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Structure and Synthesis of Alcohols Biological Activity Nomenclature Preparation Reactions Structure of Water and Methanol • 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°. © 2013 Pearson Education, Inc. Chapter 10 2 Examples of Classifications OH CH3 CH3 CH CH2OH * Primary alcohol CH3 CH3 C* OH CH3 CH CH2CH3 * Secondary alcohol OH CH3 Tertiary alcohol Phenol Some Alcohols CH3CH2OH HO OH OH CHCH2NH2 CHCHNHCH3 CH3 ethanol HO adrenaline (epinephrine) OH H HOCH2CHCH2OH glycerol H HO H cholesterol pseudephedrine Alcohols are Found in Many Natural Products HO N CH3 O H HO Morphine most abundant of opium's alkaloids Paralytic Shellfish Poisoning NH2 O O H HN A possible chemical warfare agent H N N NH N roughly 1000 times more toxic than saran gas or cyanide N H OH The toxin blocks entry of sodium OH required by cells to make "action potentials" Saxitoxin (STX) LD 50 = 2 g/kg OH O O OH OH HO OH O H2N OH OH OH OH HO PALYTOXIN LD 50 = 0.15 g/kg OH OH OH OH OH OH O HO O N N H H HO OH OH OH OH OH O OH OH OH OH HO OH O O O OH HO OH OH OH OH HO OH OH OH OH OH Ethanol: the Beverage Ethanol is a central nervous system depressant - depresses brain areas responsible for judgement (thus the illusion of stimulation) alcohol dehydrogenase CH 3CH 2OH ethanol NAD + O CH 3CH + NADH + H acetaldehyde LD 50 = 1.9 g/Kg NAD enz. + CH 3CO 2H + NADH + H acetic acid + + Enzymatic Oxidation of Ethanol Ethanol oxidizes to acetaldehyde, then acetic acid, which is a normal metabolite. Excess NADH can cause Metabolic Problems O C NH2 OO N CH3CCOH H OH + CH3CHCO2H sugar NADH pyruvic acid (+) lactic acid pyruvic acid is normally converted to glucose (gluconeogenesis) results in: acidosis and hypoglycemia Methanol: Not a Beverage CH3OH methanol ADH NAD + O + HCH + NADH + H formaldehyde LD 50 = 0.07 g/Kg 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) O O O NH OH O O O OH O OH O O O Taxus brevifolia O 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 Epothilone B inhibits tubulin aggregation O S H OH N O O OH O DNA Cross-linker 21 O CH3O O O O O N CH3 OH N H AcO H N 10 HO Azinomycin B Streptomyces sahachiroi O Prevents DNA from Unraveling O O OH OH OH OCH3 O OH O CH3 NH2 Doxorubicin (adriamycin) OH Binds to DNA and inhibits the enzyme topoisomerase II 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 OH 3 3-heptanol 6 2 5 5-methyl-6-hepten-2-ol OH 2 OH 1 1 3 CH3 CH3 3,3-dimethylcyclohexanol OH CH3 5 CH3 5,5-dimethylcyclohex-2-enol Nomenclature OH OH (E) 3-methyl-3-penten-2-ol (S) 2-hexanol OH OH trans 3-isopropylcyclopentanol H OH (R) 2-butyl-1,4-butanediol (R) 2-butylbutane-1,4-diol 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? HO H 1 2 6 4 5 8 7 # chain from end closest to alcohol group 3 HO 2 1 1 H 2 5 4-(R)-{1-(S)[cyclohexa-2,5-dienyl]ethyl}-2-methyl-6-(E)-octen-4-ol 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. oC 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): CH3CH2OH + Na CH3CH2O Na + 1/2 H2 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. © 2013 Pearson Education, Inc. Chapter 10 30 Withdrawing Groups Enhance Acidity CF3 CF3 CF3 C OH + NaHCO3 CF3 CF3 alcohol CH3OH CH3CH2OH CF3CH2OH (CH3)3COH (CF3)3COH C O Na + H2CO3 CF3 pKa 15.54 16.00 12.43 18.00 5.4 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 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 O H H H O H O H O associated liquid intermolecular H bonding O H H H O 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 1) Hg(OAc) 2 in THF/H2O 2) NaBH4 OH H Hydroboration Hydration Anti-Markovnikov 3 1) BH3-THF 2) H2O2, NaOH H OH 3 Oxidation and Reduction 3 hydrocarbon oxidation levels CH3CH3 oxidation # of carbon -3 [O] CH2=CH2 -2 [O] HC -1 CH Oxidation levels of oxygen- halogen- and nitrogencontaining molecules CH2=CH2 CH3CH3 [O] CH3CH2OH HC [O] CH CH3CH=O [O] CH3CO2H CH3CH2Cl CH 3CHCl2 CH3CCl3 CH3CH2NH2 CH3CH=NH CH3CN Oxidation Reduction 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. © 2013 Pearson Education, Inc. Chapter 10 40 Organometallic Chemistry Grignard Reaction CH3 Br + Mg "CH3 MgBr " excellent nucleophile very strong base CH3 MgBr Grignard Reagent Formation of Grignard Reagents Br + Mg ether Cl CH3CHCH2CH3 © 2013 Pearson Education, Inc. + Mg ether Chapter 10 MgBr MgCl CH3CHCH2CH3 42 Grignard Reagents React With Aldehydes to form secondary alcohols O MgBr in ether 1) H OH + 2) H3O H Grignard Reagents React With Ketones to form tertiary alcohols O CH3 1) CH3MgBr in ether HO + MgBrOH + 2) H3O o a 3 alcohol + H3O MgBrO CH3 CH3 Grignard Reagents React With Formaldehyde to form primary alcohols CH2CH2O MgBr CH2CH2OH H3O + O C H H formaldehyde CH2 MgBr CH2Br Mg, ether, Grignard Reagents open Epoxides O RCO3H CH3MgBr OH MgBrO CH3 + enant. H3O + CH3 Grignard Reagents react (twice) with Esters to form 3o Alcohols O OH C C CH 3 CH3 OCH3 1) 2 CH3MgBr + 2) H3O CH3 O C OCH 3 CH3 2nd eq. 1) CH3MgBr + 2) H3O O C CH3 ketone (more reactive than ester) Reaction of Grignards with Carboxylic Acid Derivatives Grignard Summary H H R MgX + + C O H3O workup R H formaldehyde R MgX R' + O R' H3O workup R H aldehyde R MgX R' + C R'' ketone C OH H R' + O OH H + C C H3O workup R C R'' OH Grignard Summary R O H3O workup R' MgX + epoxide R'' R R' 2 R MgX + OH + R' + C O RO ester H3O workup R C OH R + ROH Solved Problem 2 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: 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 H2O CH3OH CH3CH2CH2MgBr + CH3CO2H HC CH CH3NH2 CH3CH2CH3 An Effective Use of the Basicity Isotopic Labeling CH3 CH3 CH3 Br MgBr Mg Br 2, h ether D2O CH3 D + MgBrOD Oxidation levels of oxygen- halogen- and nitrogencontaining molecules CH2=CH2 CH3CH3 [O] CH3CH2OH HC [O] CH CH3CH=O [O] CH3CO2H CH3CH2Cl CH 3CHCl2 CH3CCl3 CH3CH2NH2 CH3CH=NH CH3CN Oxidation Reduction NaBH4 Reduction O R 1) NaBH4, ethanol R' 2) H3O + H H OH R R' H3O H R O R' + Some Examples O OH 1) NaBH 4, ether 2) H3O O CH + " CH2OH Two Alcohol Products Form in Lab O H axial approach NaBH4 (CH3)3C H O Na (CH3)3C trans O Na O NaBH4 (CH3)3C H (CH3)3C H equatorial approach cis LiAlH4 Reduction a Stronger Reducing Agent OH O 1) LiAlH 4, THF 2) H3O + LiAlH 4 will reduce: o ketones to 2 alcohols o aldehydes to 1 alcohols o carboxylic acids and esters to 1 alcohols LiAlH4 is a much stronger reducing agent 1) LiAlH 4 O OH + 2) H3O + CH3OH O 1) NaBH4 + 2) H3O no reaction NaBH4 is More Selective O O 1) NaBH4 OH 2) H3O OH + O OH OH 1) LiAlH 4 2) H3O + OH 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. © 2013 Pearson Education, Inc. Chapter 10 62 Synthesis OH ? Retrosynthetic Analysis OH ? Br MgBr 4-Step Synthesis OH 1) HCHO + 2) H3O Br 2, h Br Mg in ether MgBr Gilman Reagent Lithium dialkylcuprate Li(R) 2Cu a) R-Br + 2 Li b) 2 R Li + CuI R Li R Cu- + LiBr Li+ R Gilman reagent R can be alkyl, vinyl, aryl Gilman reagents: Source of Nucleophilic R Coupling Reaction 1) 2 Li Br 2) CuI Li(CH 3CH2CH2CH2CH2)2Cu Li(CH 3CH2CH2CH2CH2)2Cu + CH3CH2Br CH3CH2CH2CH2CH2 CH2CH3 Try these I a) Li Cu 2 1) 2 Li 2) CuI b) 3) Br Br Coupling occurs between original alkyl halide carbons I a) Li Cu 2 1) 2 Li 2) CuI b) 3) Br Br Think of it as an SN2 rxn Li Cu I + Cu + LiI Base Catalyzed Ring-Opening of Epoxides Base Opens Ring from Unhindered Side OH O NaOCH3 in CH 3OH H OCH3 O Na OCH3 regenerates base catalyst OCH3 Acid Catalyzed Ring-Opening Aqueous and in Alcohol Regiochemistry Ring Opens at More Hindered Site + H , CH3OH OH O OCH3 OH O CH3OH H OCH3 CH3OH H Different Regiosomers Propose a Mechanism Br O 1) NaOCH3 2) heat CH3OCH2 O + NaBr 2 SN2 steps CH3O Br 1) NaOCH3 2) heat O Br CH3O O CH3OCH2 O + NaBr Propose a Mechanism Br + H3O (cat.) Br H O O H Br + H3O (cat.) Br O O H H H Br H2O H O H Br H O H HO Br H Ring-Opening is Sterically Controlled CH2CH3 OH O CH3 1) CH3CH2MgBr + 2) H3O base opens epoxide at less hindered site CH3 Synthesize Using Only 1,2, or 3-Carbon Reagents OH HC CH Retrosynthesis + OH O MgBr HC Mg Br CH HBr CH3X CH3X reduce