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Structure and Synthesis of Alcohols Biological Activity Nomenclature Preparation Reactions Structure and Synthesis of Alcohols Biological Activity Nomenclature Preparation Reactions

Structure of Water and Methanol • Oxygen is sp 3 hybridized and tetrahedral. • Structure of Water and Methanol • Oxygen is sp 3 hybridized and tetrahedral. • The H—O—H angle in water is 104. 5°. • The C—O—H angle in methyl alcohol is 108. 9°. © 2013 Pearson Education, Inc. Chapter 10 2

Examples of Classifications OH CH 3 CH CH 2 OH * Primary alcohol CH Examples of Classifications OH CH 3 CH CH 2 OH * Primary alcohol CH 3 CH CH 2 CH 3 * Secondary alcohol CH 3 C* OH CH 3 Tertiary alcohol Phenol

Some Alcohols Some Alcohols

Alcohols are Found in Many Natural Products Alcohols are Found in Many Natural Products

Paralytic Shellfish Poisoning Paralytic Shellfish Poisoning

Ethanol: the Beverage Ethanol: the Beverage

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

Excess NADH can cause Metabolic Problems Excess NADH can cause Metabolic Problems

Methanol: Not a Beverage Methanol: Not a Beverage

Synergistic and Metabolic Effects • In men, ethanol lowers levels of testosterone (and sperm 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 CYP 2 E 1, which is responsible for converting acetaminophen into liver toxins, is activated by ethanol. • Ethanol has a caloric value of 7. 1 Cal/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 Synergistic Effects • Women will have higher BAL’s with the consumption of an equal number of drinks due to lower ADH activity and lower % H 2 O 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 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) From the Bark of the Pacific Yew Tree Taxol (Paclitaxel)

How Taxol Works • A large number of microtubules are formed at the start 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 May be More Effective than Taxol

DNA Cross-linker DNA Cross-linker

Prevents DNA from Unraveling Prevents DNA from Unraveling

IUPAC Nomenclature • Find the longest carbon chain containing the carbon with the —OH 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 Alcohol Nomenclature

Nomenclature Nomenclature

Naming Diols • Two numbers are needed to locate the two —OH groups. • 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 © 2013 Pearson Education, Inc. Chapter 10 24

Who am I? Who am I?

Boiling Points of Alcohols • Alcohols have higher boiling points than ethers and alkanes 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. © 2013 Pearson Education, Inc. Chapter 10 27

Physical Properties b. p. o. C CH 3 CH 2 CH 3 CH 3 Physical Properties b. p. o. C CH 3 CH 2 CH 3 CH 3 OCH 3 CH 2 OH m. D sol. in H 2 O -42 0. 08 i -25 1. 3 ss 78 1. 7 vs

Acidity of Alcohols • Due to the electronegativity of the O atoms, alcohols are Acidity of Alcohols • Due to the electronegativity of the O atoms, alcohols are slightly acidic (p. Ka 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 Formation of Alkoxide Ions • Ethanol reacts with sodium metal to form sodium ethoxide (Na. OCH 2 CH 3), a strong base commonly used for elimination reactions. • More hindered alcohols like 2 -propanol or tert-butanol react faster with potassium than with sodium. © 2013 Pearson Education, Inc. Chapter 10 30

Withdrawing Groups Enhance Acidity alcohol CH 3 OH CH 3 CH 2 OH CF Withdrawing Groups Enhance Acidity alcohol CH 3 OH CH 3 CH 2 OH CF 3 CH 2 OH (CH 3)3 COH (CF 3)3 COH p. Ka 15. 54 16. 00 12. 43 18. 00 5. 4

Formation of Phenoxide Ion The aromatic alcohol phenol is more acidic than aliphatic alcohols Formation of Phenoxide Ion 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. © 2013 Pearson Education, Inc. Chapter 10 32

Charge Delocalization on the Phenoxide Ion • The negative charge of the oxygen can Charge Delocalization on the Phenoxide Ion • 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. © 2013 Pearson Education, Inc. Chapter 10 33

Intermolecular H-Bonding Intermolecular H-Bonding

Preparation of Alcohols • • Reduction of ketones and aldehydes Reduction of esters and 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 Oxymercuration Hydration Markovnikov

Hydroboration Hydration Anti-Markovnikov Hydroboration Hydration Anti-Markovnikov

Oxidation and Reduction 3 hydrocarbon oxidation levels Oxidation and Reduction 3 hydrocarbon oxidation levels

Oxidation levels of oxygen- halogen- and nitrogencontaining molecules Oxidation levels of oxygen- halogen- and nitrogencontaining molecules

Grignard Reagents • • Formula R—Mg—X (reacts like R: – +Mg. X). Ethers are Grignard Reagents • • Formula R—Mg—X (reacts like R: – +Mg. X). 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. © 2013 Pearson Education, Inc. Chapter 10 40

Organometallic Chemistry Grignard Reaction Organometallic Chemistry Grignard Reaction

Formation of Grignard Reagents © 2013 Pearson Education, Inc. Chapter 10 42 Formation of Grignard Reagents © 2013 Pearson Education, Inc. Chapter 10 42

Grignard Reagents React With Aldehydes to form secondary alcohols Grignard Reagents React With Aldehydes to form secondary alcohols

Grignard Reagents React With Ketones to form tertiary alcohols Grignard Reagents React With Ketones to form tertiary alcohols

Grignard Reagents React With Formaldehyde to form primary alcohols Grignard Reagents React With Formaldehyde to form primary alcohols

Grignard Reagents open Epoxides Grignard Reagents open Epoxides

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

Reaction of Grignards with Carboxylic Acid Derivatives Reaction of Grignards with Carboxylic Acid Derivatives

Grignard Summary Grignard Summary

Grignard Summary Grignard Summary

Solved Problem 2 Show you would synthesize the following alcohol from compounds containing no Solved Problem 2 Show 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:

Solved Problem 2 (Continued) Solution (Continued) Any of these three syntheses would probably work, 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.

Grignard Reagents are exceptionally strong bases Grignard Reagents are exceptionally strong bases

An Effective Use of the Basicity Isotopic Labeling An Effective Use of the Basicity Isotopic Labeling

Oxidation levels of oxygen- halogen- and nitrogencontaining molecules Oxidation levels of oxygen- halogen- and nitrogencontaining molecules

Na. BH 4 Reduction Na. BH 4 Reduction

Some Examples Some Examples

Two Alcohol Products Form in Lab Two Alcohol Products Form in Lab

Li. Al. H 4 Reduction a Stronger Reducing Agent Li. Al. H 4 Reduction a Stronger Reducing Agent

Li. Al. H 4 is a much stronger reducing agent Li. Al. H 4 is a much stronger reducing agent

Na. BH 4 is More Selective Na. BH 4 is More Selective

Reducing Agents • Na. BH 4 can reduce aldehydes and ketones but not esters Reducing Agents • Na. BH 4 can reduce aldehydes and ketones but not esters and carboxylic acids. • Li. Al. H 4 is a stronger reducing agent and will reduce all carbonyls. © 2013 Pearson Education, Inc. Chapter 10 62

Synthesis Synthesis

Retrosynthetic Analysis Retrosynthetic Analysis

4 -Step Synthesis 4 -Step Synthesis

Gilman Reagent Lithium dialkylcuprate Gilman Reagent Lithium dialkylcuprate

Gilman reagents: Source of Nucleophilic R Coupling Reaction Gilman reagents: Source of Nucleophilic R Coupling Reaction

Try these Try these

Coupling occurs between original alkyl halide carbons Coupling occurs between original alkyl halide carbons

Think of it as an SN 2 rxn Think of it as an SN 2 rxn

Base Catalyzed Ring-Opening of Epoxides Base Catalyzed Ring-Opening of Epoxides

Base Opens Ring from Unhindered Side Base Opens Ring from Unhindered Side

Acid Catalyzed Ring-Opening Aqueous and in Alcohol Acid Catalyzed Ring-Opening Aqueous and in Alcohol

Regiochemistry Ring Opens at More Hindered Site Regiochemistry Ring Opens at More Hindered Site

Different Regiosomers Different Regiosomers

Propose a Mechanism Propose a Mechanism

2 SN 2 steps 2 SN 2 steps

Propose a Mechanism Propose a Mechanism

Ring-Opening is Sterically Controlled Ring-Opening is Sterically Controlled

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

Retrosynthesis Retrosynthesis