CASUAL CHEMISTRY

Excellent Catalyst, Excellent ee – Jacobsen HKR, Asymmetric Catalysis in Organic Chemistry *** This is version 2 of this video with a full description of the transition state. The old version can be found here: https://youtu.be/uWdkhNBgCS4 *** Transition 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, 1307 https://doi.org/10.1021/ja016737l J. Am. Chem. Soc. 2004, 126, 1360 https://doi.org/10.1021/ja038590z Acc. Chem. Res. 2000, 33, 421 https://doi.org/10.1021/ar960061v JACS 2009, 131, 4172 https://doi.org/10.1021/ja806151g This 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

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, 1233 https://doi.org/10.1021/ja01330a065 Tet. Lett. 1968, 9, 1441 https://doi.org/10.1016/S0040-4039(01)98974-9

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 #science The 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.

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: Cycloadditions https://youtu.be/o9ldD5FEiDk Citation for Nicolaou Endiandric Acid Synthesis: Nioloaou, KC et al. J. Am. Chem. Soc. 1982, 104, 20, 5560–5562 https://doi.org/10.1021/ja00384a080 #organicchemistry #ochem #chemistry #stem #science #education Pericyclic 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.

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, 2615–2616 https://doi.org/10.1021/ja00085a050 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.

Retrosynthesis in organic chemistry, showcasing partial alkyne reduction, Diels-Alder reaction, and aldehyde homologation. #organicchemistry #chemistry #orgo #ochem #science #stem #education The 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.

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.

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 #science The 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.

Explaining more of the science behind the Nobel Prize for Chemistry in 2021 on asymmetric organocatalysis, won by Prof. Benjamin List and Prof. David MacMillan. This video focuses on the use of imidazolidinone catalysts in Diels-Alder reactions that give high enantioselectivity for these cycloadditions (MacMillan). These transformations evolved the organic chemistry techniques that had previously been studied using transition metal catalysis as Lewis acids that can carry chiral ligands. More Nobel Prize 2021 Chemistry: Proline catalysed aldol reactions (List) https://youtu.be/bAF_hD04qrw See also for use of chiral Lewis acids for enantioselective/asymmetric catalysis (CBS reduction): https://youtu.be/rv-dZ2qyAzM #chemistry #nobelprize #chemnobel #organicchemistry #orgo #ochem #science #stem #organocatalysis For control in Diels-Alder reactions, it is required that a dienophile with an electron-withdrawing group attached is used in reaction with a diene. This is to assist in molecular orbital energy matching and preventing over-reaction. The electron-withdrawing group is most effective it is part of a pi system that can conjugate effectively with the dienophile pi system, and so lower its LUMO in energy (LUMO = lowest energy molecular orbital). Cycloaddition reactions then proceed in a smooth and predictable way in high diastereoselectivity. These reactions tend to proceed via an endo transition state, rather than an exo transition state, as this one is relatively lower in energy due to additional secondary orbital interactions – a pi stacking interaction between an electron-rich pi system and an electron-poor pi system. The LUMO of the dienophile can be further lowered in energy by coordination of this electron-withdrawing group to a Lewis acid. The Lewis acid can be used as a catalyst and could be based on either a main group element or a transition metal. Both of these options allow a chiral Lewis acid to be used by embedding an electron-deficient element (such as boron) in a chiral molecule or by employing designed chiral ligand specific for a metal centre and its preferred coordination geometry. If you ensure that the chiral Lewis acid structure is as one enantiomer, you can induce enantioselectivity into your Diels-Alder reaction as the chiral catalyst will be held close to the reacting centres in the transition state for the cycloaddition. To introduce organocatalysis into the Diels-Alder reaction, it was recognised that you could turn a pi-conjugating electron-withdrawing group on a dienophile such as an aldehyde into an iminium ion which would drastically lower the LUMO energy of the dienophile’s pi system, not least that an iminium ion bears a full positive charge. If the iminium ion is made from a secondary amine that is chiral and has sufficient steric bulk to restrict conformation of molecules, chiral information can be brought very close to the reacting centres in the Diels-Alder transition state. As the iminium ion system lowers the LUMO energy of the dienophile so much, when it is formed the Diels-Alder reaction will be a lot faster than the equivalent reaction with the parent aldehyde-bearing dienophile, and so it is possible to use a secondary amine as an organocatalyst. Pyrollidine has long been used for forming both iminium ions and enamines in organic chemistry for tempering reactivity for selective reactions. The imidazolidinone catalysts developed by the MacMillan group are an evolution of the same idea using an amine catalyst based on a five-membered ring. It is possible to make imidazolidinone ring systems relatively easily from parent amino acids and the first generation catalysts developed for the asymmetric organocatalysis of the Diels-Alder reaction were derived from phenylalanine. Further work by MacMillan and other groups explored how to optimised this type of asymmetric organocatalysis for higher enantioselectivity and yields, but also explored how the same key transition state structure and reactive intermediate could be used in many other nucleophile/electrophile chemistry, such as asymmetric Michael additions and Friedel-Crafts reactions. The organic chemistry in this video explains some of the early successes in this widely expanded area of asymmetric organocatalysis since the turn of the millennium. Small molecule organic catalysts, particularly chiral ones in high optical purity (high ee), tend to be much cheaper and environmentally friendly when compared to their transition metal counterparts and equivalents. The environmental factors have attracted attention in identifying asymmetric organocatalysis as a field of study that has big applications in green chemistry largely as the need to dispose of often toxic and/or environmentally destructive metal waste is completely removed from any synthesis. Additionally, the organocatalysts can often be separated easily from reaction products and recycled whereas transition metal catalysts are often destroyed in work-up.

Retrosynthetic analysis of a spirocyclic unsaturated ketone to showcase 1,6-diX disconnections and the pinacol rearrangement as synthesis strategies in organic chemistry. More retrosynthesis videos here: https://www.youtube.com/watch?v=lD02HC4h6yw&list=PLavaRHHaRimVhyZD79H8g08cfhxrZMcB1 #chemistry #organicchemistry #orgo #ochem #stemeducation #education #science #stem #synthesis The molecule has an alpha beta unsaturated ketone (enone) and an all carbon quaternary centre as a spiro centre joining two five-membered rings. The enone is the ketone functionality in the middle of the molecule, making it a good choice for a first disconnection in any retrosynthesis. Enones are often most easily constructed by some type of aldol reaction/condensation or by Wittig type chemistry. Here, as the disconnection across the C=C double bond does not break the whole molecule into two pieces, an intramolecular aldol condensation is very easy to set up using the general selectivity of ring closures for 5-membered rings over 7-membered rings. The aldehyde component is also usefully non-enolisable in this proposed intermediate. This intramolecular aldol condensation should proceed smoothly by the use of an equilibrating base such as sodium ethoxide (NaOEt). The next intermediate in the retrosynthesis displays two carbonyl groups in a 1,6 relationship, and a standard disconnection approach for such a 1,6-diX system is to perform a reconnection – as in deliberately reform a 6-membered ring. Here, reconnection to an alkene is sensible as it could be oxidatively cleaved easily using ozonolysis to return the required carbonyl groups if a neutral work-up is used to break down the intermediate ozonide. Alkenes can be formed by elimination reaction (E1 or E2) and so a functional group interconversion (FGI) is used as the next disconnection back to a tosylate, derived from its parent alcohol. There is a regioselectivity concern here depending on which of the carbon atoms the tosylate/hydroxyl group is installed. In one case, there are three possible eleimination products and the most likely one, by both E1 mechanism or E2 mechanism, is not the desired one, but one where the C=C double bond ends up in conjugation with a phenyl substituent. Installing the hydroxyl group adjacent to the spiro centre prevents these issues entirely. Next, a functional group interconversion is performed on the alcohol to give the more versatile ketone. The alpha branching of this ketone, particularly as it’s coming off a ring, is a good clue to take the next disconnection as an alkylation to disconnect off the benzyl group. This alkylation reaction would be easily performed by using the lithium enolate (formed by using LDA) and reacting it with benzyl bromide to do an SN2 reaction (substitution reaction). Finally the spirocyclic ketone is perfectly set up as the product of a pinacol rearrangement of a diol derived from the radical coupling of cyclopentanone. Cyclopentanone is reacted with magnesium metal, which can react to transfer single electrons to the carbonyl groups and affect a reduction mechanism. As the magnesium has two readily transferable electrons for reduction, and the fact that Mg2+ as an ion is great at coordinating to oxygen, two singly reduced cyclopentanone molecules are held in close proximity and the carbinol radicals can couple to form a new C-C bond, and hence a diol on work-up. Treatment of this diol with strong acid and heat makes one of the hydroxyl groups into a group leaving group on a tertiary carbon. Rather than forming explicitly a high energy tertiary carbocation, it is observed that one of the adjacent alkyl groups migrates first as the resulting oxycarbenium ion is much more stable (essentially can be seen as lone pair donation stabilisation of a carbocation).

Three named reactions in organic chemistry that are highly diastereoselective reductions of beta-hydroxyketones. This video discussed the synthetic chemistry aspects and the appropriate transition states for these kinetically controlled reactions. #chemistry #organicchemistry #orgo #ochem #science #stem #education #learn #synthesis #chiral #stereochemistry In complex molecule total synthesis, especially in polyketide total synthesis, it is reasonably easy to set a hydroxyl stereocentre in a specific configuration using nucleophile/electrophile organic chemistry. A really powerful C-C bond forming reaction in this context is the diastereoselective and/or enantioselective aldol reaction of enolate equivalents using, for example, soft enolisation conditions with boron Lewis acids, amongst many other options. These aldol reactions tend to be super reliable for yielding products with high stereoselectivity, and particularly well for those containing stereogenic secondardy alcohols in beta postions relative to a carbonyl group. The Narasaka reduction is a 1,3-syn diastereoselective reduction of a ketone which bears a hydroxyl group in the beta position. When you treat a beta-hydroxyketone with the bidentate Lewis acid Bu2BOMe, an activated complex forms that both activates the carbonyl group towards nucleophilic attack and ties the previously acyclic system into a cyclic six-membered ring intermediate. In its lowest energy conformation, this six-membered ring will exist as a half-chair with its biggest groups in pseudo-equatorial positions to minimise transannular steric strain. When an external hydride nucleophile, such as a borohydride (BH4-), attacks this half-chair based activated carbonyl (oxycarbenium ion) the lowest energy pathway (via the lowest energy transition state) will be the one going via a chair-like transition state, rather than the competing twist-boat-like transition state for the same lowest energy conformation. This preference will lead to high diastereoselectivity for the the 1,3-syn diol product. This is model is sometimes referred to as the Furst-Plattner rule. The next part of the video describes two types of 1,3-anti diastereoselective reductions - the Evans-Saksena reduction and the Evans-Tishchenko reduction. The Evans-Saksena reduction involves pre-coordination of an otherwise weak reducing agent, tetramethylammonium triacetoxyborohydride (Me4NBH(OAc)3), to the beta hydroxyl stereocentre, as the acetate groups act as good leaving groups. This coordination sets up an intramolecular reaction for hydride delivery that can occur with high levels of diastereoselectivity and modelled by a Zimmerman-Traxler transition state. Putting the larger alkyl groups into the pseudo-equatorial positions minimises 1,3-diaxial strain and means that the this conformation of transition state is the lowest in energy of the possible options. The Evans-Tishchenko reduction uses a similar idea for nucleophile tethering and intramolecular hydride delivery as the Evans-Saksena reduction, but in this case when the 1,3-anti relationship is set up between the two oxygen bearing stereocentres, the initially directing one beta to the ketone ends up furnished with an ester. The diastereoselective reduction uses samaroium diiodide (SmI2) traditionally in the presence of propionaldehyde (propanal, EtCHO) to set up a bound acetal group with the samarium acting as a Lewis acid. The reaction is very highly diastereoselective as the samarium can further chelate to the ketone that is to be reduced and activate it as a Lewis acid via a highly-ordered 6,6-bicyclic structure.

Retrosynthetic analysis of hydroxychloroquine using undergraduate-level organic chemistry ideas. Involves quinoline synthesis and an assessment of chemoselectivity issues from competing reactivity from multiple functional groups. #chemistry #organicchemistry #orgo #ochem #synthesis #hydroxychloroquine #science #education #stemeducation A first disconnection in the centre of the molecule by nucleophilic aromatic substitution (SNAr) splits hydroxychloroquine into an aromatic half and an aliphatic half. The aromatic quinoline ring system is electrophilic on the pyridine-like side and so all that’s required is an appropriately placed leaving group. A chloride can be installed from the hydroxyl group using POCl3. Consideration of the tautomeric form of the hydroxy quinoline as the “pyridone” form reveals the key disconnection for the construction of the quinoline directly from a substituted benzene ring. Doing a C-C disconnection here allows the natural nucleophilic reactivity of the starting material to set up a cyclisation reaction. Both the chloro and amino substituents direct to the same position, both being ortho/para directing groups by pi conjugation (using their lone pairs). Some functional group interconversions take this retrosynthesis back to nitrobenzene as a cheap, readily available starting material. The aliphatic fragment contains two amine functional groups and an alcohol. Care must be taken when assessing competing nucleophilic reactivity – in fact temporarily masking one of the amines as a nitro group and careful choice of protecting groups solves this problem surprisingly straightforwardly. The synthetic fragments has a 1,2-diX and a 1,4-diX functional group relationship. Splitting is up using a reductive amination as a standard disconnection separates out these two features. The 1,2-diX disconnection is easily address by using an epoxide (ethylene oxide/epoxyethane) as an electrophile for ethylamine as a nucleophile. The product alcohol’s hydroxy group is best protected at this stage, and I propose the use of a benzyl ether for this as it can be cleaved as at an appropriate moment using hydrogenation which can be done simultaneously with a nitroalkane reduction. The 1,4-diX functional group relationship is code for Umpolung chemistry, usually. Helpfully, a common Umpolung reagent in a nitroalkane is a really smart choice here as it brings in a nitrogen atom as well when its conjugate base is used as a soft d1 nucleophile for conjugate addition (Michael addition). At the end of the retrosynthetic analysis and discussion, I draw together a proposal for a forward synthesis of hydroxychloroquine. Although I am sure there are many valid alternative approaches to both the retrosynthesis and forward synthesis.

Another introductory video on enantioselective catalysis in Organic Chemistry. Here secondary ketones can be synthesised in high enantiomeric excess from the parent ketone by a CBS reduction reaction. Essentially the CBS reduction is a chiral version of the more familiar reagent sodium borohydride, NaBH4. #chemistry #organicchemistry #ochem #orgo #science #stem #education #learn #catalyst #catalysis #synthesis #molecule #stereochemistry The CBS reduction is one of the most reliable catalytic asymmetric transformations in organic chemistry. It take prochiral ketones and performs a nucleophilic hydride reduction with very high levels of enantioselectivity for the chiral secondary alcohol product, provided that there is good steric differentiation between the two groups attached to the carbonyl group. Products are easy to purify and are often synthesised in excellent enantiomeric excess (or diastereomeric ratio if applicable). This example of a catalytic reduction used Lewis acid and Lewis base activation of reagent and reactant is easy to perform in the lab and easy to work up and purify the product. The CBS catalyst itself has synthesised from the naturally occurring amino acid proline, which is available cheaply as either enantiomer from our natural world. Proline is first esterified and then the ester treated with a Grignard reagent to form an aminoalcohol. Coordination of a mono-alkyl boronic acid forms the key Lewis acid catalyst which consists of a 5,5-bicyclic ring structure, which has a convex face and a concave face. The prochiral ketone coordinates and is activated on the convex face. The nearby nitrogen atom is then free to act as a Lewis base on borane (BH3), activating it as a borohydride and hence also as a nucleophile or reducing agent. With this double activation, an intramolecular reaction for the reduction of the ketone is set up, and as it is intramolecular the reaction will proceed at a higher rate like this as opposed to any other possible intermolecular reaction. The intramolecular delivery of the hydride nucleophile occurs via a six-membered ring transition state. However, the lowest energy transition state is not a chair conformation as is common to reactions that are well-predicted by the Zinnerman-Traxler model. The CBS reduction transition state is a boat conformation, and so the lowest energy transition state places the largest substituent on the prochiral ketone reactant into the pseudo-equatorial position and out of the way of clashing sterically with any alkyl group on the catalyst itself.

An introduction to both transition metal catalysis and enantioselective catalysis in organic chemistry using the Sharpless Asymmetric Epoxidation. This reaction is one of the most reliable highly enantioselective transformations in organic chemistry and uses allylic alcohols as the substrate. There is generally high catalyst turnover and high yields for this reaction in many circumstances. This video will also introduce how the catalytic system can be used to perform a kinetic resolution of a racemic starting material and also to do desymmetrisation of achiral substrates with divinyl carbinols. #chemistry #organicchemistry #orgo #ochem #education #catalysis #catalyst #science #stem The Sharpless Asymmetric Epoxidation (SAE) extends the idea of pre-coordinating a peroxide type electrophile to molecules to impart facial selectivity for reaction. mCPBA can hydrogen bond to the hydroxyl groups of allylic alcohols to direct the reagent to one face in preference, which sets the stage for a diastereoselective transformation. A higher level of diastereoselectivity can be achieved using a vanadium complex, specifically vanadyl bis(acetylacetonoate), which can pre-coordinate and activate tert-butyl hydrogen peroxide as an oxidant. This system can also achieve limited levels of diastereoselectivity in the epoxidation of homoallylic alcohols. Hydroxamic acid chiral ligands were investigated extensively to attempt to boost this transition metal system from a diastereoselective set of conditions to an enantioselective set, but with only limited success on a restricted substrate scope. The breakthrough by the Sharpless Group came by switching the transition metal catalyst from vanadium to titanium. A rigid, dimeric, C2-symmetric pre-catalyst assembles with the bidendate dialkyltartrate ligands, both enantiomers of which are readily available and cheap. Hence, a reagent-controlled set of conditions was worked out for a reliable asymmetric epoxidation on a wide substrate scope of allylic alcohols. The epoxides formed in very high enantiomeric excess (e.e.) and are very versatile in synthesis as they can be further manipulated in many ways, a common one being to use a Payne rearrangement to shuttle the epoxide to a different location if required. The high levels of enantioselectivity observed when using the Sharpless Asymmetric Epoxidation means that it is often crowbarred into the early stages of complex, enantioselective synthesis even if epoxides and even oxygenation are not actually intended in the end. Setting initial stereocentres on custom molecules which are not directly from the chiral pool can be challenging to the organic chemist, but there are a large number of stereospecific reactions that can be used subsequently to faithfully install other functionality at stereogenic centres. If you use a chiral allylic alcohol (stereogenic centre at the hydroxyl group), you can use the Sharpless Asymmetric Epoxidation to do a kinetic resolution of a racemic starting material. This is when one enatiomer of allylic alcohol reacts faster than the other, so you can end up with a mixture of both an allylic alcohol and an epoxy alcohol in very high enantiomeric excess. These products are then separable by standard chromatography. The Sharpless Asymmetric Epoxidation is also very good at performing desymmetrisation reactions, where an achiral divinyl carbinol can be transformed into an epoxy alcohol in both very high enantiomeric excess and diastereomeric ratio. In the video, I explain how thinking through the kinetic factors involved here means that any formation of an undesired diastereomer is largely eliminated as itself is a great substrate for fast epoxidation, and so quickly reacts away to a bis-epoxide.

An introductory level video for retrosynthesis using 1,5-diX disconnections in organic chemistry. These disconnections often involved conjugate addition (Michael addition) using enamines or 1,3-dicarbonyl reagents. #chemistry #organicchemistry #orgo #retrosynthesis #synthesis #stem #stemeducation #science #molecule A cyclic ester (lactone) is used as an example in this video and so that functional group is a standard one for a first disconnection. There is branching alpha to the carbonyl group that would allow for an enolate alkylation type disconnection if there were a complicated substituent there – but in this example, there is just a methyl group which doesn’t add complexity later when choosing cheap and readily available starting materials. Opening the six-membered ring gives a 1,5-hydroxyester. The 1,5-diX functional group relationship lends itself to conjugate addition (Michael addition) chemistry. This is a soft reactivity for the nucleophile and electrophile pairing using an a3 synthon and a d2 synthon. A functional group interconversion (FGI) is useful for setting up the d2 synthon because enolate equivalents are generally versatile things to use as controlled nucleophiles. Here, an enamine is particularly useful for the key carbon-carbon bond forming reaction, taking us quickly back to cheap starting materials in methyl methacrylate and butanal. I also comment on some other useful reagents that come up when you encounter a 1,5-diX disconnection, and specifically when you have a 1,5-dicarbonyl system. These are 1,3-dicarbonyl reagents, that act as good soft nucleophiles and can then be quickly manipulated by decarboxylation to the usually intended reactive fragment required. This is a common technique in organic chemistry and synthesis in general.

An introduction to asymmetric catalysis, enantioselective reactions and asymmetric organocatalysis through a discussion of the proline catalysed aldol reaction. The video is pitched at an undergraduate chemistry level for those already familiar with general carbonyl reactivity in organic chemistry. 3D transition state models are used to show how certain enantiomers and/or diastereomers of organic products are formed selectively. #chemistry #organicchemistry #chemnobel #orgo #ochem #catalysis #stem #stemeducation #education #science #nobelprize #nobel2021 #nobelprize2021 #NobelPrize2021 #NobelPrizeChemistry2021 #NobelPrizeInChemistry2021 #NobelPrize #NobelPrize2020 #NobelPrize2021WinnersList A combination of kinetic control and thermodynamic control in organic chemistry means that you can use enamines in diastereoselective and enantioselective reactions. Using an enamine as an enolate equivalent allows it to act as a nucleophile alpha to the parent carbonyl group and with acid activation can be used to react with other carbonyls, such as aldehydes and ketones. The proline-catalysed aldol reactions was one of the first major steps to developing a general asymmetric (enantioselective) catalytic reaction for strategic bond formation, in this case a very useful carbon-carbon bond and up to two new stereogenic centres. Proline is a commonly occurring amino acid as both enantiomer in nature and so it is a very cheap catalyst to use. Its combination of functional groups of a secondary amine in a ring structure with restricted flexibility and a carboxylic acid mean that it is a bifunctional catalyst. It can both form an enamine with an aldehyde or a ketone, but also it carries with it an acidic proton that can be used to activate an electrophile for the new nucleophile to react with. More so than that, it can activate another carbonyl by hydrogen bonding and setting up an essentially intramolecular reaction via a 9-membered ring. That ring size does not have sufficient low energy specific conformations, but the presence of a well-placed nitrogen atom sets up a further hydrogen bond, and so essentially making a 6,5-bicyclic ring system for a reaction transition state. The lowest energy transition state will, as ever, be the one that minimises 1,3-diaxial interactions, resulting in a preference for big groups to be positioned in pseudo-equatorial arrangements. In the video, I explain how one of four possible stereoisomers of aldol product can be formed in preference to the others. I go on to show how other chemistry can be done by replacing the electrophile in the organised transition state. An enantioselective and diastereoselective Mannich reaction is also possible for creating a specific enantiomer of a 1,3-syn Mannich reaction product. You can also use nitroso compounds (such as PhNO) as oxygen-electrophiles, as the hydrogen bonding in the transition state is stronger with a nitrogen lone pair rather than with an oxygen lone pair. Hence, the normal electrophilic at nitrogen reactivity of nitroso compounds is not observed, and we have access to a mild and easy-to-handle oxygen electrophile without needing, for example, peracids or peroxides that will react easily with many other sensitive functional groups in both simple and complex molecules. The chemistry further extends to desymmetrisation reactions. I finish the video explaining an intramolecular diastereoselective desymmetrisation reaction using proline organocatalysis. This is the synthesis often called the Hajos–Parrish–Eder–Sauer–Wiechert reaction (or in some books just the Hajos–Parrish reaction), and is a classic example of early use of amino acids directly in both asymmetric catalysis in organic chemistry but also is one of the cornerstones of enantioselective organocatalysis.

Deriving a quantitative relationship to show how an equilibrium constant varies with temperature and so showing were Le Chatelier's Principle comes from in this context. Along the way, the Gibbs-Helmholtz van't Hoff equations are derived and used. My video for deriving the thermodynamics Master Equations: https://youtu.be/Fiafja2dWP0 #chemistry #physics #physicalchemistry #pchem #thermodynamics #energetics #science #stem #learn #science #stemeducation #undergraduate An equilibrium constant in chemistry is calculated from a formula (not proved here, future video perhaps) that comprised the multiplicative product of the concentrations of the reaction products (raised to their stoichiometric coefficients if appropriate) divided by the multiplicative product of the concentrations of the reactants (again raised to their stoichiometric coefficients if appropriate). All of these concentrations should be divided through by a relevant standard concentration (part of the mathematical derivation of what K actually is) and as such the equilibrium constant is always dimensionless. An equilibrium constant is always a specific value quoted for a specific temperature. This video explains how if you know what the equilibrium constant is for a certain temperature, you can work it our for a different temperature quantitatively (provided the other temperature that you're thinking of isn't massively far away from your quoted data book value). To get going with the thermodynamics, we need to use the definition of Gibbs energy for the reaction in question (as H-TS) as it is directly related to the enthalpy change and the entropy change for the reaction. The equation is also quite explicitly dependent on temperature. It is also well established (elsewhere) that the delta G (the change in Gibbs energy for a reaction/equilibrium) is equal to -RTlnK, where K is the equilibrium constant for the reaction. Both of these equations in combination show that there is a non-straightforward relationship between an equilibrium constant and the temperature that it is quoted at. To determine the mathematical relationship, we also need to use a thermodynamic Master Equation that tells us about infinitesimal changes in Gibbs energy (dG). A link to a video explaining how this is derived is at the top of this description). In the case of common chemical equilibria, they are known about in a constant pressure situation (dp = 0) and the energy changes associated with the reaction are described fully by an enthalpy change for a reaction. This simplifies the thermodynamic Master Equation going forwards. Now we consider a function: G/T, the Gibbs energy divided by temperature. Taking the derivative of this, using the product rule or the quotient rule in calculus, we can get a new expression into which we can substitute relationships for both the Gibbs energy and the derivative of the Gibbs energy with respect to temperature at constant pressure (a partial derivative). This cancels things down quickly to give the Gibbs-Helmholtz equation. It can be shown that this also holds, because of the rules of calculus, for "delta" changes such as the change in Gibbs energy for a reaction with respect to the enthalpy change of a reaction. Using the standard relationship that the standard change in Gibbs energy for a reaction equals -RTlnK, where K is the equilibrium constant, the Gibbs-Helmholtz equation can be converted into the van't Hoff equation (van't Hoff isochore) to give a direct relationship of the derivative of lnK with respect to temperature to the enthalpy change of a reaction. Qualitatively, this equation can be used to predict the effect of the change of temperature on an equilibrium composition (and equilibrium yield) as is commonly predicted by Le Chatelier's Principle, as is often learnt about in high school Chemistry. The final part of this video shows how you can use the van't Hoff equation in an experimental setting as it can relate to a gradient of straight line plots of specific data of equilibrium constants at different temperatures for a particular reaction. This data is often most easily obtained from electrochemical cell experiments. Plots of lnK versus 1/T, for example, will over modest temperature ranges give straight line graphs related to a specific reaction, from which the gradient can be used to calculate the enthalpy change for the reaction (delta H) and the "y-intercept" can be used to calculate the entropy change for the reaction (delta S).

A retrosythesis of this organic molecule using classic disconnection approach methods. The retrosynthetic analysis highlights some key strategies in organic synthesis and organic chemistry reactivity. #chemistry #organicchemistry #orgo #ochem #retrosynthesis The molecule has a fair amount of functionality and so a good first disconnection would be somewhere in the middle. For something simple to do as the last step in the forward synthesis, disconnecting the ester is a good place to start as that can be made from the corresponding acid chloride and a simple alcohol. The alcohol component is an example of a 1,2-difunctionalised compound (1,2-diX) and those can usually be easily synthesised by using epoxides. Here a simple SN2 reaction using an amine nucleophile on ethylene oxide (the epoxide, also known as epoxyethane). Next turning to the acid chloride half of the target molecule – some functional group interconversions can disconnect it back to a more easy to handle methyl ester. The alpha,beta unsaturated ester is easy to retrosynthesis back using either an aldol condensation or a Wittig type reaction for C=C double bond formation (olefination/alkenylation). Here, there is a simple bench-stable ylid (ylide) that can be used so a Wittig reaction looks simple here. This should also give the required E geometry of trisubstituted alkene. If the stereoselectivity wasn’t good enough, an HWE reaction (Horner-Wadsworth-Emmons reaction) would probably give better E selectivity and would use the corresponding beta ketophosphonate. The bicyclic ring system can be quickly formed by cycloaddition (a pericyclic reaction) and specifically here a Diels-Alder reaction. The Diels-Alder reaction is great for forming cyclohexenes but also require a dienophile component to have an appropriate electron withdrawing group attached to the C=C double bond. Careless disconnection would lead to suggesting using ketene with cyclopentadiene, but this does not fulfil the criterion of having an appropriately placed pi electron withdrawing group for LUMO lowering purposes. A functional group interconversion of the target ketone to a nitro (RNO2) functional group is a clever way to fix this problem. The nitro group is an electron withdrawing group that doesn’t contain any carbon atoms, and it can be converted into the ketone in the forward synthesis by Nef reaction. The Nef reaction would use reaction conditions such as titanium trichloride in water (TiCl3, H2O), although many other alternative reagents are available in organic chemistry for this transformation. So then the final Diels-Alder reaction disconnection is set up and this ends the retrosynthetic analysis. At the end of the video, I have proposed a forwards synthesis for assembling the pieces described above.

A retrosynthesis using classic disconnection approach ideas from organic chemistry work out how to make this target molecule. The key steps involve reductive amination, Friedel-Crafts acylation, and full carbonyl reduction. #chemistry #organicchemistry #orgo #ochem #retrosynthesis #synthesis The main functional group that this molecule has is an amine, which is a good place to start with making disconnections in a retrosynthetic analysis. The key reaction in organic chemistry that can be used is a reductive amination mechanism. This mechanism is when you do a condensation reaction between an amine and a carbonyl compound - a ketone or an aldehyde - to form an imine or inimium ion. In the presence of a suitable reducing agent, the imine or iminium ion can be reduced to an amine. The options would be to have something like sodium cyanoborohydride (NaBH3CN) added to a reaction flask while the imine condensation equilibrium is being set up. Alternatively, you could use dehydrating reaction conditions for the condensation, and then subsequently treat the imine with any hydride reducing agent or even hydrogenation conditions of hydrogen gas in combination with a metal catalyst. The next task in the retrosynthesis is to work out how to add substituents to the benzene ring. A good method for C-C bond formation in this context is to use a Friedel-Crafts acylation. Friedel-Crafts alkylation reactions are a bit unreliable due to possible carbocation rearrangements, but also impossible in this retrosynthesis as the reaction would have to go via a primary carbocation, which are not ever an observed intermediate in solution under organic chemistry lab conditions. The Friedel-Crafts acylation goes via an acylium ion intermediate instead. The final disconnections take this retrosynthesis back to anisole (methoxy-benzene), which has a good para-directing substituent for reactions of benzene with powerful electrophiles such as acylium ions. To key everything selective, a functional group interconversion is used in the retrosynthesis to install a carbonyl group (a ketone) to use as a strategic handle for reactivity. In the forward synthesis, this carbonyl can be completely removed by full reduction to the alkyl chain. Reactions that do this include the Clemmensen reduction (Zn, HCl) and the Wolff-Kishner reduction (NH2NH2, KOH), amongst many other possible alternatives. Using this disconnection means that succinic anhydride can be used in one of the Friedel-Crafts acylation reactions, instead of the usual acid chloride, and this is a cheap and readily available symmetrical starting material.

The curly arrow mechanism for acetal formation in organic chemistry presented with a commentary on reaction driving forces and organic chemistry experimental control ideas. #chemistry #orgo #organicchemistry #ochem The curly arrow mechanism starts by using an acid catalyst to protonate the carbonyl group, either an aldehyde or a ketone. This will activate the carbonyl towards nucleophilic attack – it is more electrophilic both because it is positively charged but also because the LUMO energy (carbonyl pi star MO) has been lowered in energy. Now methanol as a nucleophile can attack the activated carbonyl to form a hemiacetal. This is a reversible reaction. The rest of the mechanism requires a substitution reaction to replace the hydroxyl group with a methoxy substituent. This cannot proceed by SN2 reaction as the saturated carbon centre is very hindered. There is no access for a nucleophile to the sigma star MO that is required for the SN2 reaction – the substrate is equivalent to a tertiary haloalkane (halegenoalkane) where the other groups add a lot of steric hindrance to the attack trajectory. However, an SN1 reaction is actually very favourable here. When the hydroxyl group of the hemiacetal is protonated, it becomes a leaving group (water). If the water leaves as in the first step of an SN1 reaction, it leaves behind a relatively stable carbocation on a tertiary carbon centre. This carbocation is even more effectively stabilised by being next to an oxygen with available lone pairs. When the oxygen donates its lone pairs, essentially a new pi system is forming, and hence very favourable as an enthalpy change. This step forms an “oxycarbenium ion” which is also a good electrophile. Now another methanol nucleophile can come in and attack the oxycarbenium ion to form the protonated acetal product. Loss of that proton will be the final step in the curly arrow mechanism to get the product acetal. Hence, overall we only need a catalytic amount of acid in the reaction to get the process to go. All steps in the curly arrow mechanism are reversible, and so we have set up an equilibrium and the reaction is under thermodynamic control. Unfortunately, a quick qualitative consideration of the Gibbs free energy change for the reaction (delta G) shows that the position of equilibrium is likely over to the left, as in to the starting material side. So the chemist who wants to successfully synthesise an acetal in this way must intervene. Adding a drying agent to remove water as it is lost in the SN1 reaction step would work, making it essentially impossible for the mechanism to reverse at that point, and there is no other option but to head towards the acetal product. Alternatively, you could use methanol as the organic solvent for the reaction, in which case the methanol will always be in massive excess. This means again for the SN1 reaction mechanism, there is a competition between water and methanol for being the nucleophile and the concentration of methanol will be significantly higher than that of water. I note at this point that these interventions on the position of equilibrium are in line with what you would predict from Le Chatelier’s Prinicple, by either removing a product or increasing the concentration of one of the starting materials.