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An Introduction to the Diels-Alder Reaction

The Diels-Alder reaction involves the coupling of a conjugated diene with a dienophile, one that is normally activated by an electron-withdrawing group, to give a substituted cyclohexene ring. During the reaction, two σ bonds are formed at the expense of two π bonds. It is the archetypal pericyclic reaction, and is classed as a cycloaddition. This means it proceeds through a concerted mechanism with no intermediate. It is stereospecific in terms of the geometry of the double bonds and is stereoselective when looking at the approach of the two reactants. Invariably, the endo product is favored. All this means that up to four contiguous (adjacent) stereocenters can be formed with high predictability. This adds up to a powerful reaction that has been used in a host of syntheses. There is much more that could be discussed with the Diels-Alder reaction but this is just an introduction.

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Enamines

Enamines are relatively stable enol or enolate equivalents. They are formed by the condensation of a secondary amine with an aldehyde or a ketone. The reaction is often chemo-, regio- and stereoselective, favoring the least substituted, least sterically demanding enamine.

Enamines are more reactive than enols and silyl enol ethers due to nitrogen being less electronegative, which allows for greater delocalization of the lone pair into the double bond. They are less reactive than charged species, such as enolates. Enamines will react with haloalkanes in simple SN2 alkylations, with enones in Michael or conjugate additions, and with aldehydes in the aldol reaction.

The mechanism shows that the secondary amine can be used as a catalyst as it is regenerated when the product is released. Sub-stoichiometric quantities of chiral cyclic amines, such as proline, are used in enantioselective aldol reactions, amongst other useful reactions. This was one of the observations that kick started the organocatalyst revolution. One day I’ll do a summary on organocatalysis.

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Lithium enolates & enolate equivalents

Stable enolates or enolate equivalents are useful to achieve selectivity in the reaction of enolates. Lithium enolates are made with strong bases & are relatively stable at –78 °C, meaning they can be formed without self-condensation. They favor the formation of the kinetic enolate. Silyl enol ethers are more stable than enolates yet are still reactive. Formation of a silyl enol ether can be achieved under either thermodynamic or kinetic control. This allows chemists to control the regiochemistry. Silyl enol ethers react with strong electrophiles directly but if you want to achieve an alkylation or aldol reaction you need to activate the electrophile with a Lewis acid. Boron enolates are very effective in the aldol reaction. Boron acts as an internal Lewis acid & this intramolecularizes the reaction. Choice of boron reagent controls the geometry of enolate formation. This controls the relative stereochemistry of the aldol reaction.

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Aldol-like Reactions

The general mechanism behind the aldol reaction can be applied to a range of useful transformations involving a variety of different functional groups. Generally speaking, one component can form a nucleophile by either tautomerization or deprotonation to a delocalized anion. The other coupling partner contains an electrophilic carbonyl group (or equivalent, as in the case of the Mannich reaction). The two reactants add to form a new C–C bond by nucleophilic addition. In many examples, a subsequent dehydration step leads to a C=C double bond.


The idea that a single mechanism explains a variety of reactions (Claisen addition, Dieckmann reaction, Mannich reaction & the Henry reaction amongst others) shows the power of arrow pushing (& yes, I’m aware that these mechanism are far from ‘true’ but their predictive power is undeniable).

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An Introduction to the Aldol Reaction (addition & condensation)

The aldol addition starts with the formation of a nucleophile, an enolate or enol, that attacks an electrophilic carbonyl group. After proton transfer this leads to a β-hydroxy aldehyde or ketone. Under either acid or basic conditions, it is possible to force the reaction further and get the aldol condensation. This involves dehydration of molecule to give an enal or enone.

Both reactions can occur between identical molecules or between different carbonyl-containing compounds in what is known as the crossed or mixed aldol reaction. The crossed aldol reaction will lead to a mixture of compounds unless you find a method to control the addition. The simplest strategy involves having a single reactant that has α-protons so only one of the coupling partners can form a nucleophilic enolate or enol. The other coupling partner must be more electrophilic than the first to prevent competitive self-condensation.

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An Introduction to Enols & Enolates

Aldehydes and ketones are often in equilibrium with their enol form. The carbonyl compound undergoes tautomerization or enolization, where a proton is transferred from the α-carbon to the oxygen atom and the C=O π bond shifts to form a C=C double bond. Normally, this equilibrium favors the aldehyde or ketone to such an extend that the enol is not observable but this is not always the case. Compounds with a β-carbonyl group often favor the enol form. Formation of the enol can be either base or acid catalysed. Invariably, the thermodynamically more stable, more substituted or Zaitsev enol is formed. Enols are nucleophiles and can react at both the oxygen or carbon atom. The latter is more common (and I haven’t discussed the former in this summary). Enols react with strong electrophiles such as halogens or the nitrosonium ion to give α-haloketones and aldehydes or dicarbonyl compounds.

Enolates are the deprotonated version of an enol. They are formed by treatment of carbonyl-containing compounds with stronger bases. The negative charge makes them more nucleophilic than enols and they undergo a wider range of reactions. They react with halogens in the haloform reaction which leads to the breaking of a C–C bond and formation of a carboxylate anion. They also undergo alkylation. The regioselectivity of enolate formation can be controlled. The less substituted enolate, the kinetic enolate, can be formed by reaction with an excess of strong, bulky base at low temperatures. The more stable, more substituted enolate can be formed by establishing an equilibrium by treating the ketone with a small or weak base at room temperature or higher. Equilibrium requires a proton source so either use a weak base or less than one equivalent of base so that unreacted ketone can act as a proton source.

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Eliminations

The two most common elimination reactions at undergraduate are E1 and E2. These differ by the timing of the lose of the leaving group. An E1 elimination is a first order reaction. The first step, ionization of the substrate to give a carbocation and a leaving group, is the rate determining step. In the second step, a base removes a proton on an α carbon to form an alkene. E2 elimination is second order. It is a concerted process in which the base attacks the proton promoting formation of the π bond by kicking out the leaving group.


E2 eliminations are regio- and stereoselective but can be regio- and stereospecific. They require an antiperiplanar arrangement of proton and leaving group. This leads to good control. E1 eliminations only require the proton to be parallel to the carbocation intermediate. E1 elimination is regio- and stereoselective. It favors the more substituted alkene and the E or trans-geometry.

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Substitution Reactions (on Saturated Carbons)

There are two common mechanisms for substitution at a saturated carbon atom. These are SN1 and SN2 substitution. These differ by the number of molecules in the rate determining step. The rate of an SN1 substitution is determined the substrate only. The reaction is first order and occurs with two discrete steps, the first is dissociation of the leaving group to give a carbocation, and the second is addition of the nucleophile. If the leaving group is on a stereocentre, the reaction often occurs with lose of stereochemical information. The other mechanism, the SN2 substitution is bimolecular with both the substrate (electrophile) and nucleophile influencing the rate of reaction. It is a single step process with all bonds being made and broken at the same time. The reaction occurs with inversion of stereochemistry (when this is a factor). At undergraduate level, the most important factor for determining whether a reaction proceeds through an SN1 or an SN2 mechanism is whether the substrate can form a stable carbocation. If the leaving group can depart to give a stable carbocation (either stabilized by hyperconjugation or delocalization), the reaction will favor SN1. If it can’t, then the reaction is more likely to be SN2. Other factors, such as solvent, can play a role but they tend to be less important.

It should always be remembered that chemistry is never as simple as represented at undergraduate level. Mechanism are on a scale with the majority reactions occurring in between the two extremes outlined above. This means that the reaction may well occur in a single step (like SN2) but that the leaving group may start to depart (the bond get longer) before the nucleophile attacks (resembling SN1). Enjoy.

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Simplified Rates of Reaction from an Organic Chemist

Rates of reactions, and reaction kinetics, is a topic often skipped over by organic chemists. It is mentioned in the discussion of the classic substitution reactions (S_N1 & S_N2), and as a vague concept in catalysis (catalysts speed up reactions), but it otherwise left to physical chemists to teach. This is a mistake (interpret that statement however you want!). An understanding of the rate of a reaction, and the kinetics of a reaction (without going into mathematical detail) is very useful for a synthetic chemist. How fast a reaction occurs is important in biology, environmental science, and many other disciplines. Here is a muddled overview (I have never taught this subject so I'm a little rusty and don't have any of the normal 'lecturer's tricks/insights' that I hopefully do for other topics).

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Conjugate Addition (1,4- or Michael Addition)

Conjugate addition reactions involve the addition of a nucleophile to an activated alkene. The normally nucleophilic group alkene is transformed into an electrophile by the addition of a conjugated electron withdrawing group. This group polarized the alkene and allows the additional electrons gained during nucleophilic addition to flow out onto an electronegative atom. Good activating groups include aldehydes, ketones, esters, amides, nitro groups, nitriles, and sulfones. Alkenes conjugated to these groups are often known as Michael acceptors. When the electron withdrawing activating group contains a carbonyl group there is an added complication as there are two potential electrophilic centres within the acceptor. Nucleophiles could add directly to the carbonyl group (1,2-addition) or to the β-carbon of the alkene (1,4-addition).

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Benzyne, Arynes & Nucleophilic Aromatic Substitution

The benzyne/aryne mechanism is the third version of nucleophilic aromatic substitution. If the nucleophile is a strong base, it can deprotonate the hydrogen adjacent to the leaving group. This is followed by elimination to give a triple bond on the outside of the aromatic ring, such species are called arynes or benzyne. The triple bond is formed from the poor overlap of the two sp2 hybridized orbitals instead of the normal 2p orbitals. It is very weak and highly reactive. The triple bond is electrophilic, and the nucleophile can add to give a product that looks like substitution has occurred. In reality, the reaction was elimination and then addition. The nucleophile can add to either end of the triple bond and this can lead to regioisomers. Any substituent on the aryne can influence the regiochemistry. Simplistically, this is achieved by a combination of inductive and/or steric effects.

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Nucleophilic Aromatic Substitution

Normally, aromatic rings are considered electron rich and are good nucleophiles in the classic electrophilic aromatic substitution (SEAr) reaction. There are three common ways of reversing this reactivity, and permitting the ring to be attacked by a nucleophile. Each of these methods has a different reaction mechanism. The first version of nucleophilic aromatic substitution (SNAr) involves the addition-elimination mechanism. Before it is possible, the benzene substrate must meet a number of criteria. First the benzene must be loaded with electron-withdrawing groups. Ideally, at least one of these should allow electrons to flow outside the ring. Secondly, there must be an electron withdrawing group that can act as a leaving group. Thirdly, this leaving group must be either ortho or para to the activating group. This requirement leads to a stable anionic intermediate with the electrons outside the ring. The second method involves a really good leaving group in the form of nitrogen gas. This leads to either an aryl cation or radical. It is closer to an elimination-addition mechanism such as SN1. The precursor is a diazonium salt and there are markedly less restrictions on the structure of the substrate.

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Electrophilic Aromatic Substitution

Electrophilic aromatic substitution is a general reaction that exchanges a hydrogen atom on an aromatic (benzene) ring with an electrophile. The most common examples are halogenation, nitration, sulfonation and the Friedel-Crafts reactions.
The reaction involves activation of the electrophile to create a powerful electrophile (often a cation). This is necessary as aromatic rings are unusually stable due to delocalization of their π electrons. This is the only step that differes for all the reactions shown here. The next step is addition of the electrophile to the ring. This is hard as it breaks the aromaticity. The resulting cationic intermediate is resonance stabilized but is not aromatic. Finally, proton transfer or deprotonation regenerates the aromatic ring and gives the product. This step is easy as the molecule regains the stability of aromaticity. Almost any basic molecule can achieve it.

The addition of a substituent onto a benzene ring has two effects on electrophilic aromatic substitution. It alters the reactivity, either activating the ring, making reactions faster and more easy, or deactivating the ring. The substituent also controls the position of the reaction (it controls the regioselectivity).
Electron donating groups activate the ring either by delocalization of a conjugated lone pair, or through σ conjunction. They are ortho,para-directing.
Electron withdrawing groups behave in the opposite manner. They deactivate the ring and direct to the meta position. Again, either delocalization or the inductive effect drag electrons from the ring.
Halides are a pain. They are deactivating but ortho,para-directing.

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Asymmetric Hydroboration

A description of substrate and reagent controlled asymmetric hydroboration. Discusses the effects of sterics on stereoselective addition to an alkene. There is a brief introduction to conformational analysis of acyclic alkenes with an allylic stereocentre. There is an introduction to the use of pinene (isopinocampheyl) derivatives to achieve asymmetric alcohol formation by hydroboration-oxidation.

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Anti-Markovnikov Addition

The common addition of electrophiles across an alkene leads to Markovnikov addition product, where a hydrogen atom adds to the least substituted end of an alkene, and the heteroatom adds to the more substituted carbon. There are methods to reverse the regioselectivity and form the anti-Markovnikov product. The first method uses radical chemistry to give the anti-Markovnikov addition of H–Br. By forming a bromine radical addition leads to bromine being on the least substituted carbon of the alkene and the electron deficient carbon radical stabilized on the more substituted end. The second method is hydroboration-oxidation that gives the anti-Markovnikov addition of water across an alkene. Not only is this reaction regioselective, but it is also stereospecific with boron and hydrogen undergoing syn addition. Oxidation of the boron then gives an alcohol, this occurs with retention of stereochemistry.

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Alkenes as nucleophiles: Part 1

Isolated alkenes are good nucleophiles. The reaction mechanism depends on the nature of the electrophile. Hydrohalogenation and hydration are the addition of H–X across the alkene. These additions proceed by a stepwise mechanism and are regioselective but not stereoselective. The regioselectivity is understood by considering the carbocation intermediate. This is sometimes known as Markovnikov addition. Bromination is also a stepwise reaction but is stereospecific (giving the anti product) but not regioselective. A modification of bromination allows the formation of bromohydrins or related compounds. The mechanism of the reaction is the same as bromination and is stepwise. It is stereospecific and regioselective. Epoxidation is a concerted reaction that occurs with syn-addition. It is stereospecific while regioselectivity is not an issue. Syn-dihydroxylation is essentially a concerted process that delivers syn-diols.

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Nucleophilic Acyl Substitution

Nucleophilic acyl substitution is an important reaction in synthesis & biology. All the carboxylic acid derivatives can be prepared using variations of this substitution mechanism. Key to the reaction is the reactivity of the carbonyl group. It is polarized, making it a good electrophile, but it will reform if possible. As carboxylic acid derivatives are characterized by a leaving group on the carbonyl it can reform. There are effectively three variations on nucleophilic acyl substitution depending on whether the nucleophile is an anion or is neutral, & whether the reaction is acid-catalyzed or not. Each reaction involves a minimum of two steps, nucleophilic addition & loss of a leaving group (or elimination). Depending on the conditions & the functional group, there may be one, or more, proton transfers. The reactivity of the carboxylic acid derivatives depends on how good the leaving group is.

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Condensation reactions of aldehydes & ketones: substituting the carbonyl oxygen atom

Nucleophilic attack on the carbonyl group can occur with loss of the original carbonyl oxygen in a condensation reaction. The key step is the formation of a good leaving group by protonating the hydroxyl group of the tetrahedral intermediate. The reaction is reversible, and water must be removed to drive it forward. Hydrolysis, the addition of water to the compound, transforms the products back into the original C=O bond. When the nucleophile is an alcohol, the reaction gives a hemiacetal then an acetal. If the nucleophile is a primary amine the product is an imine, the nitrogen equivalent of the carbonyl. If it is a secondary amine, then the product will be an enamine.Mechanisms involving a leaving group on a tetrahedral intermediate are important. It is key to these condensation reactions and will be important in the next reaction of the carbonyl group, substitution reactions of carboxylic acids and their derivatives.

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Diastereoselective addition to aldehydes & ketones

Nucleophilic addition to an aldehyde or ketone can create a new stereocenter, with a flat, sp2 hybridized carbon, transformed into a tetrahedral sp3 carbon atom. If the aldehyde or ketone already contains a stereocenter, diastereoisomers are formed, and there is the opportunity for substrate control. The existing stereocenter can influence which diastereotopic face of the carbonyl the nucleophile attacks.
This summary introduces the most common models for predicting or rationalizing the stereochemical outcome of addition of an achiral nucleophile to an electrophile with an α-stereocenter.

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Nucleophilic Addition to Aldehydes & Ketones

Aldehydes & ketones contain a polarized carbonyl bond, and are good electrophiles. Nucleophilic addition proceeds by a two-step mechanism that delivers a tetrahedral product. The first step involved addition to the carbonyl, accompanied by breaking the π bond. The second step is proton transfer to quench the intermediate.
Addition can be irreversible, as seen with organometallic reagents & reducing reagents, if there is no suitable leaving group on the tetrahedral intermediate. Alternatively, the reaction is reversible and an equilibrium between aldehyde/ketone and the product is established. This occurs when the nucleophile is a good leaving group (it is a weak base).

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