MEDCHEM.04

Medicinal and Pharmaceutical Chemistry Overview

Course Title: MEDCHEM 4

Focus Area: Alkylhalides I - Structures and introduction to nucleophilic substitution reactions

Instructor: Dr. Marco Monopoli

Date: 28th of January 2025

Learning Outcomes

Key Objectives

• Recall and Identify Functional Groups:Understand the structure and systematic naming of alkyl halides, recognizing common groups and their respective roles in chemical reactivity.

• Differentiate Alkyl Halides:Classify alkyl halides into primary, secondary, or tertiary categories based on the connectivity of the carbon atoms. Identify the alpha-carbon, which is the carbon atom directly bonded to the halogen.

• Properties of Alkyl Halides:Recognize that alkyl halides are polar compounds, which significantly influences their solubility and reactivity patterns in various solvents. Discuss the impact of molecular structure on boiling and melting points, highlighting the role of intermolecular forces.

• Understand Nucleophiles:Define nucleophiles as species that donate an electron pair to form a chemical bond and list common nucleophiles such as nitrogen-based (e.g., ammonia and amines), oxygen-based (hydroxide, alkoxides), and carbon nucleophiles. Compare the reactivity and strength of neutral versus charged nucleophiles, noting how charge influences nucleophilicity.

• Nucleophilic Substitution:Explain the mechanism of nucleophilic substitution reactions, focusing on the SN2 reaction mechanism which includes:

  • The type of alkyl halide involved (primary, secondary, tertiary)

  • Formation of the transition state, featuring both the nucleophile and substrate

  • The stereochemistry of products, including configurational inversion, which is a critical aspect of SN2 reactions

  • Factors influencing the rate of reaction, including steric hindrance and nucleophile strength.

• Energy Profile Diagrams:Be able to sketch and interpret energy profile diagrams for SN2 reactions, illustrating the energy changes that occur throughout the reaction and identifying key transition states and intermediates.

Alkyl Halides

Definitions and Structures

Alkyl Halides (Halo-Alkanes):Compounds that contain a halogen atom (F, Cl, Br, I) substituted for one or more hydrogen atoms in an alkane molecule, significantly altering their physical and chemical properties.

Examples:

• Methane (CH4) → Methyl (-CH3)

• Ethane (C2H6) → Ethyl (-C2H5)

• Propane (C3H8) → Propyl (-C3H7)

Naming Alkyl Halides

IUPAC Naming Rules:

• Parent Name: Identify the longest continuous carbon chain as the base name of the compound.

• Numbering Substituents: Assign the lowest possible numbers to substituents to reflect their position on the carbon chain.

• Multiple Halogens: Use appropriate prefixes (di-, tri-, tetra-) to indicate the presence of multiple identical halogens.

• Alphabetical Listing: List substituents in alphabetical order, disregarding prefixes when nomenclature breakdown is deemed necessary.

Example Names:

• 3-Bromohexane

• 2-Iodo-2-methylpropane

• 3,4-Dichlorohexane

Types of Alkyl Halides

Classification Based on Structure:

• Primary Alkyl Halides: Carbon bonded to only one other carbon, leading to less steric hindrance and typically higher nucleophilic reactivity.

• Secondary Alkyl Halides: Carbon bonded to two other carbons, showing moderate reactivity patterns.

• Tertiary Alkyl Halides: Carbon bonded to three other carbons, resulting in increased steric hindrance and preference for SN1 substitution mechanisms in most cases.

• Example: Iodomethane is classified as a primary alkyl iodide due to its structure.

Polarity of Carbon-Halide Bonds

Electronegativity:Carbon is considered partially positive, rendering it electrophilic due to its low electronegativity compared to halogens. The presence of halogens (F, Cl, Br, I) introduces significant polarity to the carbon-halogen bond, enhancing their reactivity.

Electronegativity Values:

• C = 2.5

• F = 4.0

• Cl = 3.1

• Br = 3.0

• I = 2.6

Nucleophiles

Characteristics

Electron-Rich Species:Carry a negative charge or possess lone pairs of electrons that can be donated during chemical reactions.

Types of Nucleophiles:

• Oxygen Nucleophiles: Hydroxide (OH⁻), Alkoxide (RO⁻), Water (H2O), Alcohol (R-OH).

• Nitrogen Nucleophiles: Ammonia (NH3), primary, secondary, and tertiary amines (e.g., RNH2, R2NH, R3N).

• Strength Comparison: Charged nucleophiles (e.g., OH⁻) are generally more potent than neutral nucleophiles (e.g., H2O) due to increased electron density resulting in heightened reactivity.

Nucleophilic Substitution Reactions

General Mechanism

Reaction Equation:Nucleophile + Alkyl Halide → Product + Leaving Group.

• Role of Halide Ions: Halide ions serve as excellent leaving groups owing to their high electronegativity and ability to stabilize after dissociating from the parent compound.

Mechanisms of Nucleophilic Substitution

SN1 and SN2 Reactions:

• SN1:A unimolecular nucleophilic substitution involving a carbocation intermediate formed following the departure of the leaving group. Rate primarily depends on the stability of the carbocation.

• SN2:A bimolecular process characterized by a concerted mechanism where the nucleophile directly displaces the leaving group in one single step, resulting in an inversion of configuration at the reactive carbon center.

Curly Arrows in Reaction Mechanisms

Representation:Curly arrows are used to illustrate the movement of electron pairs in chemical reactions, typically indicating the formation and breaking of chemical bonds.

SN2 Mechanism Details

Key Features

• Inversion of Configuration:The nucleophile attacks the alpha-carbon from the opposite side of the leaving group, leading to a stereochemical inversion in the product.

• Transition State Characteristics:The transition state represents the highest energy point along the reaction pathway, which is formed during the reaction process where both the nucleophile and substrate coexist.

• Dotted Lines:Dotted lines symbolize bonds that are in the process of being formed or broken, providing clarity to the dynamic nature of reactions.

Reaction Scenarios

Case Studies

Provide examples involving chloromethane with various nucleophiles, demonstrating the intricate process of bond breaking and formation characteristic of SN2 reactions and analyzing the resulting products to highlight contrasting reactivities.

Summary of Key Points on SN2 Reactions

• Backside Attack:The nucleophile approaches the alpha-carbon from the opposite direction of the leaving group, crucial for ensuring a successful reaction.

• Transition States:In SN2 mechanisms, there are no intermediates; the correlation between reactants and products occurs directly, affecting kinetics.

• Energy Considerations:Discuss how primary alkyl halides demonstrate higher reactivity than secondary ones, while tertiary halides favor SN1 due to sterics involved in the transition state process.

• Kinetics:The overall reaction rates depend on the concentrations of both the nucleophile and the substrate, emphasizing the bimolecular nature of the SN2 mechanism.

Conclusion

The inversion of configuration due to backside attack is a hallmark characterizing SN2 mechanisms, contrasting significantly with the pathway presented in SN1 mechanisms.

Practice Questions

Consider the reaction of 1-bromobutane with:

• (a) NaI

• (b) KOH

• (c) H—C≡C—Li

• (d) NH3

Closing Remarks

Encourage continued study and engagement with medicinal and pharmaceutical chemistry concepts, stressing the relevance of alkyl halides and nucleophilic substitution mechanisms in synthetic applications and drug development.