Cycloadditions provide a controlled method for the construction of ring systems. 1,3-Dipolar cycloadditions form five-membered heterocycles. Electronically, these reactions involve 4+2 π electrons & are analogous to Diels-Alder reactions. They are concerted reactions (mostly) & the geometry of the dipole & the dipolarophile are preserved in the stereochemistry of the product. Unlike Diels-Alder…
The first introduction to the Diels-Alder reaction presented the basics of this versatile reaction, and how it could be used to synthesize cyclohexenes with four contiguous stereocenters. In this summary, the same basic components, a diene, or equivalent molecule with two conjugated π bonds, and a dienophile with a single π bond can be used to form two new σ bonds and one π bond while providing a…
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…
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…
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…
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 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…
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.…
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…
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…
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…
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…
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…
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…
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…
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.
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…
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…
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…
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…