Functional groups 1-4

MPharm Programme PHA111 Functional Group Chemistry

• The week 10 and week 11 lectures cover functional group chemistry, focusing on alkanes, alkenes, alkynes, alcohols, phenols, amines, haloalkanes, and relevant reactions.
• The course aims to explain how functional groups influence the properties and reactivity of organic molecules, including drugs.
• Learning Objectives for week 10: Appreciate the importance of functional groups in pharmacy; Define reaction mechanisms; Identify nucleophiles/electrophiles etc.; and learn how to identify functional groups in drug molecules.
• Learning Objectives for week 11: Identify and understand differences in physical properties of alcohols/haloalkanes/phenols; List reactions used to prepare alcohols; and understand nucleophilic substitution reactions of alcohols and haloalkanes.
• Learning Objectives for week 11 (additional): Identify and understand differences in physical properties of amines; describe the synthesis of amines; understand nucleophilic substitutions of amines; recognise the different types of secondary and tertiary amines; and classify amines.

Functional Groups

• Functional group chemistry is a critical aspect of understanding drug molecules and their properties.
• Understanding the chemistry of functional groups enables the determination of drug properties.
• Key properties include ionization, solubility (lipid vs. aqueous), absorption, distribution, metabolism, and excretion (ADME).

What is a Functional Group?

• Most drugs are composed of two parts: a hydrocarbon part and a functional group (FG).
• The hydrocarbon part is usually unreactive.
• The functional group is where most reactions/interactions occur.
• Molecules having the same functional group generally have similar properties and characteristic reactivities.
• Examples of functional groups are given in the lecture materials.

Chemical Similarity

• The lecture uses an example of extreme bronchospasm to illustrate the concept of chemical similarity in drug molecules.
• Different structures showing the same functional group are examples

What is a Functional Group (continued)

• The different types of hydrocarbons including alkanes, alkenes, alkynes, alcohols, and phenols are covered.
• The specific groups of each hydrocarbon are further explained.
• Examples and diagrams demonstrate different structures for each group.

3D Representations

• sp³ hybridized carbon atoms have a tetrahedral shape.
• 3D structures are represented using wedged and hashed bonds.
• Chiral centers (carbon atoms with four different groups attached) are crucial for understanding chiral molecules.

Reactivity and Reaction Mechanisms

• A chemical mechanism is a detailed step-by-step description of a chemical process.
• Chemical reactions involve the movement of electrons.
• Reactivity can be classified as ionic/polar or radical, depending on the movement of electrons.

Nucleophile

• A nucleophile is electron-rich, drawn with a curly arrow starting at the electron rich center.
• Charged and uncharged nucleophiles are both discussed and exemplified.

Electrophile

• An electrophile is electron-poor, drawn with a curly arrow ending at the electron poor center.
• Charged and uncharged electrophiles are covered.

Leaving Groups

• Leaving groups are ions or neutral molecules displaced from a reactant in a mechanistic sequence.
• Good leaving groups form stable ions or neutral molecules after leaving the substrate.
• Standard abbreviations are provided.

Bond Cleavage

• Heterolytic cleavage involves both electrons moving to one atom.
• Homolytic cleavage involves each atom retaining one electron.

Curly Arrows - Polar Mechanisms

• A double-headed curly arrow denotes the movement of two electrons.
• The lecture notes emphasize precise arrow placement for clarity.
• The various components (electron rich centers, negative charge, lone pairs, and electron-rich bonds) and their relative positions in a molecule are explained.

Curly Arrows - Radical Mechanisms

• The movement of a single electron is indicated by a single-headed curly arrow.
• Radicals must donate/accept one electron to form/break a bond.

Transition States and Intermediates

• Reaction mechanisms can involve transition states and/or intermediates.
• Graphical diagrams are provided depicting the energy change over time involved in reactions.
• The concept of activation energy is explained visually.
• The distinction between transition states and intermediates is explained.

Why Study Mechanisms?

• The need for a thorough understanding of drug formation, drug-target interactions, and reaction mechanisms for predicting metabolic drug stability is emphasized.

Penicillins MOA

• A detailed example of covalent inhibition.
• Explains how the reaction proceeds from an ester to an amide.

Hydrocarbon Compounds

• The three main types are aliphatic, aromatic, and saturated.
• Each of these are further broken down into smaller categories.
• The sub-types are explained through examples and diagrams.

Alkane

• Saturated compounds containing only C-C and C-H bonds with no double or triple bonds.
• These are usually unreactive.

Alkanes: Physical Properties

• Melting/boiling points increase with molecular weight and chain length.
• Weak London dispersion forces are the only intermolecular forces.

Alkanes: Reactivity

• Reactions include combustion, halogenation.
• Halogenation requires high temperatures or light.
• Radical halogenation is a multi-step process.

Alkanes: Halogenation

• Halogenation of alkanes follows a radical mechanism.
• Three main steps of the radical mechanism are highlighted (initiation, propagation, termination) and visual representations.

Radical Stability

• Factors affecting radical stability, such as the number of carbon atoms bonded to the radical center, are outlined.
• Hyperconjugation and/or resonance stabilization affect the stability of radicals.
• Examples are shown of radicals being generated from butane.

Hyperconjugation

• Hyperconjugation is a stabilizing interaction between σ electrons and an unfilled p orbital or a π orbital.
• This phenomenon extends the molecular orbital, increasing the stability of the system and described via suitable examples.

Radical Stability (continued)

• The stability of different radicals (methyl, primary, secondary, tertiary, benzyl, allyl) is compared.
• Resonance delocalization of electrons in radicals increases their stability, specifically in benzyl and allyl radicals.

Resonance Contributors and Hybrids

• Resonance structures (often visualized as molecules fluctuating between drawings) show different arrangements of electrons in a molecule—the actual molecule is a hybrid of all possible resonance forms.
• The concept of resonance contributors and resonance hybrids is illustrated visually with various examples.

Resonance Structures

• Resonance structures, not isomers, are alternative representations of the same molecule.
• They are connected by using double-headed arrows.

Resonance

• Resonance shows delocalization of electron/charge through resonance structures.

Resonance Structures (continued)

• The stability of resonance structures relates to the number of covalent bonds.
• The most stable resonance structure makes the greatest contribution to the molecule.

Oxidation – Radical Process

• Autoxidation, a radical process, is a significant cause of drug degradation.
• Autoxidation leads to a loss of electrons and increases in bonds to oxygen.

Functional Group Chemistry 2

• The week 11 lectures cover the reactivity of alkenes and alkynes, including electrophilic addition (Markovnikov's rule) and discuss the role and importance of chiral molecules.

Alkenes - Summary

• Contains double bonds - are more reactive than alkanes.
• The different types of isomers, such as cis and trans isomers, are described due to restricted rotation around the double bond
• Reactivity of alkenes is discussed.

Alkenes: Isomers and Vision

• Cis-retinal isomerization is central to vision.
• Light absorption triggers isomerization. Alkenes are key in this process.

Alkenes: Reactivity

• Alkene reactions discussed in the lecture include various reactions such as cracking, elimination (dehydrohalogenation and dehydration), addition reactions (electrophilic and homolytic), hydrogenation, and halogenation where different mechanisms are examined.

Alkenes: Addition Reactions

• Different types of addition reactions are included: electrophilic (with a positive charge seeking electrons) and homolytic.

Alkenes: Reactivity (Summary)

• Markovnikov/Anti-Markovnikov additions, including the principles behind these reactions.

Alkenes: Hydration

• Markovnikov addition of water to alkenes.
• Le Chatelier's principle is used to promote the addition reaction.

Alkenes: Anti-Markovnikov Addition

• Anti-Markovnikov addition requires peroxide as a radical initiator.

Alkenes: Addition of Halogens

• Additions of halogens to alkenes, especially Br2 and Cl2, are explained in detail.

Alkenes: Hydrogenation

• Hydrogenation (addition of hydrogen across a double bond) is a reaction that is stereospecific and requires a catalyst.
• The reaction can be stopped at the alkene stage.

Alkynes: Structure

• Contains triple bonds.
• Internal/terminal triple bonds exist, with reactivity being controlled by electron-rich C-C triple bonds.

Alkynes: Physical Properties

• Data on the boiling points of different terminal and internal alkynes.
• Internal alkynes have a higher boiling point than terminal alkynes.

Alkynes: Relative Acidity

• The relative electronegativities of carbon atoms are compared.

Alkynes: Reactivity

• Alkynes are more reactive than alkenes.
• Similar reactions to alkenes like addition reactions with H-X, X-X, H-H, and H-OH are described.
• Examples of alkylation of terminal alkynes are shown using a strong base.

Alkynes: Addition of HX

• Sequential addition of HX.
• Markovnikov's Rule and vinylic carbocation intermediates are involved.

Alkynes: Addition Reactions

• Anti-Markovnikov addition (with a radical initiator present).
• Halogenation reactions proceed similarly to alkenes.

Alkynes: Hydration

• Hydration of alkynes and the formation of ketones

Alkynes: Hydrogenation

• Hydrogenation reaction.
• Use of Lindlar's catalyst.

Alkynes: Versatile Reagents

• Summary of the reactions/types of molecules (alkynes) involved.
• Overview of useful reagents used.

Functional Group Chemistry 3 - Learning Objectives

• Describing and explaining differences in physical properties of alcohols (aliphatic, phenols, haloalkanes).
• Listing the reactions that alcohols undergo.
• Reactivity of alcohols and alkyl halides with regards to nucleophilic substitution reactions.

Alcohols - General Properties

• Alcohols and their classifications.
• Sub-classification into their types (primary, secondary, and tertiary).
• How alcohols act as nucleophiles
• Sub-classification into different types of alcohols

Alcohols: pKa

• Factors influencing alcohol acidity.
• Alkyl groups positively affecting acidity
• Halogens negatively affecting acidity
• Resonance structure to stabilise phenoxide ion

Alcohols: Physical Properties

• Solubility of alcohols with water.
• Like dissolves like.
• Boiling points increase compared to the analogous alkane.

Alcohols: Preparation

• Methods for preparing various types of alcohols.
• Reactions such as hydration of alkenes, alkyl halide hydrolysis reactions, and reduction of carbonyl compounds are covered.

Reduction of Carbonyl Compounds

• Methods of reduction, such as using sodium borohydride and lithium aluminum hydride to reduce aldehydes and ketones (via hydrogen transfer).

Alcohols: Useful Reagents

• Key reagents/reactions.

Alcohols: Reactivity

• Complete combustion; alkoxide formation; ester formation; oxidation reactions; reactions with HX; conversion to haloalkanes

Ester Formation

• Fischer esterification is the classical method for forming esters.

Oxidation

• Oxidation reactions using high oxidation state metal salts and/or other reagents.
• Biological oxidation is a two-step procedure.

Haloalkanes: General

• Structure of haloalkanes.
• Reactivity as electrophiles and how they are affected by the nature of the halogen and alkyl groups.

Haloalkanes: Anaesthetics

• Uses of haloalkanes in anesthetic procedures.
• Factors relating to the choice and use of particular haloalkanes.

Haloalkanes: Physical Properties

• Boiling points.
• Density.
• Solubility.

Haloalkanes: Reactivity

• Free radical substitution of alkanes; electrophilic addition; halogenation of alkenes/alkynes; halogenation of alcohols.
• Nucleophilic substitution reactions.

SN1 and SN2 Reactions

• Mechanisms and characteristics of SN1 and SN2 reactions
• Explains the differences regarding rates of reaction with different types and sizes of alkyl substituents.

Nature of the Nucleophile

• Nucleophilicity of the group attacking the substrate.

Nature of the Nucleophile (continued)

• Basicity and its relationship to nucleophilicity.

Solvent Effects

• How solvents affect S$_\text{N}2$ reactions.
• Polar aprotic solvents.

Nature of the Leaving Group

• Properties of good leaving groups, including stability as an anion.

SN1 Reaction Mechanism

• The rate-determining step (RDS) is the loss of the leaving group which forms a carbocation intermediate.

Nature of the Alkyl Substituent

• The stability of carbocations and its relationship to the stability of the alkyl group substituent.

Racemisation of Stereocentres

• The SN1 reaction of a chiral alkyl halide produces a racemic mixture.

Characteristics of the SN1 Reaction

• Tertiary alkyl halides are more reactive.
• Stability of carbocation intermediates.
• Allylic and benzylic halides are more reactive to SN2 mechanism

A Note: Vinyl and Aryl Halides

• Vinyl and aryl halides do not react via S$\text{N}1$ or S$\text{N}2$.

Nucleophilic Substitution Examples in Biology/Pharmacy

• Examples of nucleophilic substitutions used in biological systems and drug synthesis, specifically, methylation.

SN1 vs SN2 Summary

• Summarizes reaction mechanisms, reaction types, and relative reactivity.

Amines: Occurrence

• Examples of amines in biological molecules.

Synthesis of Amines

• Different methods for synthesizing amines (reduction of nitriles and amides, reduction of imines) and the considerations for monoalkylation.

Reactions with Carboxylic Acid Derivatives

• Reactions in which primary/secondary amines can react with acid chlorides, amides, and sulfonyl chlorides.

Properties of Amines

• Structure and bonding characteristics, including hybridization and presence of lone pairs in amines.
• Lone pairs make amines basic and nucleophiles.

Amines - Classification

• Sub-classification of amines into primary, secondary, tertiary and quaternary ammonium salts.

Amines - Hydrogen Bonding

• Hydrogen bonding features of amines.
• Explains the difference in H-bonding ability between amines and alcohols.

Amine Salts

• Properties of amine salts.
• Includes properties such as water solubility, and the role of these properties in formulations of amine drugs.

Acid/Base Properties of Amino Acids

• Explains how amino acids behave like acids and bases in solution.
• Details of the Zwitterion as the dipolar ion that amino acids can exist as.