Isomerism in Organic Compounds

Isomerism

  • Isomers are compounds that possess the same molecular formula but differ in their structures.
  • Isomerism is the phenomenon where multiple compounds share the same chemical formula but exhibit different chemical structures.

Isomerism in Clinical Pharmacology

  • Isomerism in clinical pharmacology involves compounds (isomers) with identical molecular formulas but varying structural arrangements or spatial orientations.
  • These differences can significantly influence a drug's behavior within the body.

Pharmacokinetics – What the Body Does to the Drug

  • Pharmacokinetics describes how the body affects a drug, including:
    • Absorption
    • Distribution
    • Metabolism
    • Excretion
  • Isomers may differ in absorption rate, metabolism speed, or excretion rate, leading to variations in drug levels in blood and tissues.

Pharmacokinetics - Details

  • Absorption:
    • Absorption is the process by which a drug enters the bloodstream after administration (e.g., oral ingestion).
    • Example: A tablet dissolving in the stomach, with the drug then passing into the blood.
  • Distribution:
    • Distribution involves the drug spreading throughout the body via the bloodstream to reach target organs and tissues.
    • Example: A painkiller traveling to muscles or joints after absorption to alleviate pain.
  • Metabolism:
    • Metabolism is the process where the body breaks down the drug, usually in the liver.
    • The drug might be converted into an active form or prepared for removal.
    • Example: The liver transforming drugs into easily excretable forms.
  • Excretion:
    • Excretion is the process by which the drug exits the body, typically through urine (via the kidneys) but also via sweat, feces, or breath.
    • Example: The kidneys filtering a drug from the blood, allowing it to leave the body in urine.

Pharmacodynamics – What the Drug Does to the Body

  • Pharmacodynamics explains how a drug affects the body, involving:
    • Receptor binding
    • Efficacy
    • Potency
    • Side effects
  • Isomers can exhibit different binding affinities to receptors.
  • One isomer can be more effective or have fewer side effects; one might be therapeutically active, while others are inactive or harmful.

Pharmacodynamics - Details

  • Receptor Binding
    • Receptor binding describes how a drug attaches to a specific receptor in the body.
    • Analogy: Like a key fitting into a lock.
    • The better the fit, the stronger the effect.
  • Efficacy
    • Efficacy measures how well a drug works once it binds to the receptor; it is about the maximum effect that a drug can produce.
    • Example: If Drug A completely relieves pain and Drug B only relieves half the pain, Drug A has higher efficacy.
  • Potency
    • Potency refers to the amount of drug required to produce an effect. A more potent drug works at a lower dose.
    • Example: If it takes 5 \, mg of Drug A and 50 \, mg of Drug B to reduce fever, Drug A is more potent.
  • Side Effects
    • Side effects are the unwanted or unintended effects of a drug.
    • A drug may treat a condition but also cause side effects like nausea, drowsiness, or headaches.

Clinical Importance

  • Understanding isomerism allows medical professionals to select the safest and most effective drug forms.
  • Thalidomide: One isomer treated morning sickness, while the other caused birth defects.
  • Ibuprofen: Sold as a mix of isomers, but only one is active in relieving pain.

Types of Isomerism

  • Isomerism
    • Structural Isomerism
      • Chain Isomerism
      • Position Isomerism
      • Functional Isomerism
    • Stereoisomerism
      • Optical Isomerism
      • Geometrical Isomerism

Types of Isomerism - Details

  • Structural Isomerism: Same molecular formula but different structural formulas.
  • Stereoisomerism: Same molecular formula, but atoms occupy different positions in space.
  • Geometrical Isomerism: Occurs due to the restricted rotation of C=C double bonds, resulting in cis and trans forms.
  • Optical Isomerism: Occurs when molecules have a chiral center, leading to two non-superimposable mirror images.

A. Structural Isomers

  • Compounds with the same molecular formula but different structural formulas.
  • Example:
    • CH3-CH2-CH2-CH2-CH3
    • CH3-CH2-CH(CH3)-CH3
    • CH3-C(CH3)2-CH3

Butane and Isobutane

  • Two structural isomers of C4H10.
  • Butane is a straight-chain molecule.
  • Isobutane is a branched molecule.
  • They have the same number of carbon and hydrogen atoms, thus the same molecular formulas, but different structural formulas.

A. Structural Isomer - Details

  • Both butane and isobutane are gaseous hydrocarbon compounds.
  • Both have the same chemical formula: C4H10.
  • They share the same molar mass values.
  • Butane can be linear or branched, while isobutane is branched.

Types of Structural Isomerism

  • Chain Isomerism.
  • Position Isomerism.
  • Functional Group Isomerism.

A.1. Chain Isomerism

  • Isomers arising from the possibility of branching in carbon chains.
  • Examples:
    • Butane (C4H10): CH3-CH2-CH2-CH3 (straight chain) vs. CH3-CH(CH3)-CH3 (branched)
    • Pentane (C5H12): CH3-CH2-CH2-CH2-CH3 (straight chain) vs. branched isomers

A.1. Chain Isomerism - Differences Between Chain Isomers

  • Chemical Properties: Similar chemical properties due to the presence of the same functional group.
  • Physical Properties: Density and boiling point show trends relative to the degree of branching.
  • Boiling Point: Straight-chain isomers have higher boiling points than branched ones.
    • Greater branching decreases intermolecular forces, reducing the energy required for separation.
    • Example: Straight chain isomer ($-0.5°C), branched ($-11.7°C).
    • Greater branching = lower boiling point.

A.2. Position Isomerism

  • Examples:
    • 1-Chlorobutane (halogen on carbon 1)
    • 2-Chlorobutane (halogen on carbon 2)
    • 1,2-Dichlorobenzene (ortho-dichlorobenzene)
    • 1,3-Dichlorobenzene (meta-dichlorobenzene)
    • 1,4-Dichlorobenzene (para-dichlorobenzene)

A.2. Position Isomerism - Details

  • The basic carbon skeleton remains unchanged but important groups are moved around on that skeleton.

A.3. Functional Group Isomerism

  • Isomers contain different functional groups; belonging to different families of compounds (different homologous series).

A.3. Functional Group Isomerism - Examples

  • Molecular formula: C3H6O
    • Propanal: CH3-CH2-CHO
    • Propanone: CH3-CO-CH3
  • Molecular formula: C3H6O2
    • Propanoic acid: CH3-CH2-COOH
    • Methyl ethanoate: CH3-COO-CH3

C4H{10}O Isomers

  • 1-butanol
  • 2-methyl-2-propanol
  • 2-butanol
  • 2-methyl-1-propanol
  • diethyl ether
  • methyl propyl ether
  • isopropyl methyl ether

Summary of Structural Isomerism

  • Chain Isomerism: Isomers differ in the carbon skeleton.
  • Position Isomerism: Isomers have a functional group in different positions.
  • Functional Group Isomerism: Isomers have different functional groups and belong to different homologous series with the same general formula.

B. Stereoisomerism

  • Stereoisomers are isomers where the order of the atoms is the same, but their arrangement in space differs.
  • Stereoisomerism refers to the arrangement of atoms in molecules whose connectivity remains the same, but their arrangement in space is different for each isomer.

Types of Stereoisomerism

  • Geometrical Isomerism
  • Optical Isomerism

B.1. Geometrical Isomerism

  • Geometric isomerism is a type of isomerism where individual atoms are in the same order but arranged differently in space.
  • The prefixes cis- and trans- are used to describe geometric isomerism.
  • Geometric isomers occur when atoms are restricted from rotating around a bond.

Details

  • Involves a double bond, usually C=C, which does not allow free rotation.
  • These isomers are not superimposable

B.1. Cis-Trans Isomers

  • Cis
    • Cis (Latin: "on this side") indicates that substituent groups are on the same side of the carbon-carbon double bond.
    • Example: cis-1,2-dichloroethene.
  • Trans
    • Trans (Latin: "across") indicates that substituent groups are on opposite sides of the double bond.
    • Example: trans-1,2-dichloroethene.

Effect of Geometric Isomerism on Physical Properties

  • trans isomer typically has a higher melting point.
  • cis isomer typically has a higher boiling point.

Further Examples:

  • cis-1-bromo-3-chlorocyclobutane
  • trans-1-bromo-3-chlorocyclobutane
  • cis-1,4-dimethylcyclohexane
  • trans-1,4-dimethylcyclohexane

B.2. Optical Isomers

  • Involves an atom (usually carbon) bonded to four different atoms or groups of atoms.
  • They exist in pairs, in which one isomer is the mirror image of the other.

Details

  • Referred to as enantiomers.
  • The central carbon atom with four different attached groups is called an asymmetrical carbon atom.
  • Enantiomers have identical physical constants (melting and boiling points).
  • Optically active: distinguished by their ability to rotate the plane of polarized light in opposite directions.

Enantiomers & Diastereomers

  • Enantiomers are stereoisomers whose molecules are non-superimposable mirror images of each other.
  • Diastereomers are stereoisomers whose molecules are not mirror images of each other.

Enantiomer - Details

  • Molecules that are mirror images of each other.
  • Example: Left and right hands are a pair of enantiomers (mirror images are not identical).

Example: 2-butanol

  • Exists as enantiomers.

Example: Asparagine

  • L-asparagine (from asparagus) has a bitter taste.
  • D-asparagine (from vetch) has a sweet taste.

Example: 2-hydroxypropanoic acid (lactic acid)

  • CH3-CH(OH)-COOH
  • Exists as two enantiomers, mirror images of each other.

Example: 2-aminopropanoic acid (alanine)

  • CH3-CH(NH2)-COOH
  • Exists as two enantiomers.
  • Naturally occurring alanine.

Asymmetric Centers

  • An asymmetric center is an atom bonded to four different groups.
  • Examples:
    • 4-octanol
    • 2-bromobutane
    • 2,4-dimethylhexane

Problem Examples

  • Examples of compounds with or without an asymmetric center.

Diastereomers

  • Diastereomers are stereoisomers that are not mirror images and are non-superimposable.

D and L Isomers

  • In a Fischer projection, the -OH group on the chiral carbon farthest from the carbonyl group determines an L or D isomer.
  • Left = L (Latin laevo, “left”).
  • Right = D (Latin dexter, “right”).

Fischer Projections

  • A Fischer projection represents 3D structures of molecules.
  • Used to represent carbohydrates.
  • Places the most oxidized group at the top.
  • Chiral carbons are shown as the intersection of vertical and horizontal lines.

Example: Alanine

  • D-Alanine and L-Alanine are shown as Fischer projections, which are mirror images.

Starch & Cellulose

  • Cellulose - beta acetal
  • Starch - alpha acetal

Difference between Starch & Cellulose

  1. Cellulose is a polymer of glucose whose units can be rotated around the axis of a backbone of polymer chains of glucose units while starch is a polymer of glucose wherein all the repeat units are directed in one direction.
  2. The glucose units in starch are connected by alpha linkages while the glucose units of cellulose are connected by beta linkages.
  3. Starch is fit for human consumption while cellulose is not.
  4. Starch is soluble in water while cellulose cannot be dissolved in water.
  5. Cellulose is stronger than starch.
  6. Cellulose is more crystalline than starch.
  7. The main function of starch is as food and supplying the body with energy and helps in its proper metabolism while cellulose has a more significant use in the clothing industry and in the production of important materials like cellophane and rayon.

R and S

  • RACEMIC MIXTURES – Assign priorities to the remaining groups based on atomic numbers.
  • Clockwise (highest to lowest priority) → R (means Rectus in Latin)
  • Counterclockwise → S (means Sinister in Latin)

Example: Thalidomide

  • S-Thalidomide (effective drug)
  • R-Thalidomide (dangerous drug)

Example: Carvone

  • S-carvone (caraway seed): Caraway Seed has a warm, pungent, slightly bitter flavor with aniseed overtones.
  • R-carvone (spearmint)

Example: Limonene

  • S-limonene (lemons)
  • R-limonene (oranges)

Why is Isomerism Important?

  • Normally, only one particular isomer is effective in treating a condition.
  • Other isomers are less effective or even harmful.
  • Example: Thalidomide – One enantiomer helped with morning sickness, but the opposite enantiomer caused birth defects.

Thalidomide Details

  • S thalidomide (effective drug)
  • The body racemizes each enantiomer, so even pure S is dangerous as it converts to R in the body.
  • R thalidomide (dangerous drug)

Thalidomide History

  • Thalidomide was banned worldwide when the effects were discovered.
  • However, it is starting to be used again to treat leprosy and HIV.
  • Its use is restricted though, and patients have to have a pregnancy test first (women!) and use two forms of contraception (if sexually active).

Thalidomide Story

  • Story of thalidomide (1960’s)
  • A racemic drug given to pregnant women to combat morning sickness
  • One of the enantiomers caused birth defects (teratogen) and death

Racemic mixture

  • What’s in Advil (ibuprofen)?
  • Production results in a racemic mixture
  • One of the enantiomers is effective as an anti-inflammatory
  • Takes about 30 minutes for the inactive enantiomer to be converted

Drug Examples

  • Ibuprofen:
    • Condition: Pain; inflammation
    • Effective Enantiomer: S-Ibuprofen
    • Ineffective Enantiomer: R-Ibuprofen
  • Albuterol:
    • Condition: Asthma
    • Effective Enantiomer: R-Albuterol
    • Ineffective Enantiomer: S-Albuterol

Importance of Isomers in Fuels

  • Octane (C8H18 or CH3(CH2)6CH3) is a common fuel and primary component of gasoline.
  • Octane has 18 isomers, each with different applications.

Useful Isomers in Fuel Design

  • Branched isomers are more useful than linear isomers.
  • Branched structures cause octane to burn more slowly and evenly.
  • The most commonly used octane isomers in fuels are those with branched structures.

Octane Rating

  • The octane rating measures how fast the fuel will burn.
  • Determined by the isomers used in the octane and the percentage of fuel, which is not octane.
  • The octane rating is largely a measure of the isomers in a given fuel.

Assignment

  • Give the 18 isomers of octane, C8H18. Structural formula and name.