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Pharmaceutical Organic Chemistry
Author Information
Abdulai Turay B.Pharm(Hons), MSc Drug Discovery and Development
Department of Pharmaceutical Chemistry
B.Pharm II COMAHS, USL
Academic Year: 2025/2026
Aim and Objectives of the Module
Provide students with fundamental concepts and techniques in organic pharmaceutical chemistry.
Subsequent applications include identification, purification, synthesis, and separation of mixtures of organic compounds.
Learning Outcomes
At the end of this module, students should be able to:
Describe bond formation and breakage in organic chemistry as well as functional groups and nomenclature of organic compounds of medicinal interest.
Explain mechanisms of substitution, elimination, and addition reactions and recognize molecules of biological and pharmaceutical interest which undergo these reactions.
Reactivity of Organic Reactions
Substrate: The reactant that provides carbon atoms when new bonds form.
Reagent: Other reactants that may not provide carbon; if both contribute carbon, the substrate is the one in focus.
Reaction Mechanism: A step-by-step explanation of a reaction.
Key Concepts in Reactivity
Electron Movement: How electrons are transferred or shared during reactions.
Energetics: Energy changes that occur when bonds are broken and formed.
Kinetics: Rates at which reactants convert to products.
Bond Fission
Covalent Bond Formation: Two atoms share a pair of electrons; chemical reactions involve breaking old bonds and forming new bonds.
Bond changes occur in two ways:
Homolysis: Bond breaks evenly; each atom retains one electron, forming two radicals (unpaired electrons).
Heterolysis: Bond breaks unevenly; one atom takes both electrons, producing a cation (positive charge) and an anion (negative charge).
Homolysis
Example: Cl—Cl → (hv) Cl· + Cl·
Characteristics of Homolytic Fission:
Equal electron distribution in the broken bond.
Creates free radicals with unpaired electrons.
Weaker bonds split more easily due to bond energy influence.
Heat or light can drive the split, indicating temperature/light sensitivity.
Represented by a half-headed arrow in diagrams.
Heterolysis
Produces a Carbocation (Carbon with positive charge) and a Carbanion (Carbon with negative charge retaining an electron pair).
Key carbon intermediates in organic chemistry; highly reactive.
Reactive Intermediates
Carbocation:
Positive charge and six outer shell electrons.
Forms when a more electronegative atom captures both electrons.
Presence indicates high reactivity.
Classification of Carbocations:
Primary: CH₃C⁺H₂
Secondary: (CH₃)₂C⁺H
Tertiary: (CH₃)₃C⁺
Carbanions: Form via heterolysis
after carbon retains the electron pair.
Organic Reagents
Electrophiles
Definition: Electron-deficient entities that attack regions of high electron density or negative centers (Lewis acids).
Types and Examples:
Positive Electrophiles: Carbocations, H⁺, H3O⁺, Cl⁺, NO⁺.
Neutral Electrophiles: AlCl₃, BF₃, SO₃.
Nucleophiles
Definition: Electron-rich species that attack low electron density or positive centers (Lewis bases).
Types and Examples:
Negative Nucleophiles: Carbanions, H⁻, OH⁻, Cl⁻, RCOO⁻.
Neutral Nucleophiles: H₂O, NH₃.
Free Radicals
Definition: Neutral species with an unpaired (odd) electron formed through homolytic cleavage.
Properties: Paramagnetic due to odd electron; forms bonds with various elements C–O, C–Cl, C–Br, C–I, C–C, C–H.
Triphenylmethyl Radical
Observation: In solution, the radical is yellow; exposure to air (O₂) oxidizes to a peroxide resulting in a colorless solution.
Factors Affecting Electron Availability
Inductive Effect
Electromeric Effect
Resonance Effect
Hyperconjugation
Inductive Effect
Definition: Electron shift along σ-bonds due to attached groups; (-I withdraws; +I donates).
Key Features:
Direction is shown along the σ-bond.
Strength weakens with distance from the electronegative atom, negligible beyond ~two carbons from the group.
Inductive Effect Series:
−I: R₃N⁺ > NO₂ > SO₂R > CN > COOH > F > Cl > Br > I > OR > COR > OH > C₆H₅
+I: (CH₃)₃C > (CH₃)₂CH > CH₃CH₂ > CH₃ > D > H
Inductive Effect & pKa
Alkyl groups release electrons, leading to decreased acidity, increasing pKa.
Shifting Cl closer to –COOH lowers pKa, leading to increased acidity.
Examples of Acidity Based on Substitution
H-COOH: pKa 3.75
CH₃(CH₂)₃-COOH: pKa 4.8
CH₃-COOH: pKa 4.75
CH₃(CH₃)₂-COOH: pKa 4.5
Electronegativity and Distance
Electron-withdrawing substituents enhance acidity.
Order of effect: F > Cl > Br > I; effects diminish with distance from acidic site.
Increasing Cl Substitution Adjacent to –COOH
Replacing more H with Cl increases acidity (pKa decreases).
Explanation: Cl withdraws electrons, stabilizing the conjugate base.
General Role of Inductive Effect
Drives trends in acidity and basicity:
Acidity increases with -I groups.
Basicity increases with +I groups.
Electromeric Effect
Definition: Involves π electrons loosely held and easily polarized, showing temporary transfer of electrons under attacking reagents.
−E: Electrons move away from nucleophile.
+E: Electrons move toward electrophile.
Applications of Electromeric Effect
Electrophilic addition to unsaturated compounds.
Nucleophilic addition to carbonyl compounds.
Ring polarization.
Comparison of Inductive and Electromeric Effects
Inductive Effect: Permanent displacement of electrons.
Electromeric Effect: Temporary transfer, dependent on attacking reagent.
Illustrative Representation: Inductive shown with polar covalent bonds; electromeric depicted by arrowhead midway and curved arrows.
Delocalization
In conjugated systems, π electrons are distributed across the framework.
Occurs in systems of alternating single/double bonds.
Overlaps may be π–π or π–p orbital.
Resonance / Mesomeric Effect
Definition: Polarity arises from the interaction of a lone pair with a π bond or adjacent π bonds.
Observations: Present in compounds with double bonds; provides compound stability/energy.
Aromatic Compounds: Renowned for stability due to resonance/delocalization.
Types of Mesomeric or Resonance Effects
−M / −R: Withdraws electron density via delocalization; decreases overall density. Example: −NO₂, C=O.
+M / +R: Donates electron density via delocalization; increases overall density. Examples: −OH, −OR.
Hyperconjugative Effect
Involves σ(C–H) π interaction; more σ -C–H bonds lead to increased electron release and higher density at terminal carbon.
Applications of Effects
Electrophilic substitution on benzene; toluene activates and directs ortho/para.
Dipoles, such as 1,1,1-trichloroethane showing increased effects compared to chloroform.
Summary of Key Concepts
Acidity/basicity trends can be predicted using inductive effects.
Resonance contributes to stability through π-delocalization.
Hyperconjugation enhances stability through σ-delocalization.
Relative hyperconjugation strength: H > D > T (in terms of bond energy).
Types of Reactions
Addition Reaction
Substitution Reaction
Elimination Reaction
Rearrangement Reaction
Importance for Pharmacists
Most drugs are organic molecules subject to these reactions.
Drug action modifies target sites (enzymes, receptors, DNA).
Drug metabolism involves addition, substitution, and elimination steps to enhance polarity.
Medicinal chemists apply these reactions to design and synthesize drug analogues.
Understanding reaction types aids in predicting stability, interactions, and possible toxic metabolites.
Addition Reaction
Definition: Two species add across a π bond (C=C, C≡C, C=O); a σ bond is formed, while the π bond may be reduced or lost.
Common Sites: C=C (alkenes), C≡C (alkynes), C=O (aldehydes or ketones).
Types of Addition Reactions in Drug Chemistry
Electrophilic addition to alkenes (e.g., addition of HX, X₂, H₂O).
Nucleophilic addition to C=O (e.g., addition of hydride or nucleophiles to aldehydes or ketones).
Effects on Drugs: Increases saturation and alters the shape, polarity, and biological activity of drug molecules.
Example of Electrophilic Addition to Alkenes
Overall Reaction:
ext{CH}2= ext{CH}2 + ext{HBr}
ightarrow ext{CH}3– ext{CH}2 ext{Br}Step 1: Polarization and ionization of HBr.
Step 2: Attack of electrophile (H⁺) on the π bond.
Step 3: Nucleophilic attack by Br⁻.
Key Pattern: π bond → σ-bonds; electrophile adds first, followed by nucleophile.
Electrophilic Addition in Synthetic Steps
Commonly introduced halogens or other groups into drug side chains.
Electrophilic Addition Reactions in Dienes
Types:
Isolated diene: Two double bonds separated by more than one single bond (e.g., CH₂=CH–CH₂–CH=CH₂).
Conjugated diene: Double bonds separated by one single bond (e.g., CH₃–CH=CH–CH=CH–CH₃); more stable than isolated due to overlap of p orbitals.
Electrophilic Addition to Conjugated Diene: 1,2 vs 1,4 products
Example: ext{1,3-butadiene} + ext{HBr}
Reaction Steps:
ext{H}^+ adds, creating an allylic carbocation.
ext{Br}^- attacks, giving two potential products: 1,2-addition and 1,4-addition.
Key Concepts:
Markovnikov’s Rule applies to the addition of the electrophile (H⁺) to the carbon that leads to a more stable carbocation.
Kinetics of Products in Diene Addition
Kinetic product (formed faster at low temperature)
Thermodynamic product (more stable, predominates at equilibrium).
Nucleophilic Addition Reaction
Overall Reaction:
( ext{CH}3)2 ext{C=O} + ext{HCN}
ightarrow ( ext{CH}3)2 ext{C(OH)–CN}Mechanism Steps:
Ionization of HCN.
Nucleophilic attack on carbonyl carbon.
Protonation of alkoxide.
Key Pattern: Nucleophile attacks C=O, breaking the π bond, with O⁻ being protonated.
Effect of Nucleophilic Addition Reaction on Drugs
Important for the formation of alcohols, hemiacetals, acetals, and many prodrug transformations.
Substitution Reactions
Definition and Types
General Equation:
ext{R–LG} + ext{Nu}^−
ightarrow ext{R–Nu} + ext{LG}^−
(LG = leaving group)New bonds to carbon form while old bonds break.
Types:
Nucleophilic substitution (SN1 and SN2)
Nucleophilic acyl substitution at carbonyl carbon (esters, amides, acyl halides).
Electrophilic aromatic substitution on benzene rings.
Nucleophilic Substitution in Detail
Definition: Replaces a leaving group on carbon with a nucleophile.
General Equation:
ext{Nu}^− + ext{R–LG}
ightarrow ext{R–Nu} + ext{LG}^−Nucleophile: An electron-rich species attacking an electron-poor carbon (e.g., HO⁻, CN⁻, NH₃).
Leaving Group: Atom or group that departs with bonding electrons (e.g., Cl⁻, Br⁻, I⁻, OTs⁻).
SN2 Reaction
Definition: Substitution Nucleophilic bimolecular (SN2).
Mechanism: One-step where nucleophile attacks as leaving group departs.
Rate Law:
ext{rate} = k[ ext{substrate}][ ext{nucleophile}]Fastest in reactivity order: methyl > primary alkyl halides > secondary > tertiary.
Favored by strong nucleophiles and polar aprotic solvents (e.g., DMSO, acetone).
SN2 Mechanism Example
Reaction: ext{HO}^- + ext{CH}3 ext{Cl} ightarrow ext{CH}3 ext{OH} + ext{Cl}^-
Backside Attack: Nucleophile approaches from the side opposite the C–Cl bond.
Transition State: Carbon is temporarily bonded to both O and Cl, leading to bond formation and breakage.
SN2 Stereochemistry
Inversion of Configuration (Walden Inversion): Backside attack causes the tetrahedral carbon to flip, resulting in inverted stereochemistry.
SN1 Reaction
Definition: Substitution, Nucleophilic, unimolecular (SN1).
Mechanism: Two-step with initially slow departure of the leaving group forming a carbocation, followed by quick nucleophilic attack.
Rate Law:
ext{rate} = k[ ext{substrate}]Favored on tertiary > secondary substrates.
SN1 Mechanism Example
Reaction: ( ext{CH}3)3 ext{CBr} + ext{HO}^-
ightarrow ( ext{CH}3)3 ext{COH} + ext{Br}^-Key Steps:
Formation of carbocation via leaving group departure.
Nucleophilic attack leading to product formation.
SN1 Stereochemistry
Gives a racemic mixture at a chiral center due to equal likelihood of approach from either side of the planar carbocation.
Factors Affecting Rates of SN1 and SN2 Reactions
Structure of substrate
Concentration and reactivity of nucleophile
Effect of solvent
Nature of leaving group
Structure of Substrate and SN2 Rate
SN2 requires backside attack, influenced by steric hindrance; order of reactivity follows: methyl > 1° > 2° >> 3°.
Structure of Substrate and SN1 Rate
Rate depends on carbocation stability; stability order is 3° > 2° > 1° > methyl.
Reactivity Trends: SN2 vs SN1
As substitution increases (from methyl to 3°), SN2 decreases due to steric hindrance, while SN1 increases due to more stable carbocations.
Solvent Effects on Reactions
SN2 Reactions
Protic solvents slow reactions by strongly solvating anions; polar aprotic solvents enhance SN2 reactions by not sufficiently solvating anions.
SN1 Reactions
Protic solvents improve reaction rates by stabilizing cations and anions through solvation and H-bonding.
Comparison of SN1 and SN2
Mechanism varies: SN2 is one-step with backside attack while SN1 is two-step involving carbocation formation.
Reactivity order differs significantly.
Rate equations are distinct for both mechanisms, impacting stereochemistry.
Elimination Reactions (E1 & E2)
Overview of Elimination Reactions
Definition: Involves removal of atoms/groups from adjacent carbons to create a double bond (C=C).
Common types include dehydration of alcohols and dehydrohalogenation of alkyl halides (β-elimination).
Key Steps in β-Elimination:
A base removes a β-hydrogen.
C–H bonding electrons form a C=C π bond.
C–X bond breaks, and X leaves as a leaving group.
Bimolecular Elimination (E2)
Mechanism: Concerted reaction; rate depends on both substrate and base.
Rate Law:
ext{Rate} = k[ ext{RX}][ ext{Base}]Occurs with primary, secondary, or tertiary alkyl halides that have β-hydrogens.
E2 Mechanism and Stereochemistry
Transition state includes partial bonds; stereochemistry is anti-periplanar arrangement.
Unimolecular Elimination (E1)
Mechanism: Two-step involving carbocation formation and subsequent deprotonation.
Rate of reaction regulated by stability of the carbocation.
Elimination Reactions with Rearrangement
Possible for carbocations formed via E1; rearrangement can lead to more stable intermediates.
Orientation of Elimination & Zaitsev’s Rule
If multiple β-carbons are present, Zaitsev’s rule asserts that the most substituted, stable alkene is typically the major product.
Factors Influencing E1 vs E2
E2 requires strong bases and good leaving groups, typically in polar aprotic solvents. Meanwhile, E1 relies on weak bases under polar protic conditions with carbocation stability playing a crucial role.
Competition Between SN2 and E2
Strong bases which are also nucleophiles can initiate either substitution (SN2) or elimination (E2); competition increases with the size of the base and degree of substitution.
Nature of the Leaving Group
Good leaving groups are integral for ensuring efficient reaction pathways, with a ranking for halides.
Mechanism Descriptions and General Principles
Detailed understanding of mechanisms essential for predicting outcomes of various substitution and elimination pathways is necessary for pharmaceutical chemistry.
Rearrangement Reactions
Definition
Involves reshuffling or migration of atom groups to form structural isomers; typically 1,2-shifts but can occur over longer distances too.
Classification
Intermolecular Rearrangement: Migration between two molecules.
Intramolecular Rearrangement: Rearrangement occurs within the same molecule without complete detachment of the migrating group.
Types of Rearrangement
Nucleophilic Rearrangement: Group migrates toward electrodeficient atoms.
Electrophilic Rearrangement: Group moves to more electron-rich centers.
Free Radical Rearrangement: Involves shifts toward a free-radical center.
Aromatic Rearrangement: Migration toward an aromatic nucleus.
Nucleophilic Rearrangements Examples
Case studies: Pinacol-pinacolone, Wagner-Meerwein, among others.
Features of Pinacol Rearrangement
Stability of the carbonium ion dictates the preferred hydroxyl group for removal.
Migratory aptitude influences which group migrates preferentially.
Mechanisms of Rearrangement Reactions
Specific Examples
Wagner-Meerwein Rearrangement: Addresses hydride or alkyl migration to stabilize carbocations.
Pinacol Rearrangement: Illustrates four steps leading to carbonyl compounds from glycols.
Curtius Rearrangement: Transforms acyl azides to isocyanates; widely applicable in synthetic organic chemistry.
Key Applications
Synthesis of carbonyl compounds from alkenes, ring expansion, and ketones from cyclic diols via reactions involving rearrangement.
Summary of Rearrangement Mechanisms
Understanding these mechanisms provides insight into greater synthetic utility in medicinal chemistry, ensuring effective compound development and modification.
Concluding Remarks
Pharmaceutical organic chemistry employs a vast array of reactions, each holding significance for drug development and metabolic processes. Mastery of these principles ensures informed synthesis strategies and insight into biochemical interactions.
Thank You
Acknowledgements for engagement with the material; encouraging continued study and exploration in the field of pharmaceutical organic chemistry, essential for future innovations in drug development.