PHM 1107-Pharmaceutical Organic Chemistry

Definition: An alkyl halide has a halogen atom bonded to one of the sp³ hybridized (tetrahedral) carbon atoms of an alkyl group.
Bond Polarity: The carbon–halogen bond in an alkyl halide is polarized due to the higher electronegativity of the halogen compared to carbon. This results in:
- Carbon atom having a partial positive charge (δ+)
- Halogen atom having a partial negative charge (δ−)

Alkyl halides are classified based on the number of carbon groups (R) directly bonded to the carbon bearing the halogen:
- Primary (1°): One carbon group attached.
- Secondary (2°): Two carbon groups attached.
- Tertiary (3°): Three carbon groups attached.

Generally known as alkyl halides, they are systematically named as haloalkanes. The naming procedure consists of the following steps:
1. Identify the Longest Chain: Find the longest carbon chain and name it as the parent chain. If a multiple bond is present, it must be included in the parent chain.
2. Number the Chain: Begin numbering the carbons from the end closer to the first substituent (alkyl or halo). If substituents are equidistant from both ends, prioritize by alphabetical order.
3. Write the Name: List all substituents in alphabetical order, using prefixes like di-, tri-, etc., for multiple same substituents.

The most effective method to prepare alkyl halides involves conversion from alcohols, which are easily obtained from carbonyl compounds.
- Common reactions involve treating the alcohol with:
- HCl or HBr (works best with tertiary alcohols)
- Example: 1-Methylcyclohexanol is treated with HCl to yield 1-chloro-1-methylcyclohexane.
For primary and secondary alcohols, conversion is best achieved using:
- Thionyl chloride (SOCl₂) or Phosphorus tribromide (PBr₃) (high yield)
Alternative reagents for producing alkyl fluorides from alcohols:
- Diethylaminosulfur trifluoride [(CH₃CH₂)₂NSF₃]
- HF-pyridine (pyridine acts as an analog of benzene).

Substitution Reactions: Occur when a nucleophile replaces the halogen.
Elimination Reactions: Occur when a π bond (alkene) is formed through the departure of the halogen.

Leaving Group: The halogen can leave with its bonding pair of electrons to form a stable halide ion, making it a good leaving group.
Dehydrohalogenation: A specific elimination reaction where a hydrogen halide is removed, resulting in the formation of an alkene.

In a nucleophilic substitution reaction, a nucleophile displaces a leaving group from a carbon atom, using a lone pair of electrons to form a new bond.
Good Leaving Group:
- A substituent that can leave as a stable, weakly basic molecule or ion (e.g., halide anions).
Example of nucleophilic substitution:
- Reaction of iodomethane (CH₃I) with hydroxide ion (OH⁻) yields methanol (CH₃OH).

Order: This one-step reaction is referred to as the SN2 mechanism (Substitution, Nucleophilic, Bimolecular).
Bimolecular: The rate-limiting step involves two molecules colliding; therefore, the overall reaction is second order.
Stereospecificity: Inversion of configuration occurs at the chiral carbon.
- The nucleophile attacks from the back side, opposite of the leaving group.

Occurs mainly on tertiary substrates in neutral or acidic conditions.
Mechanism Steps:
1. Loss of leaving group forms a carbocation intermediate.
2. The nucleophile attacks the carbocation in a second step.
Unimolecular: Rate depends solely on the substrate (one molecule) and not the nucleophile.
Result: The intermediate carbocation can be attacked from either face leading to potential retention and inversion of configuration (racemization).

Can be first-order (E1) or second-order (E2) processes, focusing on bases rather than nucleophiles.
Beta Elimination: Involves removal of a proton from the β position and ejection of the leaving group from the α position, forming a double bond.
- Requires a strong base.
Mechanisms:
- E1: Two-step mechanism with a carbocation intermediate.
- E2: Concerted mechanism with no intermediate.

Hydride Shift: A movement of hydrogen with its electrons from one atom to another, converting less stable carbocations into more stable ones.
Example: Reaction of 2-bromo-3-methylbutane where the product shows rearrangements to form 2-ethoxy-2-methylbutane.

Nitrogen Mustard Anticancer Drugs: These drugs utilize two SN2 reactions to alkylate DNA.
Chloroform: Historically used as an anesthetic; replaced due to toxicity. Current uses include:
- Solvent for fats and oils, extracting compounds like penicillin.
- General anesthesia; associated risks include liver toxicity and heart failure.

Uses: Production of tetraethyllead (TEL, a fuel additive), refrigerant, anesthetic, and diagnostic agent in dentistry.
Toxicity: Overexposure risks; heart rate reductions at high concentrations.

Uses: Pesticide formulation, solvent for various compounds, and historical anesthetic.
Toxicity: Known to be toxic to the liver with historical risks in anesthetic applications.

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McMurry, J. E. (2010). Fundamentals of Organic Chemistry. Cengage Learning.
Sathe, N., Sharma, R., Malav, M., & Thagele, R. (n.d.). A Textbook of Pharmaceutical Organic Chemistry-1. CP Publication.
Solomons, G., Fryhle, C. B., & Snyder, S. A. (2016). Organic Chemistry.
Wade, L. G. (2013). Organic Chemistry. Pearson.