Functional Group 4

MPharm Programme - PHA111 Functional Group Chemistry 4

• Course lecturer: Dr. Stephanie Myers
• Lecturer title: Senior Lecturer in Medicinal Chemistry
• Contact details: Dale 1.21, [email protected], 0191 5152760
• Week 11, Slide 1 of 29

Learning Objectives

• Deduce reaction mechanisms (SN1 or SN2) based on reagents and conditions.
• Describe physical and chemical properties of amines, including their nucleophilic behaviour.
• Provide examples of amine reactions in drug synthesis, including reagents and conditions.
• Understand synthetic challenges in alkylating amines via nucleophilic substitution and potential solutions.
• Describe physical properties of amino acids with ionisable functional groups, referencing ionisation.

SN1 and SN2 Mechanisms

• Reaction mechanism choice depends on alkyl halide structure, nucleophile reactivity, nucleophile concentration, and solvent type.
• Kinetics studies reaction rates.
• Reaction order is the sum of exponents in the rate law (dependence on reagent concentrations).
• First-order reactions depend on one reagent in the rate-determining step.
• Second-order reactions depend on the concentration of two reagents in the rate-determining step.

Experimental Evidence Supporting SN2 Mechanism

• Reaction rate depends on both haloalkane and nucleophile concentration.
• Reaction rate decreases with increasing haloalkane size (for a given nucleophile).
• Inversion of chirality in chiral haloalkane substrates occurs during substitution.

Size of Alkyl Halide

• Reaction rate with a given nucleophile decreases with increasing haloalkane size.
• Relative reactivity follows the order: Tertiary < Neopentyl < Secondary < Primary < Methyl.

SN2 Reaction Mechanism

• One-step, concerted reaction mechanism.
• Transition state is the highest energy species.
• Activation energy for methyl bromide reaction is lower than for sterically hindered alkyl bromides.
• Transition state is planar.

Inversion of Stereochemistry

• Chirality of the substituted product inverts relative to the original reacting alkyl halide.
• Inversion is due to back-side attack during SN2 reaction.
• This is known as Walden Inversion.
• Incoming nucleophile approaches from opposite face to the leaving group.

Nature of the Nucleophile

• Nucleophilicity measures how readily a compound reacts with an electron-deficient atom.
• Polarizability measures how well a nucleophile can encroach on an electrophile’s bonding orbital.
• Atoms with larger electron shells are generally better nucleophiles.
• Halide reactivity order is I⁻ > Br⁻ > Cl⁻.

Nature of the Nucleophile (Basicity)

• Basicity is a measure of a compound’s tendency to donate a lone pair of electrons to a proton.
• Bases are nucleophiles, and the dissociation constant (Ka or pKa) measures basicity.
• Negatively charged species are stronger nucleophiles.
• Relative strength of nucleophiles: OH⁻ > CH₃O⁻ > NH₂⁻ > CH₃CH₂NH⁻.

Solvent Effects

• Solvents with hydrogen bonding capability (e.g., alcohols, amines) can slow down SN2 reactions by interacting with reactants.
• Energy is needed to break interactions between solvent and reactants.
• Polar aprotic solvents (e.g., DMF, DMSO) permit faster reactions.

Nature of the Leaving Group

• Good leaving groups lower the activation energy for a reaction.
• Stable anions that are weak bases are usually excellent leaving groups, as they can stabilize the resulting negative charge.
• Weaker bases are generally better leaving groups.
• Poor leaving groups include strong bases and small anions.
• Relative reactivity for leaving groups varies: OH⁻ << NH₂, OR⁻ << F⁻ < Cl⁻ < Br⁻ < I⁻.
• Relative reactivity follows the order: I⁻ > Br⁻ > Cl⁻ > F⁻

SN1 Mechanism

• Reaction rate depends only on the concentration of the haloalkane.
• Increasing nucleophile concentration has no effect on the rate.
• Rate-determining step is the loss of the leaving group and formation of the carbocation.
• Carbocation stability increases with alkyl substituent bulkiness: methyl < primary < secondary < tertiary.

Nature of the Alkyl Substituent

• Reaction rates are favoured by bulkier alkyl substituents.
• This is due to the stability of the carbocation intermediates, which increases with increasing alkyl carbon branching.
• Methyl, primary, secondary, and tertiary carbocations are ordered by stability with tertiary being the most stable.

Racemisation of Stereocentres

• Substitution of a chiral alkyl halide leads to a racemic mixture of products (a 1:1 mixture of stereoisomers).
• Carbocations are planar.
• Nucleophile attack can occur from either side, leading to equal amounts of products with retained and inverted configurations.

Characteristics of the SN1 Reaction

• Tertiary alkyl halides react most readily through the SN1 mechanism due to carbocation stability.
• Allylic and benzylic carbocations are stabilized by resonance delocalisation.
• Primary allylic and benzylic halides show increased SN2 reactivity.

Note: Vinyl and Aryl Halides

• Vinyl and aryl halides do not typically react via SN1 or SN2 mechanisms.

Nucleophilic Substitution Examples in Biology/Pharmacy

• Methylation is used in drug synthesis (e.g., adrenaline synthesis).
• Nitrogen mustards are used in cancer treatment through DNA crosslinking.

SN1 vs SN2 Summary

• SN1 is a stepwise carbocation substitution mechanism.
• SN2 is a one-step bimolecular substitution mechanism.
• Reactivity trends vary by alkyl halide type.

Amines: Occurrence

• Many biologically significant molecules, including amino acids, vitamins, DNA and RNA bases, and alkaloids, contain amine groups.
• 70% of pharmaceuticals contain nitrogen.

Synthesis of Amines

• Amides and nitriles reduction methods are used to generate primary amines from carboxylic acids and alkyl halides.
• Imine reduction yields secondary and tertiary amines.
• Monoalkylated products can be synthesised via other methods to avoid product mixtures.

Reactions with Carboxylic Acid Derivatives

• Primary or secondary amines react with acid chlorides to yield amides.
• Amines react with sulfonyl chlorides to create sulphonamides (used for antibacterial sulfa drugs).
• These are NOT SN2 reactions.

Amines - Structure and Bonding

• Amines are similar to ammonia in bonding.
• Nitrogen is sp³ hybridised.
• Lone pair electrons reside in sp³ hybrid orbitals.
• Tetrahedral geometry.
• C−N−C bond angles are approximately 109°C.
• Nitrogen has a strong electrostatic potential due to its lone pairs.
• Amine reactivity characteristics centre on the lone electron pairs (basic and nucleophilic).

Amines - Classification

• Alkylamines have alkyl substituents.
• Arylamines have aryl substituents.
• Amines are classified as primary (RNH₂), secondary (R₂NH), or tertiary (R₃N).
• Quaternary ammonium ions have a positively charged nitrogen atom with four attached groups (e.g., R₄N⁺).

Amines - Hydrogen Bonding

• Amines can form hydrogen bonds.
• NH is less polar than OH.
• Amines form weaker hydrogen bonds than alcohols.
• Boiling points of amines are lower than those of alcohols, as amines have weaker hydrogen bonds.
• 1° and 2° amines act as both hydrogen bond donors and acceptors, 3° amines only accept.

Amine Salts

• Amine salts are formed when amine lone pairs react with acids.
• Amine salts are ionic solids with high melting points.
• Amine salts are soluble in water.
• Amine salts are odourless.

Acid/Base Properties of Amino Acids

• Amino acids have both carboxylic acid and amino groups.
• Neutral solutions: both groups are ionised, creating a dipolar ion (zwitterion).
• Acidic solutions: carboxylic acid group predominately non-ionised and amino group predominately ionised.
• Basic solutions: Opposite to acidic solutions.
• Uncharged form of the amino acid does not exist.