Structure and Synthesis of Alcohols Biological Activity Nomenclature Preparation Reactions

Structure of Water and Methanol File Name: AAAKWXK0 Oxygen is sp3 hybridized and tetrahedral. The H—O—H angle in water is 104.5°. The C—O—H angle in methyl alcohol is 108.9°.

Examples of Classifications H 3 2 O * C H 3 O 2 * Primary alcohol Secondary alcohol C H 3 O * Tertiary alcohol Phenol

Some Alcohols

Alcohols are Found in Many Natural Products

Paralytic Shellfish Poisoning

Ethanol: the Beverage

Enzymatic Oxidation of Ethanol Ethanol oxidizes to acetaldehyde, then acetic acid, which is a normal metabolite.

Excess NADH can cause Metabolic Problems

Methanol: Not a Beverage

Synergistic and Metabolic Effects In men, ethanol lowers levels of testosterone (and sperm count) due to lack of enzymes needed for the steroid biosynthesis. The enzyme CYP2E1, which is responsible for converting acetaminophen into liver toxins, is activated by ethanol. Ethanol has a caloric value of 7.1Cal/g (fat has a value of 9 Cal/g). Alcohol can cause a degenerative muscle disease called alcoholic myopathy (3 times more common than cirrhosis).

Synergistic Effects Women will have higher BAL’s with the consumption of an equal number of drinks due to lower ADH activity and lower % H2O in blood. Estradiol levels increase in women (and men). This has been associated with higher incidences of heart disease and a change in bone density. A higher than normal concentration of Cytochrome P-450 enzymes (in the liver) are activated by ethanol creating a potential dependency.

Antitumor Agents Often functionalized with alcohols Designed to fit into specific geometic sites on proteins Hydrogen bonding is crucial for binding Water solubility is crucial for cell membrane transport

From the Bark of the Pacific Yew Tree Taxol (Paclitaxel)

How Taxol Works A large number of microtubules are formed at the start of cell division, and as cell division comes to an end, these microtubules are normally broken down into tubulin – a protein responsible for the cell’s structural stability. Taxol promotes tubulin polymerization then binds to the microtubules and inhibits their depolymerization back into tubulin. The cell can't divide into daughter cells and therefore the cancer can’t spread.

May be More Effective than Taxol

DNA Cross-linker

Prevents DNA from Unraveling

IUPAC Nomenclature Find the longest carbon chain containing the carbon with the —OH group. Drop the -e from the alkane name; add -ol. Number the chain, giving the —OH group the lowest number possible. Number and name all substituents and write them in alphabetical order.

Alcohol Nomenclature

Nomenclature

Naming Diols Two numbers are needed to locate the two —OH groups. Use -diol as suffix instead of -ol. 1 2 3 4 5 6 hexane-1,6-diol

Who am I?

Boiling Points of Alcohols Alcohols have higher boiling points than ethers and alkanes because alcohols can form hydrogen bonds. The stronger interaction between alcohol molecules will require more energy to break, resulting in a higher boiling point. File Name: AAAKWYJ0

Physical Properties b.p. oC m D sol. in H2O CH3CH2CH3 -42 0.08 i   CH3OCH3 -25 1.3 ss CH3CH2OH 78 1.7 vs

Acidity of Alcohols Due to the electronegativity of the O atoms, alcohols are slightly acidic (pKa 16-18). The anion dervived by the deprotonation of an alcohol is the alkoxide. Alcohols also react with Na (or K) as water does to give the alkoxide (red-ox):

Formation of Alkoxide Ions Ethanol reacts with sodium metal to form sodium ethoxide (NaOCH2CH3), a strong base commonly used for elimination reactions. More hindered alcohols like 2-propanol or tert-butanol react faster with potassium than with sodium. File Name: AAAKWYQ0

Withdrawing Groups Enhance Acidity alcohol pKa CH3OH 15.54 CH3CH2OH 16.00 CF3CH2OH 12.43 (CH3)3COH 18.00 (CF3)3COH 5.4

Formation of Phenoxide Ion File Name: AAAKWYU0 The aromatic alcohol phenol is more acidic than aliphatic alcohols due to the ability of aromatic rings to delocalize the negative charge of the oxygen within the carbons of the ring.

Charge Delocalization on the Phenoxide Ion File Name: AAAKWYT0 The negative charge of the oxygen can be delocalized over four atoms of the phenoxide ion. The true structure is a hybrid between the four resonance forms.

Intermolecular H-Bonding

Preparation of Alcohols Reduction of ketones and aldehydes Reduction of esters and carboxylic acids Hydration of Alkenes Nucleophilic addition Grignard reaction Acetylide addition Substitution Epoxide opening

Oxymercuration Hydration Markovnikov

Hydroboration Hydration Anti-Markovnikov

Oxidation and Reduction 3 hydrocarbon oxidation levels

Oxidation levels of oxygen- halogen- and nitrogen-containing molecules

Grignard Reagents Formula R—Mg—X (reacts like R:– +MgX). Ethers are used as solvents to stabilize the complex. Iodides are most reactive. Fluorides generally do not react. May be formed from primary, secondary, or tertiary alkyl halides. File Name: AAAKWZG0

Organometallic Chemistry Grignard Reaction

Formation of Grignard Reagents

Grignard Reagents React With Aldehydes to form secondary alcohols

Grignard Reagents React With Ketones to form tertiary alcohols

Grignard Reagents React With Formaldehyde to form primary alcohols

Grignard Reagents open Epoxides

Grignard Reagents react (twice) with Esters to form 3o Alcohols

Reaction of Grignards with Carboxylic Acid Derivatives File Name: AAAKXAC0

Grignard Summary

Grignard Summary

Solved Problem 2 Solution Show how you would synthesize the following alcohol from compounds containing no more than five carbon atoms. Solution This is a tertiary alcohol; any one of the three alkyl groups might be added in the form of a Grignard reagent. We can propose three combinations of Grignard reagents with ketones: Copyright © 2006 Pearson Prentice Hall, Inc.

Solved Problem 2 (Continued) Solution (Continued) Any of these three syntheses would probably work, but only the third begins with fragments containing no more than five carbon atoms. The other two syntheses would require further steps to generate the ketones from compounds containing no more than five carbon atoms. Copyright © 2006 Pearson Prentice Hall, Inc.

Grignard Reagents are exceptionally strong bases

An Effective Use of the Basicity Isotopic Labeling

Oxidation levels of oxygen- halogen- and nitrogen-containing molecules

NaBH4 Reduction

Some Examples

Two Alcohol Products Form in Lab

LiAlH4 Reduction a Stronger Reducing Agent

LiAlH4 is a much stronger reducing agent

NaBH4 is More Selective

Reducing Agents NaBH4 can reduce aldehydes and ketones but not esters and carboxylic acids. LiAlH4 is a stronger reducing agent and will reduce all carbonyls.

Synthesis

Retrosynthetic Analysis

4-Step Synthesis

Gilman Reagent Lithium dialkylcuprate

Gilman reagents: Source of Nucleophilic R- Coupling Reaction

Try these

Coupling occurs between original alkyl halide carbons

Think of it as an SN2 rxn

Base Catalyzed Ring-Opening of Epoxides

Base Opens Ring from Unhindered Side

Acid Catalyzed Ring-Opening Aqueous and in Alcohol

Regiochemistry Ring Opens at More Hindered Site

Different Regiosomers

Propose a Mechanism

2 SN2 steps

Propose a Mechanism

Ring-Opening is Sterically Controlled

Synthesize Using Only 1,2, or 3-Carbon Reagents

Retrosynthesis