Organic - Alex Cresswell

What is chirality?

The property of a molecule being non-superimposable on its mirror image

What is a stereogenic centre?

An atom where two attached groups form a stereoisomer

What is stereogenicity at the non-carbon atoms?

Chirality arising from heteroatoms

Why are most amine not configurationally stable?

Rapid lone-pair inversion at nitrogen interconverts the two enantiomeric forms, making them achiral

Why can phosphines and sulfoxides often exist as isolable enantiomers?

They possess much larger inversion barriers than amines, making them configurationally stable

What is axial chirality?

Chirality that arises from a stereogenic axis rather than a stereogenic centre

Name two common classes of compounds that exhibit axial chirality?

Allenes and rotationally restricted biaryls

What is planar chirality?

Chirality arising from a stereogenic plane whose substituent arrangement creates non-superimposable mirror images

What are homotopic faces or groups?

Faces or groups that give identical products when reacted or replaced

What are enantiotopic faces or groups?

Faces or groups that give enantiomeric products when reacted or replaced

What are diastereotopic faces or groups?

Faces or groups that give diastereomeric products when reacted or replaced

What is a stereoselective reaction?

A reaction that preferentially forms one stereoisomer over another

What is a stereospecific reaction?

A reaction where different stereoisomeric reactants give different stereoisomeric products

What is a stereoconvergent reaction?

A reaction where different stereoisomeric starting materials give the same stereoisomeric product

What is the difference between enantioselective and diastereoselective reactions?

Enantioselective reactions preferentially form one enantiomer, whereas diastereoselective reactions preferentially form one diastereomer

What is simple diastereoselectivity?

Selectivity that determines the relative configuration between two newly formed stereocentres

What is induced diastereoselectivity?

Selectivity where a pre-existing stereocentre influences the configuration of a newly formed stereocentre

What type of faces or groups must be differentiated in an enantioselective reaction?

Enantiotopic faces or enantiotopic groups

What type of faces or groups must be differentiated in a diastereoselective reaction?

Diastereotopic faces or diastereotopic groups

Can a reaction be both enantioselective and diastereoselective?

Yes. The two concepts are not mutually exclusive and can occur simultaneously in the same reaction

What is the chiral pool?

A collection of naturally occurring or readily available enantiopure compounds that can be used as starting materials for asymmetric synthesis

What is the main advantage of the chiral pool strategy?

Existing stereochemistry is already present, reducing the need to create stereocentres through asymmetric reactions

What is the main disadvantage of the chiral pool strategy?

The available chiral starting materials may not possess the carbon skeleton or stereochemistry required for the target molecule

Name the four major classes of chiral pool starting materials

Amino acids, sugars, terpenes, and hydroxy acids

Why are amino acids useful as chiral pool starting materials?

They are naturally occurring, available in high enantiopurity, and contain useful functional groups for synthesis

Why are sugars attractive chiral pool building blocks

They contain multiple pre-existing stereocentres and are readily available from renewable sources

What is a major drawback of using sugars in synthesis?

They often contain too many oxygen-containing functional groups, requiring extensive protection and deprotection chemistry

Why are terpenes useful in asymmetric synthesis

They possess rigid carbon frameworks and pre-existing stereocentres that can be exploited during synthesis

What are hydroxy acids?

Chiral compounds containing both hydroxyl and carboxylic acid functional groups that can serve as stereochemically defined starting materials

What is Brown asymmetric allylboration?

An enantioselective reaction in which a chiral allylborane reagent adds to a carbonyl compound to form a homoallylic alcohol

What type of bond is formed during Brown asymmetric allylboration?

A new carbon-carbon bond

Why is Brown asymmetric allylboration important?

It creates new stereocentres with high levels of stereochemical control

What is double diastereocontrol?

A situation where both a chiral substrate and a chiral reagent influence the stereochemical outcome of a reaction

What is a matched case in double diastereocontrol?

The stereochemical preferences of the substrate and reagent reinforce one another, leading to enhanced selectivity

What is a mismatched case in double diastereocontrol?

The stereochemical preferences of the substrate and reagent oppose one another, reducing selectivity

What is reagent control?

Stereochemical control exerted primarily by the reagent rather than by the substrate

Why is reagent control useful?

It can override the substrate's inherent stereochemical preference and allow access to otherwise difficult stereoisomers

What is facial selectivity?

The preferential reaction of one face of a molecule over another, resulting in stereoselective product formation

Why does facial selectivity occur?

One face of the molecule is often more sterically or electronically accessible than the other, leading to a lower-energy transition state

What is meant by a convex face in a bicyclic system?

The outward-facing, less hindered face of a bicyclic molecule

What is meant by a concave face in a bicyclic system?

The inward-facing, more hindered face of a bicyclic molecule

Which face of a bicyclic system is usually attacked by a reagent?

The convex face, because it is generally less sterically hindered

What is an exo attack?

Attack on a bridged bicyclic system from the face directed away from the bridge

What is an endo attack?

Attack on a bridged bicyclic system from the face directed towards the bridge

Which is generally favoured in bridged bicyclic systems: exo or endo attack?

Exo attack is usually favoured due to lower steric and torsional strain

What is 1,2-induction?

Diastereoselective control exerted by a stereocentre located on the carbon adjacent to the reacting carbonyl group

What is the main purpose of the Felkin-Anh model?

To predict the preferred face of nucleophilic attack on an α-stereogenic carbonyl compound

What is the key prediction of the Felkin-Anh model?

The nucleophile approaches from the face that avoids the largest substituent on the adjacent stereocentre

When is the Cram chelate model applicable?

When a heteroatom adjacent to the carbonyl can coordinate to a metal reagent and form a chelated intermediate

How does the Cram chelate model differ from the Felkin-Anh model?

The Cram model assumes chelation occurs, whereas the Felkin-Anh model assumes a non-chelated transition state

What is the Fráter-Seebach alkylation?

A stereoselective alkylation of β-hydroxy esters in which an existing stereocentre controls formation of a new stereocentre

What is 1,3-induction?

Diastereoselective control exerted by a stereocentre located one carbon further away from the reacting carbonyl group (at the β-position)

What is chelation control in 1,3-induction?

Stereoselectivity that arises when a metal coordinates to both the carbonyl and a nearby heteroatom, restricting conformation

What is dipole control in 1,3-induction?

Stereoselectivity that arises from conformations that minimise unfavourable dipole-dipole interactions

What stereochemical outcome is associated with the Narasaka-Prasad reduction?

Formation of syn-1,3-diols

What stereochemical outcome is associated with the Evans-Saksena reduction?

Formation of anti-1,3-diols

What is the key difference between 1,2-induction and 1,3-induction?

In 1,2-induction the stereocentre is adjacent to the reacting carbonyl; in 1,3-induction the stereocentre is one carbon further away

What is allylic strain?

Steric repulsion between substituents in an allylic system that influences molecular conformation and reaction selectivity

What is A¹,³ allylic strain?

Steric interaction between substituents located at the 1- and 3-positions of an allylic system

How is A¹,³ allylic strain usually minimised?

By placing the largest substituent in the less crowded position and the smallest substituent in the more crowded position

What is A¹,² allylic strain?

Steric interaction between substituents on adjacent carbons within an allylic system

Why is allylic strain important in stereoselective synthesis?

It influences the preferred conformation of a molecule, which in turn affects which stereoisomer is formed

What is meant by a reactive conformation?

The conformation that a molecule adopts during a reaction to reach the lowest-energy transition state

Is the lowest-energy ground-state conformation always the reactive conformation?

No. A molecule may adopt a different conformation during the reaction if it leads to a lower-energy transition state

What is alkene facial selectivity?

The preferential reaction of one face of an alkene over the other

What factors control alkene facial selectivity?

Steric effects, allylic strain, stereoelectronic effects, and directing groups

What is directed epoxidation?

Epoxidation in which a nearby functional group helps orient the oxidising reagent and controls which alkene face reacts

What functional group commonly directs epoxidation?

An allylic alcohol or hydroxyl group

What is hydroboration?

Addition of boron and hydrogen across a carbon-carbon double bond in a stereoselective manner

How can allylic strain influence hydroboration?

The alkene adopts a conformation that minimises allylic strain, favouring one approach of the borane reagent

What is directed hydrogenation?

A hydrogenation in which a nearby functional group influences the approach of the catalyst to one face of the alkene

What is the difference between substrate control and reagent control in alkene reactions?

Substrate control arises from the molecule's own structure, whereas reagent control arises from the properties of the reagent or catalyst

What is the inside alkoxy effect?

The tendency of an alkoxy substituent to prefer the inside position in certain allylic systems, influencing stereoselectivity

Why does the inside alkoxy effect influence stereoselectivity?

It affects the electronic properties and preferred conformation of the alkene, altering the preferred reaction pathway

What is enantiomeric excess (ee)?

A measure of how much one enantiomer is present in excess over the other in a mixture

How is enantiomeric excess related to a racemic mixture?

A racemic mixture contains equal amounts of both enantiomers and therefore has 0% ee

What is enantiomeric ratio (er)?

The ratio of one enantiomer to the other in a mixture, typically expressed as x:y (e.g. 95:5)

What is the difference between ee and er?

er gives the actual ratio of enantiomers present, whereas ee measures the excess of one enantiomer over the other

What is chiral HPLC?

A chromatographic technique that separates enantiomers using a chiral stationary phase

Why can chiral HPLC separate enantiomers?

The chiral stationary phase interacts differently with each enantiomer, giving different retention times

What is the purpose of Mosher's method?

To determine enantiomeric purity and stereochemical information by converting enantiomers into diastereomeric derivatives

Why does Mosher's method work?

Diastereomers have different NMR properties, whereas enantiomers do not in an achiral environment

What is absolute configuration?

The actual three-dimensional arrangement of atoms around a stereogenic centre, usually designated as R or S

What is X-ray crystallography used for in stereochemistry?

Determining the absolute configuration and three-dimensional structure of molecules

What is anomalous scattering?

An X-ray diffraction phenomenon that allows determination of absolute configuration when suitable atoms are present

What is the Flack parameter?

A value used in X-ray crystallography to assess whether an assigned absolute configuration is correct

What Flack parameter value indicates the correct absolute configuration?

A value close to 0

What is Vibrational Circular Dichroism (VCD)?

A technique that compares the absorption of left- and right-circularly polarised infrared light by chiral molecules

What is resolution?

The separation of a racemic mixture into its individual enantiomers

What is preparative HPLC?

Large-scale HPLC used to isolate and purify significant quantities of separated enantiomers

What is preparative SFC?

Supercritical Fluid Chromatography used for large-scale enantiomer separations with reduced solvent use

What are the advantages of preparative SFC compared to preparative HPLC?

Faster separations, lower solvent consumption, and improved environmental sustainability

What is Simulated Moving Bed (SMB) chromatography?

A continuous chromatographic process that mimics movement of the stationary phase to achieve efficient large-scale separations

What is resolution by diastereomeric salt formation?

A method of separating enantiomers by reacting a racemate with a single-enantiomer resolving agent to form diastereomeric salts with different physical properties

Why can diastereomeric salts be separated whereas enantiomers cannot?

Diastereomers have different physical properties (e.g. solubility and melting point), whereas enantiomers have identical physical properties in achiral environments

What is kinetic resolution (KR)?

A process in which one enantiomer reacts faster than the other in the presence of a chiral catalyst or reagent

What is the major limitation of kinetic resolution?

The theoretical maximum yield of a single enantiomer is 50%

Why is kinetic resolution stereoselective?

The two enantiomers experience different transition-state energies and therefore react at different rates

What is the selectivity factor (s)?

A measure of the efficiency of a kinetic resolution, defined as the ratio of reaction rates for the fast- and slow-reacting enantiomers

What does a high selectivity factor indicate?

Excellent discrimination between enantiomers and an efficient kinetic resolution