Casual Chemistry 2023-08-24 | A disconnection approach to a retrosynthesis of this organic molecule. The different ring systems can be made by classical named reactions involving metals in the forward synthesis.The 1,4-cyclohexadiene is clue for using a Birch reduction disconnection back to the benzene ring in the retrosynthesis. A mixture of sodium metal dissolved in liquid ammonia makes a solution of solvated electrons that act as a powerful reducing agent. Solvated electrons are transferred into the benzene pi system (pi cloud) to give a conjugated carbanion. This carbanion can be protonated by an external source of H+ such as an alcohol. The video includes a discussion of the reaction mechanism and the effect of both electron-withdrawing and electron-donating substituents on the regioselectivity for the Birch reduction.The cyclopropane can be synthesised by Simmons-Smith reaction. The reagent for the Simmons-Smith cyclopropanation is a carbenoid formed by mixing zinc metal with diiodomethane. In this retrosynthetic analysis, the substrate for cyclopropanation is a chiral allylic alcohol. Due to restricted rotation, high levels of diastereoselectivity for cyclopropanation should be observed as the Z geometry of alkene next to the chiral centre leads to just one low energy conformation (energy minimum for this conformer). The Simmons-Smith zinc carbenoid reagent will coordinate to the hydroxyl group on the stereocentre and direct reaction to the same face.The remainder of the retrosynthesis shows that the key intermediates can be made using simple disconnections and redox steps back to simple benzene ring systems. 1,2-diX difunctional patterns are common here which can nudge towards the use of epoxides in a forward synthesis, although other synthetic pathways are possible.#chemistry #organicchemistry #education
Disconnecting with a sneaky furan? Casual Chemistry 2023-08-14 | Retrosynthetic analysis of a highly potent, selective, and orally bioavailable factor Xa inhibitor originally made by Bristol-Myers Squibb (BMS). The disconnection approach uses an amide to break the molecule into two halves, each of which contains two aromatic systems. These aromatic systems include heterocycles – a pyrazole, an imidazole, and a benzisoxazole. The retrosynthesis will construct the pyrazole and benisoxazole using common disconnections, but taking care to account for regioselectivity challenges. For the construction of the pyrazole, a furan ring can be used as a masking group (protecting group) for a carboxylic acid to help differentiate a 1,3-dicarbonyl on chemoselectivity (electrophilicity) arguments when a hydrazine is required to be a nucleophile.BMS Medicinal Chemistry route and original paper that this video is based on:J. Med. Chem. 2005, 48, 6, 1729doi.org/10.1021/jm0497949Other key steps in the organic chemistry synthesis include an Ullman coupling between two aromatic rings. This is useful in the medicinal chemistry approach as it makes analogue synthesis more easy and convergent. The benzisoxazole is synthesised from and SNAr nucleophilic substitution step of a hydroxylamine; intramolecular attack on to a nearby nitrile group completes the heterocycle synthesis.More retrosynthesis videos:youtube.com/playlist?list=PLavaRHHaRimVhyZD79H8g08cfhxrZMcB1More heterocyclic chemistry videos:youtube.com/playlist?list=PLavaRHHaRimUCE5F83Ier19ksegJvJL7hChemistry used in this video includes:SNAr (Nucleophilic Aromatic Substitution)Furan oxidationLithiation of imidazoleReductive aminationUllman coupling (Ullman reaction)Dehydration of amidesFriedel-CraftsIodination of benzeneBromination of benzeneGrignard reagentsHeterocycle formationIsoxazole formationPyrazole constructionRegioselectivity for reactions on benzene ringsAmide formation from acid chloridesUse of copper salts in organic chemistryAromatisation reactions#chemistry #organicchemistry #science
Retrosynthesis Explained Casual Chemistry 2023-07-22 | Full video on my channel. Retrosynthetic analysis using Diels-Alder reaction and homologation of aldehyde. Use of acetylene and epoxide to set up 1,2 functional group relationship. Disconnection approach and forwards synthesis explained.Retrosynthesis 11 - Organic Chemistryyoutu.be/uSzn4FdRD2g#chemistry #organicchemistry #science
Pfizer’s Paxlovid Needs Careful Couplings Casual Chemistry 2023-07-18 | A video on retrosynthesis in organic chemistry. Paxlovid is the rapidly developed anti-viral pharmaceutical agent for the treatment of Covid-19 (coronavirus) by the team of scientists at Pfizer. It’s a mixture of two ingredients: Nirmatrelvir and Ritonavir. The mode of action of Nirmatrelvir is thought to be as a covalent inhibitor, with a bond forming between the molecule’s nitrile group and a cysteine residue on the virus protein.This video is a discussion on organic chemistry synthesis issues when trying to use a disconnection approach (retrosynthetic analysis) on Nirmatrelvir. In particular, there is a focus on chemical coupling reagents for forming amides to minimise risk of epimerisation of alpha-stereocentres, which can be a problem when using acid chlorides. The video includes a discussion of amide coupling reagents, such as DCC, EDC (EDCI), and HATU - these are commonly used in peptide synthesis.The remainder of the retrosynthesis focuses on three amino acid fragments. These can be synthesised from commercially available starting materials in a few steps using conventional synthesis methods in organic chemistry, including cyclopropanation and exploiting bicyclic structures to impart diastereoselective transformations. Discovery process discussion from the Pfizer team:ACS Cent. Sci. 2023, 9, 5, 849–857doi.org/10.1021/acscentsci.3c00145Derek Lowe’s excellent blog posts:science.org/content/blog-post/making-paxlovidscience.org/content/blog-post/paxlovid-drug-development-full-sprintHanessian dianion chemistry:Tet. Lett., 1998, 39, 5887doi.org/10.1016/S0040-4039(98)00900-9#chemistry #organicchemistry #science
How are you making that diene though? Casual Chemistry 2023-05-08 | Stereocontrolled organic synthesis of an intermediate used in the total synthesis of the cytotoxic marine macrolide aplyronine by the Paterson Group (Department of Chemistry, University of Cambridge). Many alternative organic chemistry concepts and options are evaluated for practicality on scale and for solving chemoselectivity problems. These are highlighted by retro synthetic analysis using a standard disconnection approach to retrosynthesis. Key steps in the chemistry include a boron aldol reaction, an Evans-Tishchenko reduction and a Trost alkyne to diene isomerisation. The aim of the video is to explain challenges in organic synthesis. LINKS and REFERENCES:Paterson Aplyronine Synthesis:I. Paterson, C. J. Cowden, M. D. Woodward, Tetrahedron Lett. 1998, 39, 6037–6040doi.org/10.1016/S0040-4039(98)01191-5Org. Lett. 2013, 15, 12, 3118–3121doi.org/10.1021/ol401327rUsing TCA reagents for mild benzylation reactions:youtu.be/tcvTAdRsjLgBoron-mediated aldol reactions with E enolates:youtu.be/b9KWPWeVkZg1,3 hydroxyl directed reductions of ketones:youtu.be/FNuma99tNvgAcetal formation mechanism:youtu.be/PjBGN19tQuwTrost Chemistry for alkyne to diene isomerisation:Isr. J. Chem. 2021, 61, 340 – 36doi.org/10.1002/ijch.202000103B. M. Trost, U. Kazmaier, J. Am. Chem. Soc. 1992, 114, 7933–7935doi.org/10.1021/ja00046a062#organicchemistry #science #chemistry
How I Used Mosher Esters in my PhD Casual Chemistry 2023-04-11 | How to determine the absolute stereochemistry at oxygen of a chiral secondary alcohol by NMR spectroscopy.References: Ikuko Ohtani, Takenori Kusumi, Yoel Kashman, and Hiroshi KakisawaJournal of the American Chemical Society 1991 113 (11), 4092-4096DOI: 10.1021/ja00011a006James A. Dale and Harry S. MosherJournal of the American Chemical Society 1973 95 (2), 512-519DOI: 10.1021/ja00783a034In asymmetric organic synthesis, frequently a stereocentre at oxygen will be synthesised and it is usually important that it is formed in high enantiomeric excess. It is also important to confirm that you have synthesised the correct absolute stereochemistry of the centre – as in the absolute chirality. Most commonly, these oxygen-based stereocentres are hydroxyl groups are as part of a secondary alcohol.To determine enantiomeric excess (ee), any chiral derivitising agent can be used, but forming the Mosher ester is an easy option given the availability of the reagent itself in high ee. The idea is that if you have a molecule with a single or isolated hydroxyl-based stereocentre, the NMR spectrum of molecules with either configuration will be identical (or nearly identical). If you have a compound with a mixture of both configurations, you make, for example, an ester by condensation reaction with a carbonyl derivative, such as a carboxylic acid (using a coupling reagent like DCC) or acid chloride, that is known to of very high enantiopurity – as in essentially only one enantiomer – with a stereocentre as close as possible to the carbonyl itself, ideally in the alpha position. Following this procedure will synthesise two diastereomers that are distinct by NMR spectroscopy. The diastereomeric ratio (dr) can be found by determining the integrations for equivalent peaks in the NMR spectrum, from which an enantiomeric excess can be calculated for the parent alcohol. A really clear way of doing this is to use the 19F NMR spectrum instead, exploiting the -trifluromethyl (CF3) group on the Mosher ester. The signals corresponding to each diastereomer will be clean singlets and very likely to be well separated by ppm. Another common chiral derivitising agent is one of the enantiomers of menthol.To determine the absolute stereochemistry of an unknown hydroxyl stereocentre, you need a compound which is already of high enantiomeric excess. This technique is good for structural determination of new natural products. First you split your sample of secondary alcohol and separately react a portion with each of the two enantiomerically pure Mosher acids (MTPA) using a coupling agent or via the acid chloride. This will generate two diastereomers of Mosher ester in separate flasks, and the 1H NMR spectrum should be obtained for both of them. These Mosher esters (MTPA derivatives) will have a major preferred conformation around the ester linkage. Pseudo-allylic strain (A1,3), as modelled by the Houk model, with mean the carbinol proton (C-H of the secondary alcohol stereocentre) will prefer to sit eclipsed to the carbonyl C=O bond. Furthermore, the trifluoromethyl group on the MTPA will prefer to sit antiperiplanar to the C-O “single” bond of the ester linkage due to a favourable molecular orbital interaction (hyperconjugation).Next you look at all the chemical shift (delta) values in each diastereomer separately for the equivalent peaks in the structures, and it will be found that there are some reasonably significant differences, particularly close to the unknown sterocentre. For each corresponding signal you then compute the difference between the chemical shifts (delta delta) conventionally as those found in the (S)-MTPA derivative minus those found in the (R)-MTPA derivative. Due to the major conformers of these molecules, the two R groups on the esters will sit either close in space to the phenyl or the methoxy group of the Mosher ester-based stereocentre. Any protons in the 1H NMR spectrum that sit close to the phenyl group will be shielded by being placed inside the ring current of the aromatic system. Comparatively, any proton sitting near in space to the methoxy group will be slightly deshielded (towards a higher ppm). Hence, whether or not the delta delta value is positive or negative will tell you which R group a certain signal belongs too, and hence determine the absolute stereochemistry of the original chiral secondary alcohol. It is best practice to get as many delta delta values determined as possible to reinforce your conclusion for the alcohol’s configuration.#chemistry #science #education
Sharpless Asymmetric Epoxidation (SAE) Casual Chemistry 2023-02-21 | Full video: youtu.be/yxcipaAT1-0A key reaction in asymmetric catalysis in Organic Chemistry explained, with transition state models, kinetic resolutions, and desymmetrisation.
They think its all Overman... It is now! - Organic Chemistry Retrosynthesis Casual Chemistry 2023-02-18 | Using asymmetric catalysis for the enantioselective synthesis of this chiral allylic amine, highlighting selectivity issues and rearrangement disconnections.CBS Reduction Explained:youtu.be/rv-dZ2qyAzMMore retrosynthesis videos:youtube.com/playlist?list=PLavaRHHaRimVhyZD79H8g08cfhxrZMcB1A discussion involving enantioselectivity in hydrogenations in asymmetric catalysis to form chiral amines from enamine intermediates. Why rhodium and ruthenium catalysis with DIPAMP and BINAP ligands, respectively, cannot solve this problem easily.This retrosynthesis uses a pericyclic sigmatropic rearrangement to simplify the disconnection approach. Specifically, the Overman rearrangement of an allylic alcohol to an allylic amine removes a regioselectivity issue in the synthesis. The Overman rearrangement is a type of [3,3]-sigmatropic rearrangement that can convert a trichloroacetimidate to the corresponding amide with faithful transfer of stereochemistry.Reframing this retrosynthesis as requiring disconnection of an allylic alcohol makes it much more easy as a problem in organic chemistry as there are many methods for making such a functional group enantioselectively. This video proposed the use of a CBS reduction, a cornerstone of asymmetric catalysis, to generate the chiral allylic alcohol in likely very high enantiomeric excess for the desired configuration at the stereogenic centre (chiral centre).The precursor for the CBS reductions – an alpha,beta-unsaturated ketone – can be easily synthesised by HWE olefination (Horner-Wadsworth-Emmons reaction), with probably a higher selectivity for the E (trans) geometry of the carbon-carbon double bond.The starting material requires a simple bromination of a meta-directing substituted benzene ring. Then the aryl bromide product can be made into the Grignard organometallic and converted to the soft cuprate ready for Michael addition (conjugate addition, 1,4-addition) at a soft electrophile.
Retrosynthesis with Aldols Casual Chemistry 2023-01-05 | A classical disconnection approach for a retrosynthesis of this molecule with a benzyl protecting group on a base-sensitive aldol product.More retrosynthesis videos available at this playlist:youtube.com/playlist?list=PLavaRHHaRimVhyZD79H8g08cfhxrZMcB1Retrosynthetic analysis identifies disconnection of the benzyl ether as a protecting group for the hydroxyl group of an aldol product. A Williamson ether synthesis is not possible to form this C-O bond due to a risk of retro-aldol fragmentation under strongly basic conditions. A more mild trichloroacetimidate reagent (TCA) can be used to benzylate under mild acidic conditions instead.The next disconnection will come from identifying a 1,3-difunctional relationship (1,3-diX) which is best formed by enolate chemistry using an aldol reaction. The lithium enolate formed by reaction of ethyl acetate with LDA is appropriate for this transformation.The aldehyde required for this aldol reaction also has a 1,3-difunctional relationship between the aldehyde carbonyl and an alkene. To use enolate chemistry and aldol reactions again, a functional group interconversion must be used. The alkene can be formed by elimination reaction from an alcohol. An E2 elimination reaction can be done by first converting the hydroxyl group into a tosylate leaving group, and then treating the tosylate species with a non-nucleophilic base such as potassium tert-butoxide (KOtBu).The final intermediate in the retrosynthesis can also be disconnected by aldol chemistry back to isobutyraldehyde. Isobutyraldehyde will be treated with a reversible base to cause the aldol self-reaction between the enolate and the aldehyde forms of this molecule, as nucleophile and electrophile, respectively.#organicchemistry #retrosynthesis #chemistry
Retrosynthesis with Hypervalent Iodine Casual Chemistry 2022-11-14 | Disconnecting this tricyclic ring molecule using hypervalent iodine reagents. Also showcasing Umpolung chemistry and the Diels-Alder reaction.Reference: Desymmetrisation of phenols by an asymmetric Stetter reaction (Rovis)J. Am. Chem. Soc. 2006, 128, 8, 2552–2553doi.org/10.1021/ja058337uThe cyclohexene ring can be targeted first in the retrosynthetic analysis of this molecule to give an electron-rich diene and electron-poor dienophile with the correct molecular orbital coefficients to lead to the required regioselectivity. The diastereoselectivity for the Diels-Alder reaction comes from going through the usual exo transition state.This leaves a 1,4-diX disconnection for the diketone, which can be achieved by Stetter reaction. A thiazolium salt catalyst can form a nucleophilic ylid when it is treated with a mild base. The nucleophile can attack the aldehyde intermediate in the retrosynthesis, and after a few proton transfers will form the Breslow intermediate, essentially an enamine generated in situ. The enamine is held right next to the alpha,beta-unsaturated ketones and so a Michael addition (conjugate addition) is easy to form the 6,5-fused ring system.The Michael acceptor intermediate can be made by dearomatisation of a phenol using PIDA (also known as BAIB or PhI(OAc)2 ). This hypervalent iodine reagent is a strong oxidising agent and makes the aromatic ring of the phenol electrophilic. When the benzene ring is attacked by a nucleophile, a new C=O double bond (carbonyl) is formed at the same time as the loss of two leaving groups in iodobenzene and an acetate anion.In the video, hypervalent iodine is also used for the oxidation of an alcohol to an aldehyde as the Dess-Martin oxidation. The mechanism for the oxidation of the alcohol by Dess-Martin periodinane (DMP) is given.#chemistry #organicchemistry #science
Staudinger Reactions - Bioothogonal before Click Chemistry Casual Chemistry 2022-11-07 | The original bioorthogonal chemistry using azides and their reaction phosphines to form aza-ylids, which can do bioconjugation reactions and other useful transformations in organic synthesis. The aza-ylid (aminophosphorane) generated can react directly with water in a hydrolysis reaction to give an amine product. The reduction of the azide to the amine under these conditions is mild and tolerant of many other functional groups, whereas a hydrogenation or borohydride reduction might not be. The only by-product it triphenylphosphine oxide which is inert, separable and provides a strong enthalpy driving force. The aza-ylid can also react with carbonyl functional groups. If it reacts with a ketone or an aldehyde, you make the imine product, that can be useful in general synthesis of nitrogen containing molecules, including heterocycles.#chemistry #organicchemistry #science
Stille Cross-Coupling Reaction Casual Chemistry 2022-10-15 | Organic chemistry reaction mechanism for the Stille cross-coupling reaction using palladium catalysis.My Chemistry Channel: www.youtube.com/c/CasualChemistry
Chichibabin Reaction Casual Chemistry 2022-10-15 | Organic chemistry reaction mechanism for converting a pyridine to a 2-aminopyridine by reaction with NaNH2.Heterocyclic Chemistry playlist: youtube.com/playlist?list=PLavaRHHaRimUCE5F83Ier19ksegJvJL7hMy Chemistry Channel: www.youtube.com/c/CasualChemistry
Retrosynthesis Casual Chemistry 2022-10-15 | Retrosynthesis and disconnections of this random molecule, using a Witting reaction, Michael addition and an epoxide.Retrosynthesis playlist: youtube.com/playlist?list=PLavaRHHaRimVhyZD79H8g08cfhxrZMcB1My Chemistry Channel: www.youtube.com/c/CasualChemistry
Fischer Indole Synthesis Casual Chemistry 2022-10-15 | Mechanism of the Fischer Indole Synthesis in Organic Chemistry.Heterocyclic Chemistry playlist: youtube.com/playlist?list=PLavaRHHaRimUCE5F83Ier19ksegJvJL7hMy Chemistry Channel: www.youtube.com/c/CasualChemistry
Asymmetric Organocatalysis - Proline Aldol Casual Chemistry 2022-10-15 | Full explanation of this reaction: youtu.be/bAF_hD04qrwNobel Prize in Chemistry 2021 won for this chemistry using asymmetric organocatalysis to do aldol reactions catalysed by proline.Nobel Prize in Chemistry playlist:youtube.com/playlist?list=PLavaRHHaRimUxm3ZH9fG9YMVvcshQrhcLMy Chemistry Channel: www.youtube.com/c/CasualChemistry
Drawing Glucose Casual Chemistry 2022-10-15 | Fischer projection, Haworth projections and cyclohexane chair projections for a (D)-glucose sugar molecule.My Chemistry Channel: www.youtube.com/c/CasualChemistry
Dess-Martin Oxidation Casual Chemistry 2022-10-15 | Organic Chemistry mechanism for the Dess-Martin OxidationMy Chemistry Channel: www.youtube.com/c/CasualChemistry
A Cycloalkyne for Click Chemistry - Nobel Prize 2022, Retrosynthesis Casual Chemistry 2022-10-07 | A special retrosynthesis connected to the 2022 Nobel Prize in Chemistry on Click Chemistry, won by Bertozzi, Meldal and Sharpless. This discussion uses a disconnection approach to analyse a strained cycloalkyne made by Bertozzi and her research group. The strained cycloalkyne can do a cycloaddition reaction with an azide to form a triazole without the need for a copper catalyst (or other metal catalyst). This type of strain-promoted Click Chemistry (SPAAC) is an example of bio-orthogonal chemistry, and can be used for bioconjugation when the azide is attached to a biological molecule.Reference: Discussion inspired by this paper by BertozziJ. Am. Chem. Soc. 2010, 132, 3688doi.org/10.1021/ja100014qMore uses of Click Chemistry using copper (CuAAC) in this video on making dyes for OLEDs and organic electronics: youtu.be/RqA4xQ4ujWIVideos on the 2021 Nobel Prize for Chemistry on asymmetric organocatalysis:youtu.be/bAF_hD04qrwyoutu.be/vQZ5U_Kxgq8Research by Sharpless that won him his other Nobel Prize in Chemistry in 2001 (Sharpless Asymmetric Epoxidation):youtu.be/rv-dZ2qyAzM#chemistry #nobelprize #nobelprize2022
Copper and Click Chemistry for OLEDs and Organic Electronics - Nobel Prize 2022, Retrosynthesis Casual Chemistry 2022-09-26 | Nobel Prize 2022: Organic Chemistry - Click Chemistry: Retrosynthetic analysis of this small molecule chromophore, a dye with push-pull functionality across its conjugated pi system.(CORRECTION: at 16:45, bottom-left corner of screen - the reagent should be NaOH, not LiAlH4)Discussion inspired by this reference:Eur. J. Org. Chem.2013, 5591doi.org/10.1002/ejoc.201300458Click Chemistry is also known as Bio-Orthogonal Chemistry. This type of Chemistry won the Nobel Prize in 2022 for Bertozzi, Meldel and Sharpless.This molecule is typical of a small molecule chromophore that could be investigated as part of a library of organic compounds in the development of organic electronics. For example, in organic light-emitting diodes (OLEDs) or organic solar cells (photovoltaics, OPVs). The push-pull arrangements of hetereocycles at the ends of this molecules will lead to molecular orbitals that are spatially distinct - with big differences in space for the bonding and antibonding orbitals. This allows rapid charge mobility in a semiconductor device made from a crystal of a compound such as this, that could be used as part of an OLED or organic solar cell based on small molecules.To adopt a molular retrosynthesis of this chromophore small molecule, click chemistry is used to assemble the two triazole motifs. This type of click chemistry uses copper to assist an azide alkyne cycloaddition (CuAAC) and favour the 1,4-triazole product isomer.The fluorene core is differentially halogenated using bromine and iodine to give chemoselectivity in two different Sonogashira reactions for sp-sp2 cross-coupling reaction. The alkynes involved are temporarily protected using silyl groups of different size by coupling on TMS-acetylene and TIPS-acetylene separately.The outer heterocycles - an aniline and a pyrimidine - are synthesised using traditional heterocyclic and aromatic chemistry. Competing reactivity is discussed, including the fact that the pyrimidine that bears an azide functional group can isomerise to a 10 pi aromatic bicyclic heterocycle, based on a tetrazole.#nobelprize #chemistry #physics
Disconnecting Dactylol - Retrosynthesis Casual Chemistry 2022-09-22 | Organic Chemistry: Diastereoselective retrosynthetic analysis of racemic dactylol, a terpenoid natural product.More retrosynthesis videos available here: youtube.com/playlist?list=PLavaRHHaRimVhyZD79H8g08cfhxrZMcB1If you enjoyed the video and want to know when new videos drop, please subscribe to my channel here: youtube.com/CasualChemistry?sub_confirmation=1Reference:Discussion inspired by this paper:J. Org. Chem. 1996, 61, 8746doi.org/10.1021/jo961600cThis bicyclic molecule has a tricky 8-membered ring to synthesise and also a not particularly favourable 8,5-trans ring junction. Medium-sized rings tend to be hard to synthesise as ring closure of a linear precursor is made by the fact that the product has transannular strain that can overturn the good enthalpy change of forming a new sigma bond. Also, the two ends find it hard to meet in the correct orientation for e.g. a substitution reaction as all the degrees of rotational freedom around the other sigma bonds means that there’s a large number of populated conformations that are not reactive for ring closure.Luckily, we can identify the alkene in the 8-membered ring as a key point for disconnection in the retrosynthesis. We can use a ring closing metathesis reaction to cleave through the C=C bond and leave us with two separate chains with new alkenes. Ring closing metathesis (RCM) is good at forming pretty much any ring size by this sort of this disconnection, easily up to 20-membered rings, and probably beyond, provided that the reaction conditions are dilute enough to prevent intermolecular reaction (polymerisation) and allow the intramolecular ring closure to occur at an acceptable rate of reaction.After this ring closing metathesis disconnection, we are left with a tertiary alcohol with three different substituents. These alcohol motifs are easily constructed using Grignard reagents acting as hard nucleophiles on carbonyls, here a ketone. The diastereoselectivity for the bottom face of the cyclopentanone ring will be largely controlled by the adjacent alpha stereocentre on steric grounds. That alkyl group, even though it is likely pseudo-equatorial, provides steric hindrance on the top face when compared to the back face which only has a hydrogen at this carbon atom. This leaves us with an substituted cyclopentanone with its groups arranged in an anti fashion. In this retrosynthesis, we are heading to the racemic product, so we just need to make the correct diastereomer next and not a specific enantiomer. As the Grignard addition to the ketone was diastereoselective, if we wanted to make a single enantiomer of the final natural product, we should try to make the next part of the retrosynthetic analysis enantioselective or enantiospecific.The anti alpha,beta substitution pattern on the cyclopentanone can be disconnected back to the unsaturated cyclopentenone. Addition of a methyl cuprate will add a methyl group to one face (50:50 top face to bottom face) as if a conjugate addition has occurred. This will leave an enolate product with an adjacent new stereocentre right next to the nucleophilic carbon centre. Hence if we don’t do a work up and instead add an electrophile to this enolate intermediate directly, the enolate will react as a nucleophile and pick up a new substituent on the opposite face to the initial methyl group that came from the cuprate organometallic. So we will always form the anti diastereomer from this type of chemistry.#chemistry #orgo #organicchemistry #ochem #synthesis #retrosynthesis #science #stem #education
Making a Polyene with Metals - Retrosynthesis Casual Chemistry 2022-09-20 | Organic Chemistry: Retrosynthesis of this polyene hydrocarbon exploiting symmetry and transition metal catalysis for the stereoselective formation of C-C bonds.This fully conjugated polyene has rotational symmetry about its centre. A powerful disconnection for dienes and more extended conjugated hydrocarbons is to use cross-coupling methodology that uses palladium catalysis to form bonds between two sp2 carbon centres – one that is bound to a leaving group (often a halogen such as bromine or iodine), and one that is bound to another cheaper metal (or semi-metal). These alkenyl bromides/iodides (vinyl bromides/iodides) react with palladium in the zero oxidation state by oxidative addition to form the alkenyl palladium(II) species – an organometallic. This palladium(II) species will perform a transmetallation with the stoichiometric alkenyl metal species, made using, for example, zinc, tin or boron. Reactions based on these metal species are, respectively, called a Negishi cross-coupling reaction, a Stille cross-coupling reaction, and a Suzuki cross-coupling reaction. After transmetallation, and possible precipitation of a salt (depending on the solvent used), both organic (carbon-based) fragments have been assembled on to a palladium(II) centre. Then a reductive elimination can occur to form a new C-C bond and joining the two sp2 carbon centres to form the central C-C bond of a diene. At the same time, the palladium is reduced back to the zero oxidation state – palladium(0) – which can cycle round and react with another alkenyl halide. Hence, the expensive palladium metal compounds used in this reaction can be used catalytically and it turns out with a low molar loading. This catalytic cross-coupling reaction is a very common technique in modern synthetic organic chemistry and has found great use in the pharmaceutical industry. Transition metal catalysis really is a cornerstone of synthesis and these reactions are an example of homogeneous catalysis in chemistry. The reactions are game-changers in organic chemistry.In this particular molecule’s retrosynthesis, both the alkenyl halide (vinyl halide) and alkenyl metal (vinyl metal) species can be disconnected back to a common precursor alkyne with a carbon-carbon triple bond. This is because you can exploit a carboalumination reaction to install both the required methyl groups, an E-geometry alkene (C=C double bond), and a terminal functional group at once. This reaction uses trimethylaluminium (AlMe3) to add across the alkyne in a stereoselectively syn fashion, and the reaction is catalysed by the zirconium-containing compound zirconocene dichloride, Cp2ZrCl2. This carboalumination reaction forms an alane as a new organometallic intermediate. This alane can be converted to both a more reliable organometallic for cross-coupling reaction, such as the organozinc for a Negishi coupling, but also to the vinyl halide by reaction with an electrophilic halogen source, for example elemental bromine (Br2) or iodine (I2).With the common intermediate in hand, it can be further disconnected by palladium-mediated cross-coupling reaction in a similar way. The one of the coupling partners needed for this cross-coupling can, in fact, be synthesised again by carboalumination reaction. In this video, I choose it to be the organometallic component, as the smaller coupling partner is quickly made as the vinyl halide.The other component of this intermediated can be made by another palladium-mediated cross-coupling. This time a Sonogashira reaction is appropriate for joining an sp2 carbon to an sp carbon. In this reaction, you do not need to make the organometallic separately – the cuprate can be formed in situ by treating the alkyne with copper iodide and triethylamine.The smaller alkyne needs to be synthesised now and this is simply and cheaply done by dehydration of beta-ionane, a very cheap terpene-type molecule found readily in nature. You should just buy this in and perform a dehydration, via the enolate, using an electrophilic phosphorus reagent or equivalent. This allows elimination reaction across an enolate’s C=C bond. Alternatively, you could make the beta-ionane by carbocation-mediated cyclisation of a linear precursor, in a biomimetic fashion.#chemistry #organicchemistry #orgo #ochem #retrosynthesis #synthesis #catalysis #stem #education #scienceReference: Discussion inspired by this synthesis of a similar polyene:F. Zeng, E. Negishi Org. Lett. 2001, 3, 719doi.org/10.1021/ol000384y
Jacobsen HKR - The best reaction in organic chemistry? Casual Chemistry 2022-09-12 | Excellent Catalyst, Excellent ee – Jacobsen HKR, Asymmetric Catalysis in Organic ChemistryTransition metal asymmetric catalysis to resolve a racemic mixture of terminal epoxides by reaction, due to diastereomeric transition states leading to differences in rates of reaction.References:J. Am. Chem. Soc. 2002, 124, 1307doi.org/10.1021/ja016737lJ. Am. Chem. Soc. 2004, 126, 1360doi.org/10.1021/ja038590zAcc. Chem. Res. 2000, 33, 421doi.org/10.1021/ar960061vJACS 2009, 131, 4172doi.org/10.1021/ja806151gThis is a truly excellent method for making hydroxyl stereocentre in high enantiomeric excess (ee) using asymmetric transition metal catalysis. The Jacobsen Hydrolytic Kinetic Resolution (HKR) takes a racemic, and importantly, terminal epoxide and opens it up in the least sterically hindered terminal position (primary centre vs. secondary centre). Using a chiral Lewis acid to activate the electrophile means that one of the enantiomers as part of the racemic mixture will bind more effectively to the catalyst, and react much more quickly than the other. Using water as a nucleophile will lead to the enantio-enriched diol and also the (oppositely configured) enantio-enriched epoxide left behind. These are very easily separable by standard flash column chromatography. It is also possible to use this method to install other nucleophiles such as azides.The asymmetric catalyst used in these reactions is a chiral cobalt salen complex, for which both enantiomers are readily available.Depending on what you require in your synthesis, you might want to vary the stoichiometry of the experiment that you use. If the enantiomeric excess of the epoxide left behind is your priority – add a little more than 0.5 equivalents of nucleophile. The reverse if you require the epoxide-opened product as your priority for ee. In either scenario you make a sacrifice in yield in favour of enantiomeric excess, but if the Jacobsen HKR is an early step in your synthesis this is usually a good compromise. #chemistry #organicchemistry #orgo #ochem #synthesis #catalysis #stem #education #science
Rings and Retrosynthesis for this Natural Product - Organic Chemistry Casual Chemistry 2022-09-11 | A classical disconnection approach to the retrosynthesis of racemic mesembrine, showcasing an intramolecular Mannich reaction, enolate chemistry, Michael additions and decarboxylation strategies.#chemistry #organicchemistry #orgo #ochem #education #science #stem #This natural product has a 6,5-cis ring fused structure which contains a ketone, a tertiary amine and a quaternary all-carbon stereocentre. Analysis of the functional group relationships indicates a 1,3-diX difunctionalised setup, which can be disconnected using enolate chemistry – in this case as an intramolecular Mannich reaction. This leads back to a 1,5-diX system which are easily synthesised using conjugate addition (Michael addition) of an enamine on to an enone (alpha,beta-unsaturated ketone). This reactivity is matched as both the intended nucleophile and electrophile are soft. The Michael acceptor needed is methylvinylketone (MVK) which is cheap and readily available.The substituted enamine can be constructed by elimination of water from a tertiary alcohol. Tertiary alcohols are simply synthesised from the addition of Grignard reagents to ketones. This approach will work well for this molecule as E1 is favourable when the product is treated with acid, based on good carbocation stabilisation. The Grignard reagent here can be made from 1,2-dimethoxybenzene, doing some standard aromatic chemistry for bromination (Br2, FeBr3), and then final metalation by treatment of the aryl bromide with magnesium metal.The Grignard reagent will be added to the pyrrolidone, which can be made by functional group interconversion to the beta-keto ester, by installation of a temporary extra ester functional group – this can be removed by decarboxylation later. A number of other strategies are explored for synthesis of the pyrrolidone that won’t be easy in practice. These strategies involves cleavage of the carbon-heteroatom (C-N) bond and ring closure. These ring closures should be assessed by Baldwin’s Rules to check if they are favourable (5-exo-trig is favourable, 5-endo-trig is not favourable). The C-N disconnections also go back to small molecules with a few too many reactive functional groups that would make control in reactions tricky due to chemoselectivity problems.References for related total synthesis/work:J. Am. Chem. Soc. 1933, 55, 1233doi.org/10.1021/ja01330a065Tet. Lett. 1968, 9, 1441doi.org/10.1016/S0040-4039(01)98974-9
Retrosynthesis 12, PKI-166 - Organic Chemistry Casual Chemistry 2022-09-02 | Retrosynthetic analysis of PKI-166 – a EGFR tyrosine kinase inhibitor that inhibits pancreatic cancers. The retrosynthesis uses a cheap chiral pool starting material and involves the construction of the bicyclic nitrogen heterocycle from scratch.#orgo #organicchemistry #ochem #synthesis #scienceThe retrosynthesis begins by separation of the aromatic component of the molecule from the single stereocentre at the C-N bond. This disconnection is sensible as an amine can be attached to an aromatic ring when it acts as the nucleophile in an SNAr substitution reaction. The amine nucleophile is actually cheap and readily available from the chiral pool as 1-phenylethylamine. 1-Phenylethylamine is obtained as a single enantiomer by chiral resolution with L-malic acid, which occurs naturally as part of the citric acid cycle and the Calvin cycle in biochemistry. A racemic mixture of 1-phenylethylamine is first synthesised from the reductive amination of acetophenone with ammonia. When this racemic mixture is treated with the single enantiomer of malic acid, two diastereomeric salts form. The salt formed with D-1-phenylethylamine crystallises out of solution, whereas the salt formed with L-1-phenylethylamine stays in solution allowing for easy physical separation. The malic acid salts can then be treated with a base to return the free amine and the malic acid resolving agent washed away. Single enantiomers of 1-phenylethylamine are themselves used frequently in organic synthesis as chiral resolving agents (for other chiral resolutions).Turning to the nitrogen heterocycle, we can envisage creating each half – the pyrrole-like half and the pyridone-like half – separately by ring closing reactions. Firstly, the aryl chloride required for the SNAr substitution with 1-phenylethylamine must be disconnected first as it is reactive. These 2-chloropyridine type structures can be easily constructed from the parent pyridone using a deoxygenating reagent, such as phosphoryl chloride (POCl3). The 6-membered ring part of this nitrogen heterocycle can be disconnected between the two nitrogens and extracting the carbon which is of the same oxidation level of an amide. The bonding pattern can therefore be constructed by condensing a reagent such as formamide (HCONH2) or methyl formate (HCOOMe) between two nitrogen centres. This disconnection leaves behind a trisubstituted pyrrole (2,4,5-substituted). This type of pyrrole ring can be synthesised from a variety of methods exploiting either the inherent reactivity of the pyrrole heterocycle or by de novo construction of the aromatic heterocycle from a linear precursor, which is proposed in this video.When the pyrrole ring is disconnected between the 1- (N) and 2-positions, the linear precursor for cyclisation will be a 1,4-diX (1,4-difunctionalised) carbonyl species, which will form the 5-membered heterocycle. 1,4-diX compounds are often synthesised by using Umpolung chemistry (reversed polarity). One possible option would be to use an alpha-halocarbonyl reagent that incorporates the C2 and C3 from the target pyrrole, and target it’s soft electrophilic centre with a soft nucleophile. An appropriate soft nucleophile would be based on a 1,3-dicarbonyl species (based on a malonate) which would also bring in the correct oxidation levels at both C5 and the branched position coming off C4. An anion of a 1,3-dicarbonyl species would form the soft nucleophile at the position that would become the C4 position in the target pyrrole.The alpha-halo carbonyl required for the Umpolung chemistry above can be simply constructed by monobromination, for example, of the 4’-methoxy-acetophenone (4-acetylanisole). This is compound is pretty cheap in itself, but could be synthesised by Friedel-Crafts acylation of anisole. The standard nucleophilic reactivity of a benzene ring bearing a pi electron donating group would ensure that the major product of such a Friedel-Crafts acylation would be substitution in the para position.
Pericyclic Reactions: Electrocyclisations. How to Use Woodward-Hoffmann Rules in Organic Chemistry 2 Casual Chemistry 2022-08-31 | How to use the Woodward-Hoffmann Rules to determine if a pericyclic electrocyclisation reaction is proceeds in a disrotatory or conrotatory fashion under either thermal or photochemical conditions.Complementary Video - Part 1: Cycloadditionsyoutu.be/o9ldD5FEiDkCitation for Nicolaou Endiandric Acid Synthesis: Nioloaou, KC et al. J. Am. Chem. Soc. 1982, 104, 20, 5560–5562doi.org/10.1021/ja00384a080#organicchemistry #ochem #chemistry #stem #science #educationPericyclic electrocyclisation reactions can be identified as a distinct class of pericyclic reaction. During a ring-closing mechanism, one sigma bond is formed between two ends of a single longer conjugated pi-system and there is an overall shortening of the total pi-system in the product when compared to the starting material. Electrocyclic ring-opening mechanisms are also possible as the exact reverse of the ring-closing process. Forming one new sigma bond in a ring-closing is often the thermodynamic driving force (enthalpy mainly) for these mechanisms – for example a carbon-carbon sigma bond is normally stronger than the energy lost by shortening a conjugated system. However, if this results in ring strain or a weak sigma bond, the reverse ring-opening process is favoured.The Woodward-Hoffmann Rules were developed as a quick way for organic chemists to rationalise experimental observations and make predictions about pericyclic reactions. The Woodward-Hoffmann Rules have their basis in quantum mechanics and molecular orbital theory (MO theory) and are concerned with analysing the whole set of molecular orbitals associated with a fully conjugated pi system. The Woodward-Hoffmann Rules are a summary of the results obtained by setting up correlation diagrams that track molecular orbital symmetry conservation in a reaction as a reactant is converted into a product via a transition state. All electrocyclisations are allowed, but depending on the reaction conditions – either thermal or photochemical – the reaction proceeds either in a disrotatory or conrotatory fashion. This has important consequences on the stereochemistry of a product of a pericyclic electrocyclization and hence these reactions can be used to install otherwise complicated stereochemistry on demand by careful choice of conditions. Firstly a three-dimensional diagram should be drawn to analyse a specific electrocyclisation. The pi system involved should be identified and labelled with the number of electrons that it contains. It is conventional to add pi or sigma qualifiers as subscripts to the left of the electron count.It is sensible to work with as few defined pi systems as possible to simplify the Woodward-Hoffmann analysis. This is done by remembering to recognise that adjacent pi bond, lone pairs and/or empty p-orbitals are considered to be conjugated, forming one larger delocalised molecular orbital system, which usually provides a setup for the electrons to lower their total combined energy. In analysing pericyclic electrocyclisations, it is usually possible to analyse using the Woodward-Hoffmann rules an arrangement with only a single pi system for ring closure. Proving how the ring closure works means that a ring opening mechanism must proceed via the same disrotatory or conrotatory mode. With one sysyem being considered, the single pi component is then assigned as suprafacial or antarafacial depending on what the conditions require to as part of the Woodward-Hoffmann rules.The Woodward-Hoffmann Rules tell you that: if you count the number of suprafacial components with 4n+2 electrons (where n is an integer) and add that number to antarafacial components with 4n electrons, then the reaction will be thermally allowed when the total sum is an odd number. If the sum is an even number, the reaction is only possible/allowed under photochemical reaction conditions and will not proceed if only heated. This video on pericyclic reactions involves a retrosynthesis using both a cycloaddition (Diels-Alder) and two electrocyclization reactions to form a natural product with a cage structure. These reactions in total synthesis are showcased in the Nicolao synthesis of Endiandric acid A in 1982. The retrosynthesis begins by identification of two cyclohexenes. Disconnection of one of these cyclohexenes by Diels-Alder reaction (pericyclic [4+2] cycloaddition) leads back to two dienes, one of which is inside a 6-membered ring. This cyclohexene can then be disconnected by electrocyclisation to a triene, breaking open a the cyclobutene motif. The correct stereochemistry is attained by doing this under thermal conditions so the process is disrotatory. The triene in a 8-membered ring can also be made by electrocyclisation, also under thermal conditions, to ensure a conrotatory process.
Ultimate Guide to the Felkin-Anh Model - Organic Chemistry Casual Chemistry 2022-04-11 | 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.#chemistry #organicchemistry #orgo #ochem #science #education #stem #stemeducation Reference:Total Synthesis of (-)-Preswinholide A; I Paterson, et al.J. Am. Chem. Soc. 1994, 116, 6, 2615–2616doi.org/10.1021/ja00085a050The 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. .
Retrosynthesis 11 - Organic Chemistry Casual Chemistry 2022-03-23 | Retrosynthesis in organic chemistry, showcasing partial alkyne reduction, Diels-Alder reaction, and aldehyde homologation.#organicchemistry #chemistry #orgo #ochem #science #stem #educationThe retrosynthetic analysis of this molecule starts by analysing the functional groups present. The acidic proton on the primary alcohol hydroxyl group will need a protecting group, perhaps as a silyl ether. The cis alkene can be synthesised by partial reduction of an alkyne by Lindlar reduction – a hydrogenation reaction with a poisoned catalyst. The alkyne is a useful intermediate as it can be used as a good nucleophile when an unfunctionalized alkyne is deprotonated. The anion of an alkyne is easy to deprotonate, with a proton of pKa around 25, and is also a good nucleophile as it is not sterically hindered. In this molecule, a hydroxyl protected butynol can be deprotonated and used as a nucleophile for an aldehyde to comprise of the other half of the molecule.The aldehyde component also contains a cyclohexene motif, which is a classic disconnection pattern for a Diels-Alder reaction. A Diels-Alder reaction is a pericyclic cycloaddition that could be done here with butadiene, but the reaction also requires a dienophile with and electron-withdrawing group directly attached. At first sight, we cannot the aldehyde carbonyl is too far away from the C=C alkene bond, being unconjugated. However, in a retrosynthesis, we could simply disconnect with a homologation reaction. A homologation reaction is one that increases a carbon chain length to the next member of a homologous series in organic chemistry. In this case, we need to add a methylene unit (CH2), and an aldehyde can be homologated by Wittig reaction with a specific ylid. This ylid is methoxymethylenetriphenylphosphine (Ph3P=CH(OMe)), which can be prepared by P-alkylation of triphenylphoshine, and subsequent deprotonation of the phosphonium salt to the ylid by LDA, for example. This reaction forms an enol ether product and this product can be revealed as the homologated aldehyde on further reaction with aqueous acid.
Pericyclic Reactions: Cycloadditions - How to Use Woodward-Hoffmann Rules in Organic Chemistry 1 Casual Chemistry 2022-03-11 | How to use the Woodward-Hoffmann Rules to determine if a pericyclic cycloaddition reaction is allowed under either thermal or photochemical conditions.#organicchemistry #ochem #orgo #chemistry #stem #science #education Pericyclic cycloaddition reactions can be identified as a distinct class of pericyclic reaction. During the reaction mechanism, two sigma bonds are formed between two separate pi-bonded components simultaneously and there is an overall shortening of the total pi-system in the product when compared to the starting material(s). Forming two sigma bonds in this way, more often than not, is a strong thermodynamic driving force (enthalpy mainly) for these pericyclic steps.To determine if a specific cycloaddition reaction is allowed by the symmetry of its molecular orbitals under given conditions, the Woodward-Hoffmann Rules were developed as a quick way for organic chemists to rationalise experimental observations and predictions. The Woodward-Hoffmann Rules have their basis in quantum mechanics and molecular orbital theory (MO theory) and, in cycloadditions, are concerned with analysing the whole set of molecular orbitals associated with a full pi system, including (frequently) conjugated ones. The Woodward-Hoffmann Rules are a summary of the results obtained by setting up correlation diagrams that track molecular orbital symmetry conservation in a reaction as a reactant is converted into a product via a transition state. A pericyclic reaction will be symmetry forbidden if the molecular orbital symmetry is not conserved, and this is a result of a large activation energy barrier. Firstly a three-dimensional diagram should be drawn to analyse a specific cycloaddition. A diagram like this defines the molecular orbital overlaps between the pi systems that will become the sigma bonds. The pi systems involved should be identified and labelled with the number of electrons that they contain. It is conventional to add pi or sigma qualifiers as subscripts to the left of the electron count.It is sensible to work with as few defined pi systems as possible to simplify the Woodward-Hoffmann analysis. This is done by remembering to recognise that adjacent pi bond, lone pairs and/or empty p-orbitals are considered to be conjugated, forming one larger delocalised molecular orbital system, which usually provides a setup for the electrons to lower their total combined energy. In cycloadditions, it is usually possible to analyse using the Woodward-Hoffmann rules an arrangement as two larger components interacting at each end. Hence the two sigma bonds that form so all the work for us in defining the facial requirements for the molecular orbitals that must be interacting for the reaction in question. The two components are then assigned as suprafacial or antarafacial depending on each component’s overlap requirement.The Woodward-Hoffmann Rules tell you that: if you count the number of suprafacial components with 4n+2 electrons (where n is an integer) and add that number to antarafacial components with 4n electrons, then the reaction will be thermally allowed when the total sum is an odd number. If the sum is an even number, the reaction is only possible/allowed under photochemical reaction conditions and will not proceed if only heated. Photochemical reactions are performed in the laboratory usually with an ultraviolet light source.
Retrosynthesis 10 - Organic Chemistry Casual Chemistry 2022-03-06 | Retrosynthetic analysis of a substituted caprolactam, highlighting the Beckmann rearrangement, Michael addition, and protecting group chemistry using the THP group.#chemistry #organicchemistry #orgo #synthesis #ochem #retrosynthesis #stem #education #scienceThe 7-membered ring in this molecule can be a challenging motif to synthesise by conventional ring closing synthetic strategies, for example here an intramolecular amidation, as transannular strain disfavours the reactive conformation in such systems. However, this 7-membered ring cyclic amide – also known as a lactam, specifically here a caprolactam – can be made by a rearrangement reaction that can expand a 6-membered ring cyclic ketone into the required amide. The Beckmann rearrangement is a reaction sequence in which a ketone is transformed into the corresponding oxime by condensation with hydroxylamine. It is important that there is some stereoselectivity achieved in this condensation reaction on the C=N double bond and, given reversibility in the mechanism, some steric differentiation between the two sides of the parent carbonyl is required. The oxime has a weak N-O sigma bond which contributes to the driving force for the Beckmann rearrangement. When the oxime is treating with strong acid or when the hydroxyl group is converted into a good leaving group such as a tosylate, the alkyl group that is antiperiplanar across the C=N double bond is able to migrate (1,2-migration) leaving a carbocation behind on the carbon that was originally part of the parent carbonyl. This carbocation is quickly trapped by water and then tautomerises to the much more stable amide functional group. Hence the thermodynamically tricky 7-membered ring is constructed by a ring expansion method not reliant on the rules for ring closure.The 6-membered ring ketone intermediate has two branching points on either side, one alpha and one beta, which are good points for further disconnections. The ethyl group in the alpha position can be installed by enolate alkylation by, for example, generating the lithium enolate by reaction with LDA (LiNiPr2) at –78°C and performing an SN2 reaction with bromoethane (ethyl bromide). The branch point with an alkyne in the beta position can be synthesised by Michael addition (conjugate addition) of an acetylide type nucleophile, the deprotonated alkyne being made softer by the use of a Cu(I) catalyst. A hydrogen directly attached to an alkyne triple bond is rather acidic, pKa 25 ish, and so is deprotonated by a base such as NaNH2 or BuLi more simply than you might expect for something that generates a carbanion. The carbanion is in an sp-hybridised molecular orbital which has 50% s-character and is quite low in energy as a result.The alkyne nucleophile used has a protected alcohol functional group using the THP protecting group, which itself is a reasonably stable acetal due to the anomeric effect. The starting material for the synthesis is therefore propargyl alcohol which is cheap and readily available. The THP protecting group (tetrahydropyran acetal) can be installed by reacting the free hydroxyl group with DHP (dihydropyran) in the presence of an acid catalyst. The enol ether functional group in DHP is, in equilibrium, converted to the oxycarbenium ion that is then trapped by the alcohol.
