Isomers

Lecture 17

Theoretical Foundations of Molecular Structure

• Lewis structures combined with Valence Shell Electron Pair Repulsion (VSEPR) theory provide the fundamental framework for representing and understanding three-dimensional molecular structures.

• Hybridisation serves as an alternative quantum mechanical explanation for how electron pairs adopt preferred spatial orientations.

• The local arrangement of electron pairs is the primary determinant for the three-dimensional shape and flexibility of carbon scaffolds.

• While the carbon scaffold of large organic compounds is mostly inert, its arrangement dictates the position and orientation of reactive heteroatoms ($N$, $O$, $S$, $Cl$) found in functional groups.

• Molecular shape is critical for the efficacy and function of sophisticated pharmaceuticals, including:

  • Antibiotics

  • Anticancer agents

  • HIV/AIDS treatments

  • Antidepressants such as Prozac

Hybridisation and VSEPR Relationships

• Specific local environments around central atoms (primarily carbon) correspond to determined geometries and hybridisation states:

  • Tetrahedral Geometries: Characterized by $sp^3$ hybridisation, single bonds, and bond angles of approximately $109.5^\circ$.

  • Trigonal Planar Geometries: Characterized by $sp^2$ hybridisation, the presence of a double bond, and bond angles of approximately $120^\circ$.

  • Linear Geometries: Characterized by $sp$ hybridisation, the presence of a triple bond (or two adjacent double bonds), and bond angles of $180^\circ$.

Comparative Methods for Representing Bonding

• Line Structure (Skeletal Structure):

  • Features: Indicates connectivity through lines representing bonds. It is easily written and quickly identifies constitutional isomers.

  • Limitations: Does not represent stereochemistry or true molecular shape. Bond angles are often misrepresented as $90^\circ$, and drawing can be tedious for certain groups.

• Condensed Formula (e.g., $CH_3CH_2OH$):

  • Features: Very fast to write and identifies connectivity.

  • Limitations: Fails to show molecular shape or stereochemistry. It can be ambiguous.

• Structural Formula:

  • Features: Shows every atom and every bond.

  • Limitations: Molecule is limited to two dimensions and fails to represent actual bond angles or three-dimensional shape.

• Traditional 3-D Representation:

  • Features: Utilizes wedges and dashes to illustrate 3-D structure and bond angles. It enables accurate naming and advanced mechanistic understanding.

  • Limitations: More time-consuming to draw manually.

• Ball-and-Stick Models:

  • Features: Explicitly shows molecular shape and size while indicating 3-D perspective. Atom types are usually color-coded.

  • Limitations: Typically requires computer software or physical modeling kits; bonds and angles may be somewhat obscured compared to technical drawings; difficult to use for illustrating chemical mechanisms.

• Space-Filling Models:

  • Features: Shows the space actually occupied by the electron clouds (van der Waals radius).

  • Limitations: Discrete bonds and internal bond angles are totally hidden; requires computer elements for generation.

General Concepts and Conventions of Line Notation

1. Bond Representation: Lines are used to denote chemical bonds. Single, double, and triple bonds are shown using 1, 2, or 3 lines respectively.

2. Carbon-Centric Scaffold: Carbon is the basis of organic structures. Carbon atoms themselves are not explicitly labeled but are assumed to exist at every intersection of lines and at the end of every line.

3. Hydrogen Omission: $C-H$ bonds are omitted from the drawing. The number of hydrogens attached to each carbon is assumed based on the carbon's valence requirements.

4. Heteroatoms: All atoms other than Carbon or Hydrogen ($N$, $O$, $S$, etc.) must be shown explicitly, along with any Hydrogen atoms bonded directly to them.

5. Valence Rules: Standard valences are assumed:

   • Carbon ($C$): $4$

   • Nitrogen ($N$): $3$

   • Oxygen ($O$): $2$

   • Hydrogen ($H$), Chlorine ($Cl$), Bromine ($Br$), Iodine ($I$): $1$

6. Geometric Fidelity: Drawings should reflect the underlying hybridisation by indicating approximate bond angles ($109.5^\circ$, $120^\circ$, or $180^\circ$).

7. Condensed Form Ordering: In condensed formulas, atoms bonded to a specific carbon are listed immediately after that carbon.

Molecular Shape and Olfactory Recognition

• Molecular shape directly influences sensory perception, specifically smell. Smell molecules stimulate receptors in the olfactory epithelium, which are bare nerve endings.

• Unlike pain, smell is highly discriminating. The mechanism is based on molecular shape recognition, documented as the Lock and Key concept, where the molecule acts as a key for a specific receptor protein lock.

• Examples of Shape Sensitivity:

  • Benzaldehyde: Possesses a strong smell of bitter almonds.

  • Phenylethanal: Differs from benzaldehyde by only a single $-CH_2-$ (methylene) group, yet smells of hyacinths.

  • Vanillin: A derivative of benzaldehyde containing an $-OH$ and $-OCH_3$ group; smells distinct from benzaldehyde.

  • Musk: Sourced from the anal glands of the Ethiopian civet cat or rutting Himalayan musk deer at a cost of approximately $US\$12,000$ per kg. The key active compounds are large $15$- and $17$-membered rings.

• Odorant Receptors: Located on olfactory receptor cells in the nasal cavity. When a specific odorant attaches, the receptor protein's shape is altered, triggering an electrical signal in the olfactory receptor neuron.

• Receptor Categorization:

  • Sweet-aromatic receptors: Respond primarily to benzene-like (aromatic) molecules.

  • Fatty receptors: Respond to long alkene or alkane chains.

Biological Recognition and Enzyme Interaction

• The Lock and Key concept extends beyond smell to taste, drug action, nerve action, pheromones, and enzyme catalysis.

• Hexokinase Case Study: This enzyme facilitates the interaction with glucose. Detailed X-ray diffraction studies and high-resolution models show the hexokinase enzyme literally "closing" around the glucose molecule upon recognition.

• Opioid Receptor Interactions:

  • Receptors are proteins or polypeptide chains folded into specific 3-D shapes.

  • The idealized opioid receptor features a flat surface for planar rings, a cavity for protruding groups, and an anionic charge center.

  • In solution, the Nitrogen in molecules like morphine or heroin is protonated ($H^+$), becoming positively charged. This positive charge is attracted to the receptor's anionic center.

• Agonists vs. Antagonists:

  • Agonists: Bind to receptors and cause a conformational change in the protein, generating physiological effects (e.g., Morphine, Heroin).

  • Antagonists: Bind to receptor sites without causing a conformational change. They block drug uptake by occupying the site. They typically share very similar structures and shapes with agonists (e.g., Nalorphine, Naloxone).

Structural Characteristics of Hydrocarbons

• Alkanes (Saturated Hydrocarbons):

  • Carbons possess four single bonds and are $sp^3$ hybridised.

  • The geometry is tetrahedral with bond angles of $109.47^\circ$.

  • Members include ethane ($CH_3-CH_3$), propane, n-butane, isobutane, and n-pentane.

• Alkenes (Unsaturated Hydrocarbons):

  • Contains at least one $C=C$ double bond.

  • Carbons involved in the double bond are $sp^2$ hybridised and trigonal planar ($120^\circ$).

  • The double bond consists of one $\sigma$ (sigma) bond and one $\pi$ (pi) bond.

  • Examples include propene, 1-butene, and 2,3-dimethyl-2-butene.

• Alkynes and Allenes:

  • Alkynes: Contain a $C\equiv C$ triple bond ($sp$ hybridised carbon). Geometry is linear ($180^\circ$). The bond consists of one $\sigma$ bond and two orthogonal $\pi$ bonds. Examples: propyne, 1-butyne.

  • Allenes: Contain two adjacent $C=C$ double bonds. The central carbon is $sp$ hybridised (linear), while the terminal carbons are $sp^2$. The two adjacent $\pi$ orbitals are orthogonal to each other.

• Chemical Properties of Hydrocarbons:

  • Generally chemically inert, serving as stable scaffolds.

  • Highly exothermic combustion reactions release large amounts of energy.

  • Combustion Reaction (Methane): $CH_4 + 2O_2 \rightarrow CO_2 + 2H_2O + 890\,kJ\,mol^{-1}$.

  • Large alkanes often undergo incomplete combustion, resulting in soot (graphite) or carbon monoxide ($CO$).

  • Example Larger Scale Combustion: $C_{12}H_{26} + 12.5O_2 \rightarrow 12CO + 13H_2O$; $C_{40}H_{76} + 19O_2 \rightarrow 40C(\text{graphite}) + 38H_2O$.

Hybridisation in Functional Groups

• Carbonyls ($sp^2$): Found in aldehydes ($R'=H$), ketones, carboxylic acids, esters, acid chlorides (acyl chlorides), amides (primary, secondary, tertiary), carbonate esters, and acid anhydrides.

  • Examples: Aspirin, Taxol, Benzaldehyde.

• Nitriles and Ketenes:

  • Nitriles: Characterized by $sp$ hybridisation of the Carbon and Nitrogen in the $C\equiv N$ group. Example: Letrozole.

  • Ketenes/Acid Chlorides: Highly reactive compounds used in organic synthesis. Ketenes feature $sp^2$ hybridisation. Example: Cyamemazine (which also contains a thioether).

• Others ($sp^3$):

  • Alcohols (Hydroxyls): $sp^3$ hybridised terminal groups.

  • Ethers: $sp^3$ hybridised Oxygen bridging two carbons.

  • Amines: categorized as primary, secondary, or tertiary based on the number of Carbon substituents; Nitrogen is $sp^3$ hybridised. Examples: Methamphetamine, Pseudoephedrine.

Isomerism: Classification and Properties

• Isomer Definition: Compounds with the same molecular formula but different structures.

• Structural Complexity Example: The formula $C_2H_2BrClO$ alone yields 16 different possible constitutional isomers (excluding oxygen-halogen bonds).

• Classification Tree:

  • Constitutional Isomers: Differ in the nature or sequence of bonding (connectivity of atoms).

  • Stereoisomers: Have the same connectivity but differ in the 3-D arrangement of groups in space.

    • Configurational Isomers: Interconversion requires breaking and remaking bonds (high energy, does not happen at room temperature).

      • Enantiomers: Non-superposable mirror images.

      • Diastereoisomers: Stereoisomers that are not mirror images.

    • Conformational Isomers (Conformers): Differ by rotation about a single $sp^3$ ($C-C$) bond (low energy, happens easily at room temperature; usually inseparable).

Constitutional Isomers and Homologous Sequences

• The number of possible constitutional isomers increases exponentially with the number of carbon atoms ($n$):

  • $n=1$ ($CH_4$): $1$ isomer

  • $n=2$ ($C_2H_6$): $1$ isomer

  • $n=3$ ($C_3H_8$): $1$ isomer

  • $n=4$ ($C_4H_{10}$): $2$ isomers ($n$-butane and isobutane)

  • $n=5$ ($C_5H_{12}$): $3$ isomers

  • $n=10$ ($C_{10}H_{22}$): $75$ isomers

  • $n=20$ ($C_{20}H_{42}$): $366,319$ isomers

• Properties: Constitutional isomers have different physical (e.g., boiling points decrease with branching) and chemical properties. A formula like $C_4H_8O$ could represent a ketone, aldehyde, alkene/ether, or alkene/alcohol, each possessing distinct reactivity.

• Atmospheric Chemistry Note: Ethenol (vinyl alcohol) can react with atmospheric $OH$ to produce formic acid. It is involved in photo-tautomerization with ethanal (acetaldehyde).

Questions & Discussion

• Question 1: Which of the following statements are true about constitutional isomers?

  • a) They have the same empirical formula.

  • b) They have the same molar mass.

  • c) They have the same order of attachment of the atoms.

  • d) They have the same physical properties.

  • Note: Responses to this question were not explicitly provided in the material beyond the definitions above.

• Question 2: For each of the following, state whether the two structural formulae shown represent constitutional isomers. Have a go at naming them too. [Images shown include pairs of varied organic chains for identification].

• Humor in Chemistry: Why are unsaturated hydrocarbons considered a diverse subject? Because there are "Alkynes" of them (a pun on "all kinds").

Lecture 18

Taxonomy and Classification of Isomers

Isomers are defined as molecules that possess the same molecular formula but have different structures. They are categorized into two primary divisions:

• Constitutional Isomers: These molecules differ in the nature or sequence of their bonds.

• Stereoisomers: These molecules have the same connectivity but differ in the arrangement of groups in space. Stereoisomers are further divided into:

  • Configurational Isomers: The interconversion of these isomers requires the breaking of chemical bonds. Sub-categories include:

    • Enantiomers: Non-superposable mirror images of each other.

    • Diastereoisomers (Diastereomers): Stereoisomers that are not mirror images of each other.

  • Conformational Isomers: Also known as conformers, these differ by rotation around a single bond.

Conformational Isomers in Alkanes

Conformational isomers result from the rotation around carbon-carbon ($C-C$) single bonds.

• Linear Alkanes:

  • Rotation around each $C-C$ bond occurs readily.

  • Because rotation is almost free, the molecule is continually changing its conformation.

  • Conformers cannot be isolated as separate entities at room temperature.

  • A "flexible" hydrocarbon chain refers to this rotational freedom rather than the bonds being physically bendy.

• Cyclic Alkanes:

  • Rotation is restricted or impossible within the rigid scaffold of a small ring.

Visualizing Molecular Conformations

Two primary methods are used to represent the spatial arrangement of atoms looking down a bond:

• Sawhorse Representation: Shows the bond between two carbon atoms at an angle to illustrate the spatial relationship of the attached groups.

• Newman Projection:

  • The observer looks directly down the axis of a specific bond.

  • The carbon atom closer to the observer is drawn as a single point at the center of a circle.

  • The carbon atom further away is represented by the circle itself.

  • Staggered Conformation: The groups on the front carbon and back carbon are as far apart as possible (dihedral angle of $60^{\circ}$). This is a lower energy state.

  • Eclipsed Conformation: The groups on the front carbon are aligned directly in front of the groups on the back carbon. This is a higher energy state due to steric interactions.

Rotational Energy Barriers

• In straight-chain alkanes, rotation about $C-C$ bonds is rapid at room temperature.

• Energy differences between conformations arise from steric interactions.

• For ethane ($CH_3CH_3$), the energy barrier for rotation is approximately $12\,kJ/mol$.

• The energy required to rotate through the eclipsed state is comparable to ambient room temperature energy, which is why rotation is constant.

• For comparison, the actual $C-C$ bond energy is significantly higher at $348\,kJ\,mol^{-1}$.

• Energy minima occur at staggered positions ($60^{\circ}$, $180^{\circ}$, $300^{\circ}$) and maxima occur at eclipsed positions ($0^{\circ}$, $120^{\circ}$, $240^{\circ}$, $360^{\circ}$).

Diastereoisomers and Double Bond Isomerism

Double bond isomers are a type of diastereoisomer that occur when both ends of a $C=C$ bond have two different groups attached. If a carbon has two identical groups attached (e.g., two hydrogens), no diastereoisomers exist for that bond.

• General Condition: For carbons in the bond $W(X)C=C(Y)Z$, the molecule exists as diastereoisomers if $W \neq X$ and $Y \neq Z$.

• E/Z Naming System: This system uses the Cahn-Ingold-Prelog priority rules:

  1. Assign priority to the two groups on each carbon of the double bond.

  2. Priority is determined by atomic number; the higher the atomic number, the higher the priority.

  3. If atoms attached directly to the carbon are identical, move along the chain until the first point of difference is found, then compare by atomic number.

  4. Z (Zusammen, "together"): The higher priority groups are on the same side of the double bond.

  5. E (Entgegen, "opposite"): The higher priority groups are on opposite sides of the double bond.

• Cis/Trans Naming: A special case of stereoisomerization used when the same substituent is present on both ends of the double bond.

  • cis: Substituents are on the same side.

  • trans: Substituents are on opposite sides.

Photoisomerization and Vision

The biological process of vision is driven by the isomerization of retinal, which is derived from $\beta$-carotene and Vitamin A.

• Mechanism: A photon ($h\nu$) provides the energy required to break the $\pi$ bond of $11-(Z)\text{-retinal}$ via $\pi \rightarrow \pi^*$ excitation.

• Conversion: This allows free rotation around the remaining single bond, converting it into $11-(E)\text{-retinal}$.

• This specific light-induced change in molecular shape is the primary event in the visual signal transduction pathway.

Akamptisomerism

Discovered in 2018 by Professor Max Crossley’s group (P.J. Canfield, I.M. Blake, Z.-L. Cai, I.J. Luck, E. Krausz, R. Kobayashi, J.R. Reimers, and M.J. Crossley), akamptisomerism is the first new form of isomerism identified in over 50 years.

• It is described as a fundamental type of conformational isomerism.

• Mathematical analysis of molecular connectivity suggests this is the final undiscovered form of isomerism.

• Applications include molecular computing (as small-scale switches) and drug design.

Configurational Isomers in Cycloalkanes

Configurational isomers do not exclusively require double bonds; they can also occur in rigid cyclic structures where rotation is restricted.

• cis: Substituents (e.g., chlorine atoms in dichlorocyclopropane) are located on the same side of the ring scaffold.

• trans: Substituents are located on opposite sides of the ring scaffold.

• These structures are classified as diastereoisomers.

Chirality and Enantiomers

• Chirality: An object is chiral if it is not superimposable on its mirror image. The term is derived from the Greek word cheir, meaning hand.

• Enantiomers: These are a pair of molecules that are non-superposable mirror images of each other.

• Stereogenic Center: A carbon atom with four different groups attached. This is also referred to as a stereocentre or chiral centre.

• Criteria for Chirality in Molecules:

  • Presence of a stereogenic center.

  • Lack of a plane of symmetry.

  • Non-superposability on the mirror image.

Questions & Discussion

Question 1: Which of the following cycloalkanes shows cis-trans isomerisation? For each that does, draw both forms.

• a) methylcyclopentane

• b) 1,1-dimethylcyclobutane

• c) 1,3-dimethylcyclobutane

Question 2: Do any other dimethylcyclobutanes show cis-trans isomerisation? If so, name them.

Question 3: Name each of the following alkenes, and, using the E/Z system, specify their configuration.

• (Specific structures for alkenes would be provided as visual aids in a worksheet context.)

Lecture 19

Classification of Isomers

Isomers are defined as molecules that share the same molecular formula but possess different structures. They are classified into a hierarchy based on the nature of their differences:

• Constitutional Isomers: These molecules have the same molecular formula but a different nature or sequence of chemical bonds.

• Stereoisomers: These molecules have the same molecular formula and sequence of bonds but differ in the arrangement of their groups in space.

  • Configurational Isomers: A sub-type of stereoisomers where interconversion between forms requires the breaking of chemical bonds.

    • Enantiomers: Chiral molecules that are non-superposable mirror images of one another.

    • Diastereoisomers: Stereoisomers that are not mirror images of one another.

  • Conformational Isomers: These differ only by rotation about a single bond and do not require bond breaking for interconversion.

Chirality and Enantiomers

All molecules have mirror images, but not all molecules are chiral. A molecule is considered chiral if it is not superimposable on its mirror image. This characteristic typically arises from the presence of a stereogenic centre.

• Stereogenic Centre: Also known as a stereocentre or chiral centre, this is a carbon atom attached to four different groups.

• Symmetry: Chiral molecules have no plane of symmetry.

• Physical Properties: A pair of enantiomers will share identical physical properties such as melting point, boiling point, solubility, Nuclear Magnetic Resonance (NMR) spectra, and Infra-Red (IR) spectra.

• Chemical Interactions: Enantiomers behave identically when interacting with achiral reagents or objects. However, they may interact differently with other chiral objects or reagents. This is significant in pharmacology, where over $40\%$ of pharmaceuticals are chiral. Enantiomers of the same drug can have vastly different effects based on their specific mode of biological action.

Polarisation of Light and Optical Activity

Optical activity is the ability of chiral molecules to rotate plane-polarised light.

• Unpolarised Light: Consists of light waves oscillating in random directions perpendicular to the direction of propagation.

• Polarised Light: Oscillation occurs in only one plane after passing through a polarising filter; other planes are filtered out.

• Interaction with Molecules: For light absorption to occur, the direction of the electrical oscillation of the light wave must correspond with the direction of electron oscillation within the molecule.

• Rotation measure ($\alpha$): When plane-polarised light passes through a solution of a pure enantiomer, the plane of polarisation is rotated. The amount of rotation ($\alpha$) is characteristic of the specific enantiomer and also depends on the solution concentration and the sample path length.

Enantiomers and Direction of Rotation

Enantiomers are distinguished by the direction in which they rotate plane-polarised light:

• Clockwise Rotation: Labelled as $(+)$.

• Anti-clockwise Rotation: Labelled as $(-)$.

• Predictability: It is not possible to predict whether a specific enantiomer will be $(+)$ or $(-)$ without conducting an experiment.

• Racemate (Racemic Mixture): A 50:50 mixture of both enantiomers. Because they rotate light in equal amounts but opposite directions, the net rotation is zero.

• Biological Example: Limonene exists as two enantiomers: $(+)$-limonene provides the characteristic odour in oranges, while $(-)$-limonene provides the odour in lemons.

The Cahn-Ingold-Prelog Naming System (R and S)

To systematically name enantiomers, a priority-based system is used:

1. Prioritise Groups: Assign priority to the four groups attached to the stereocentre based on atomic number. Higher atomic numbers receive higher priority. If atoms are identical, compare the atoms at the next bond down the chain until a difference is found.

2. Orientation: Rotate the molecule so that the lowest priority group (priority 4) is pointing backwards (away from the viewer).

3. Determine Configuration: Draw an arrow from priority 1 to priority 2 to priority 3.

   • If the arrow moves clockwise (right), the configuration is assigned as $R$ (from the Latin Rectus).

   • If the arrow moves anti-clockwise (left), the configuration is assigned as $S$ (from the Latin Sinister).

Fischer Projections

Fischer projections provide a 2-D method to represent 3-D molecules while retaining stereochemical information. They are primarily used for biomolecules like amino acids and sugars.

• Conventions:

  • Horizontal lines: Represent bonds sticking "out of the page" (towards the viewer).

  • Vertical lines: Represent bonds sticking "into the page" (away from the viewer).

• Usage: These projections show structure from a specific, standardized point of view.

Molecules with Multiple Stereogenic Centres

A molecule with $n$ stereogenic centres can have a maximum of $2^n$ possible isomers.

• Example (2,3,4-trihydroxybutanal): This molecule has two stereogenic centres, resulting in 4 isomers.

  • Isomer Relationships: If Isomers A and B are enantiomers and C and D are enantiomers, then the relationship between A and C, or B and D, is that of Diastereomers.

  • Diastereomer Characteristics: These are stereoisomers that are not mirror images of one another. They occur when there is opposite configuration at some, but not all, stereocentres.

  • Enantiomer Characteristics: These occur when there is an opposite configuration at all stereocentres.

Meso Compounds

A special case occurs when a molecule has two identical stereogenic centres and an internal plane of symmetry.

• Symmetry: One stereogenic centre is the mirror image of the other within the same molecule.

• Optical Activity: Meso compounds are optically inactive because the internal symmetry cancels out any net rotation of plane-polarised light.

• Isomer Count: In the case of tartaric acid, while the $2^n$ rule suggests 4 isomers, there are actually only 3: a pair of enantiomers and one meso isomer.

Biological Molecules: Sugars and Amino Acids

Sugars and amino acids are often complex molecules with many chiral centres.

• Sugars: Defined as hydroxy-substituted cyclic ethers (e.g., D-glucose). They are often represented in their open-chain form using Fischer projections.

• Amino Acids and Polypeptides: Polypeptides are long chains of amino acids. These molecules are amenable to Fischer projection representation to track multiple stereocentre configurations.

Questions & Discussion

• Worksheet Q1 & Q2: These questions relate to the interaction of enantiomers with chiral and achiral objects and the pharmaceutical implications of chirality.

• Worksheet Q3: This question focuses on the application of the R/S naming system.

• Worksheet Q4: This question concerns the identification and rotation of meso isomers and diastereoisomers.