Functional Group 4

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Questions and Answers

What primary factor does not influence whether a reaction will proceed via an SN1 or SN2 mechanism?

Reactivity of the nucleophile

Structure of the alkyl halide

Solvent used for the reaction

Temperature of the reaction (correct)

Which statement accurately describes the concept of reaction order in the context of kinetics?

It is the number of steps in the reaction mechanism.

It is determined solely by the concentration of the alkyl halide.

It indicates the speed of the reaction independent of concentration.

It reflects the sum of the exponents of the concentrations in the rate law. (correct)

In nucleophilic substitution reactions, what are amines primarily known for?

Acting as electrophiles in chemical reactions

Being the least reactive among functional groups

Their inability to participate in nucleophilic substitutions

Their ability to react as nucleophiles (correct)

Which of the following is a challenge when attempting to alkylate amines via nucleophilic substitution reactions?

Steric hindrance and product overalkylation Signup and view all the answers

What is the primary focus of studying reaction kinetics?

To analyze the rates of reactions Signup and view all the answers

Which of the following is NOT a factor that impacts a nucleophile's reactivity?

Presence of a catalytic agent Signup and view all the answers

Which type of functional groups do amino acids contain that influences their physical properties?

Two ionisable functional groups Signup and view all the answers

When deducing if a reaction is SN1 or SN2, which option is least likely to be relevant?

Reactivity of the solvent Signup and view all the answers

Which classification describes an amine where the nitrogen atom is attached to one alkyl group and two hydrogen atoms?

Primary amine Signup and view all the answers

What is the approximate bond angle around the nitrogen atom in amines?

109 degrees Signup and view all the answers

What type of reaction occurs when primary or secondary amines react with acid chlorides?

Formation of amides Signup and view all the answers

Which statement correctly describes the hydrogen bonding capabilities of amines compared to alcohols?

Amines have weaker hydrogen bonds than alcohols. Signup and view all the answers

Which reaction would yield a primary amine through reduction?

Reduction of nitriles Signup and view all the answers

Which type of amine would react with an electrophile to form an amine salt?

Any type of amine Signup and view all the answers

How are amine drugs typically formulated for better solubility in body fluids?

As salts Signup and view all the answers

Which of the following statements is true regarding the classification of amines?

Tertiary amines have three alkyl groups attached. Signup and view all the answers

Which amphoteric nature in amino acids is referred to as zwitterion?

Simultaneous ionization of both carboxylic and amino groups Signup and view all the answers

Which type of amine is characterized by having all substituents on nitrogen being either alkyl or aryl groups?

Quaternary ammonium ion Signup and view all the answers

What primarily influences the rate of an SN1 reaction?

The concentration of the haloalkane Signup and view all the answers

Which type of alkyl halide is most reactive in an SN1 reaction?

Tertiary alkyl halides Signup and view all the answers

What is a consequence of using a chiral alkyl halide in an SN1 reaction?

Formation of a racemic mixture Signup and view all the answers

Which factor does NOT affect the rate of an SN1 reaction?

Concentration of the nucleophile Signup and view all the answers

Which type of carbocation is stabilized by resonance?

Allylic carbocation Signup and view all the answers

Which alkyl halides do not participate in SN1 or SN2 mechanisms?

Vinyl and aryl halides Signup and view all the answers

What determines the stability of a carbocation in an SN1 reaction?

The alkyl substituent's bulkiness Signup and view all the answers

What is the primary reason SN1 reactions favor bulky alkyl groups?

They stabilize carbocations Signup and view all the answers

What do chiral alkyl halides produce upon undergoing substitution?

Equal amounts of two stereoisomers Signup and view all the answers

Which statement about primary alkyl halides in SN1 reactions is correct?

They do not form stable carbocations. Signup and view all the answers

What effect does increasing the size of the haloalkane have on the rate of reaction with a given nucleophile?

It decreases the reaction rate. Signup and view all the answers

In an SN2 reaction, how does the chirality of the substituted product compare to the starting material?

It is inverted. Signup and view all the answers

What is the relationship between nucleophilicity and basicity?

More basic nucleophiles are more reactive. Signup and view all the answers

What is a characteristic of the transition state (TS) in an SN2 reaction?

It is the highest energy species. Signup and view all the answers

What can slow down SN2 reactions when using certain solvents?

Solvents that can form hydrogen bonds. Signup and view all the answers

Which of the following best describes a good leaving group in a reaction?

It can stabilize the resulting negative charge. Signup and view all the answers

Which of the following nucleophiles is generally more nucleophilic?

HS- Signup and view all the answers

What type of reaction mechanism takes place in an SN2 reaction?

One-step concerted mechanism. Signup and view all the answers

What generally happens during back side attack in an SN2 reaction?

The nucleophile approaches from the opposite face of the leaving group. Signup and view all the answers

Which statement accurately describes the effect of haloalkane size on reaction rate with a given nucleophile?

Smaller haloalkanes react faster than larger ones. Signup and view all the answers

Study Notes

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.

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Description

This quiz focuses on the functional group chemistry relevant to the MPharm programme. It covers reaction mechanisms (SN1 and SN2), the properties and reactions of amines, and challenges in alkylating amines. Enhance your understanding of these concepts essential for drug synthesis.