PHM 1107 - Pharmaceutical Organic Chemistry Alcohols

Definition: Alcohols are compounds characterized by the presence of a hydroxyl group (OH) connected to an $sp^3$ -hybridized carbon atom.
Nomenclature: Alcohols are named with the suffix “-ol”.
Occurrence: A vast number of naturally occurring compounds are known to contain a hydroxyl group.
Classification:
- Primary Alcohols (1°): One carbon substituent bonded to the hydroxyl-bearing carbon.
- Secondary Alcohols (2°): Two carbon substituents bonded to the hydroxyl-bearing carbon.
- Tertiary Alcohols (3°): Three carbon substituents bonded to the hydroxyl-bearing carbon.

Steps for Naming Alcohols:
1. Identify the longest carbon chain containing the hydroxyl group.
- Remove the final -e from the alkane name.
- Add the suffix -ol to create the root name.
1. Number the carbon chain, starting at the end nearest the hydroxyl group.
- The number indicates the position of the hydroxyl group.
- The hydroxyl group takes precedence over double and triple bonds.
1. The locant (position number) can either be placed before the parent name or before the suffix ‘-ol’.
2. Name all substituents and their corresponding numbers, similar to alkanes or alkenes.
- Example: Longest chain (4 carbons) = butanol; if on the second carbon = butan-2-ol; complete name = 1-bromo-3,3-dimethylbutan-2-ol.
1. For a chiral center present, indicate the configuration at the beginning of the name.
2. Cyclic Alcohols: Numbering starts at the hydroxyl-bearing carbon (C–1 is understood).

Boiling Points: Alcohols exhibit higher boiling points than hydrocarbons due to hydrogen bonding interactions.
- Example: Ethanol's boiling point is significantly higher than those of ethane and chloroethane.
Intermolecular Forces: Strong hydrogen bonds are essential for interactions with water.
- Miscibility: Methanol is miscible with water, indicating it can mix in any proportion without separation.
- Hydrophobic vs. Hydrophilic: The hydrophobic region (larger alkyl groups) decreases solubility in water as size increases, while the hydrophilic region (hydroxyl groups) interacts favorably with water through hydrogen bonds.

Antibacterial Properties:
- Primary Alcohols: Such as methanol, ethanol, n-propanol, and n-butanol show increasing antibacterial potency with molecular weight, peaking at an alkyl chain length of eight carbon atoms (n-octanol).
- Beyond Eight Carbons: Antibacterial potency diminishes.
- Chain Branching: Reduces alcohol's ability to penetrate cell membranes; for instance, isopropanol is less potent than n-propanol, despite being more cost-effective to produce.
Resorcinol: A weak antiseptic used for skin conditions (e.g., eczema, psoriasis).
- The potency increases with alkyl chain addition; hexylresorcinol is more effective and exhibits bactericidal and fungicidal properties, commonly used in throat lozenges.

Substitution Reactions: Alcohols can be prepared by substitution where a leaving group is replaced by a hydroxyl group.
- Primary Substrate: Requires SN2 conditions (strong nucleophile).
- Tertiary Substrate: Requires SN1 conditions (weak nucleophile).
- Secondary Substrate: Neither SN2 nor SN1 is highly effective (refer to alkyl halides discussion).
Acid-Catalyzed Hydration of Alkenes:
- Alkenes react with water in the presence of an acid catalyst generating alcohols, following Markovnikov regioselectivity.
- This process is reversible; the mechanism is essentially the reverse of alcohol dehydration.
Preparation via Reduction:
- A decrease in oxidation state represents reduction (e.g., formaldehyde to methanol).
- Reduction of ketones/aldehydes to yield alcohols requires a reducing agent.
Common Reducing Agents:
- Sodium Borohydride (NaBH4):
- Acts as a hydride source, suitable for ketones/aldehydes.
- Mechanism involves hydride transfer to the carbonyl, followed by proton transfer.
- Hydride itself is a poor nucleophile; NaBH4 is effective as a nucleophile.
- Geometric Change: The carbon of the carbonyl transitions from $sp^2$ to $sp^3$ hybridization during the reduction.
- Lithium Aluminum Hydride (LiAlH4): A stronger reagent than NaBH4, reacts violently with protic solvents; requires a two-step process (treatment followed by workup with proton source).

General Reactivity:
- Hydroxyl oxygen is nucleophilic and weakly basic; the hydrogen is weakly acidic.
- Hydroxyl groups can become leaving groups for substitution and elimination.
Protonation Impact: Protonation converts the poor leaving group (HO−) into a better leaving group (H2O), enhancing the carbon's electrophilicity for nucleophilic attack.
Substitution Mechanisms:
- SN1 Mechanism: Tertiary alcohols utilize SN1, starting with hydroxyl group protonation leading to a carbocation intermediate.
- SN2 Mechanism: Primary and secondary alcohols necessitate SN2 to convert alcohols into alkyl halides.
- Conversion to Tosylate: An alcohol can be transformed into a tosylate with tosyl chloride and pyridine, facilitating subsequent SN2 attacks.
Oxidation Processes:
- Primary alcohols can be oxidized to aldehydes, and further to carboxylic acids.
- Secondary alcohols oxidize to ketones; tertiary alcohols resist oxidation due to the lack of protons at the alpha position.

Definition: Refers to the reactions in an organism that convert drugs to compounds usable by the body or excretable.
Glucuronidation: A common metabolic pathway wherein a bad leaving group is converted into a good one, followed by an SN2 reaction involving UDPGA (uridine-5’-diphospho-α-D-glucuronic acid).
1. Formation of UDPGA involves converting a hydroxyl group from glucose into a good leaving group.
2. The drug being metabolized undergoes a nucleophilic attack on UDPGA to expel a good leaving group, managed by enzyme UDP-glucuronyl transferase.
Biological Redox Reactions:
- NADH: Functions as a hydride delivery agent (reducing agent), reducing ketones or aldehydes to form alcohols while being oxidized to NAD+.
Role of NAD+: Can act as an oxidizing agent by accepting a hydride from alcohol, thus participating in redox reactions integral to metabolism (e.g., citric acid cycle, ATP synthesis).

Oxidation Pathway: Ethanol as a primary alcohol undergoes two oxidations, producing acetaldehyde first, followed by acetic acid, which is non-toxic compared to acetaldehyde causing undesirable effects (e.g., nausea).
Binge Drinking Effects: Consumption of large quantities of ethanol leads to acetaldehyde buildup, resulting in hangover symptoms, managed minimally by hydration between drinks.

Effectiveness: Ethanol and propan-2-ol are both effective as topical antiseptics, with ethanol used in mouthwashes.
Mechanism: These alcohols kill microorganisms without harming human cells at low toxicity levels.

Klein, D. R. (2016). Organic Chemistry (4th ed.). John Wiley & Sons, Inc.
Solomons, G., Fryhle, C. B., & Snyder, S. A. (2016). Organic Chemistry. John Wiley & Sons.
Wade, L. G. (2013). Organic chemistry. Pearson.