Química Orgânica I. Ciências Farmacêuticas Bioquímica Química AFB QO I 2007/08 1

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1 Química Orgânica I Ciências Farmacêuticas Bioquímica Química AFB QO I 2007/08 1

2 alcohols Adaptado de Organic Chemistry, 6th Edition; Wade Organic Chemistry, 6 th Edition; McMurry Organic Chemistry, 5 th Edition; Vollhardt AFB QO I 2007/08 2

3 FG -OH Alcohols contain an OH group connected to a a saturated C (sp 3 ) Phenols contain an OH group connected to a carbon in a benzene ring Enols are unstable relative to ketones AFB QO I 2007/08 3

4 Common Alcohols Methanol, methyl alcohol, wood alcohol common solvent fuel additive antifreeze fuel produced in large quantities by hydrogenation of carbon monoxide preparation of formaldehyde, HCHO CO CO + 2H 2H 2 2 CH CH 3 OH 3 OH Catalyst: zinc oxide/chromia AFB QO I 2007/08 4

5 Common Alcohols AFB QO I 2007/08 5

6 Common Alcohols Ethanol, ethyl alcohol, grain alcohol, CH 3 CH 2 OH, EtOH Solvent Fuel Beverage industrial chemical Most ethanol comes from fermentation Synthetic ethanol is produced by hydration of ethylene (intense research on synthesis) ernativefuels/articles/109194/article. html AFB QO I 2007/08 6

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8 Sugar alcohols Polyalcohols, e.g. Mannitol, Xylitol, Maltitol, Galactitol, Erythritol, Inositol, Ribitol, Dithioerythritol, Dithiothreitol, and Glycerol hydrogenated starch hydrolysates found in berries, apples, plums... produced commercially from carbohydrates such as sucrose, glucose and starch. AFB QO I 2007/08 8

9 Sugar alcohols Name Sweetness (S) kcal/g S/kcal/g Arabitol Sucrose Erythritol Glycerol HSH Isomalt Lactitol Maltitol Mannitol Sorbitol Xylitol AFB QO I 2007/08 9

10 Erythritol (2R,3S)-butane-1,2,3,4-tetraol) natural sugar alcohol It occurs naturally in fruits and fermented foods. Produced industrially from glucose by fermentation with a yeast, Moniliella pollinis. AFB QO I 2007/08 10

11 Natural alcohols lauryl alcohol cetyl alcohol (Cetanol, Ethal, Ethol, Hexadecanol, Hexadecyl alcohol, Palmityl alcohol) stearyl alcohol (Octadecyl alchohol) (lubricants, resins, perfumes and cosmetics) behenyl alcohol (antiviral agent) AFB QO I 2007/08 11

12 Bombykol Prostaglandin E 1 AFB QO I 2007/08 12

13 Nomenclature of alcohols General classifications of alcohols based on substitution on C to which OH is attached Methyl (C has 3 H s), Primary (1 ) (C has two H s, one R), secondary (2 ) (C has one H, two R s), tertiary (3 ) (C has no H, 3 R s) AFB QO I 2007/08 13

14 AFB QO I 2007/08 14

15 IUPAC Rules for Naming Alcohols Select the longest carbon chain containing the hydroxyl group, and derive the parent name by replacing the -e ending of the corresponding alkane with -ol Number the chain from the end nearer the hydroxyl group Number substituents according to position on chain, listing the substituents in alphabetical order AFB QO I 2007/08 15

16 Unsaturated Alcohols Hydroxyl group takes precedence. Assign that carbon the lowest number. Use alkene or alkyne name. OH CH 2 CHCH 2 CHCH 3 4-penten-2-ol pent-4-ene-2-ol AFB QO I 2007/08 16

17 Naming Priority Acids Esters Aldehydes Ketones Alcohols Amines Alkenes Alkynes Alkanes Ethers Halides => AFB QO I 2007/08 17

18 Nomenclature OH CH 2 CH 2 CH 2 COOH 4-hydroxybutanoic acid HO OH 1,6-hexanediol hexane-1,6-diol AFB QO I 2007/08 18

19 Glycols 1,2 diols (vicinal diols) are called glycols. Common names for glycols use the name of the alkene from which they were made. CH 2 CH 2 OH OH 1,2-ethanediol CH 2 CH 2 CH 3 OH OH 1,2-propanediol ethylene glycol propylene glycol => AFB QO I 2007/08 19

20 Many Alcohols Have Common Names These are accepted by IUPAC AFB QO I 2007/08 20

21 Structure of Alcohols Hydroxyl (OH) functional group Oxygen is sp 3 hybridized. => AFB QO I 2007/08 21

22 Structure of alcohols The O-H bond is shorter than the C-H bonds. The bond strength of the O-H bond is greater than that of the C-H bonds: DH o O-H DH o C-H = 104 kcal mol-1 = 98 kcal mol-1 AFB QO I 2007/08 22

23 O-H bond Due to the electronegativity difference between oxygen and hydrogen, the O-H bond is polar. AFB QO I 2007/08 23

24 Hydrogen bonding in alcohols high boiling points Hydrogen bonding between alcohol molecules is much stronger than the London forces and dipole-dipole interactions in alkanes and haloalkanes O H-O DH o ~ 5-6 kcal mol -1 Covalent O-H DH o = 104 kcal mol -1. An alcohol molecule makes ~ 2 hydrogen bonds to other alcohol molecules on the average. A water molecule forms hydrogen bonds to ~ 4 other water molecules. AFB QO I 2007/08 24

25 Properties of Alcohols The structure around O of the alcohol is similar to that in water, sp 3 hybridized Alcohols have much higher boiling points than similar alkanes and alkyl halides AFB QO I 2007/08 25

26 Alcohols Form Hydrogen Bonds AFB QO I 2007/08 26

27 solubility alcohols are soluble in water: The OH groups of alcohols are hydrophilic and enhance solubility. Alkanes and most alkyl chains are said to be hydrophobic In order to dissolve, alkanes must interrupt the strong hydrogen bonding between water molecules which is then replaced by weaker dipole induced-dipole forces ( H > 0). In addition, long hydrocarbon chains force water molecules to form a cage like (or clathrate) structure about the nonpolar chain which greatly reduces the entropy of the water molecules involved ( S < 0). Alcohols are popular protic solvents for S N 2 reactions. AFB QO I 2007/08 27

28 Solubility in Water Solubility decreases as the size of the alkyl group increases. AFB QO I 2007/08 28 =>

29 Properties of Alcohols AFB QO I 2007/08 29

30 Acidity and Basicity Alcohols are weak Brønsted bases, protonated by strong acids to yield oxonium ions, ROH 2 + AFB QO I 2007/08 30

31 Brønsted Acidity Measurements The acidity constant, K a, measure the extent to which a Brønsted acid transfers a proton to water [A ] [H 3 O + ] K a = and pk a = log K a [HA] Relative acidities are more conveniently presented on a logarithmic scale, pk a, which is directly proportional to the free energy of the equilibrium Differences in pk a correspond to differences in free energy AFB QO I 2007/08 31

32 AFB QO I 2007/08 32

33 Relative Acidities of Alcohols Simple alcohols are about as acidic as water Alkyl groups make an alcohol a weaker acid The more easily the alkoxide ion is solvated by water the more its formation is energetically favored; steric effects are important AFB QO I 2007/08 33

34 Steric disruption effects control the acidity of alcohols. The acidity of an alcohol varies (relative pk a in solution): Strongest acid CH 3 OH < primary < secondary < tertiary Weakest acid AFB QO I 2007/08 34

35 Alkoxides from Alcohols Alcohols are weak acids requires a strong base to form an alkoxide such as NaH, sodium amide NaNH 2, and Grignard reagents (RMgX) AFB QO I 2007/08 35

36 Inductive Effects Electron-withdrawing groups make an alcohol a stronger acid by stabilizing the conjugate base (alkoxide) AFB QO I 2007/08 36

37 Inductive Effect Greater inductive effects are seen with a greater number of electronegative atoms and with closer proximity to the anion CH 3 CH 2 OH pk a = 15.9 ClCH 2 CH 2 OH pk a = 14.3 CF 3 CH 2 OH pk a = 12.4 CF 3 CH 2 CH 2 OH pk a = 14.6 CF 3 CH 2 CH 2 CH 2 OH pk a = 15.4

38 alcohols basicity The lone electron pairs on oxygen make alcohols basic. Alcohols may be weakly basic as well as being acidic. Molecules that can be both acidic and basic are called amphoteric. Very strong acids are required to protonate alcohols. AFB QO I 2007/08 38

39 Alkoxides from Alcohols AFB QO I 2007/08 39

40 Spectroscopy rev. No UV/vis IR MS H1-NMR C13-NMR AFB QO I 2007/08 40

41 O H stretching: cm 1 (broad) C O stretching: cm 1 (broad) C-H bands around 3000 cm-1. AFB QO I 2007/08 41

42 OH C H O H C O Wave number, cm -1 AFB QO I 2007/08 42 Francis A. Carey, Organic Chemistry, Fourth Edition. Copyright 2000 The McGraw-Hill Companies, Inc. All rights reserved.

43 1H NMR Spectroscopy The O-H proton is highly variable in its chemical shift, normally broad (due to H-bonding) not coupled to other protons except under special circumstances. D2O exchange The second signal is that for any proton on the oxygenbearing carbon; this will occur between ppm and will couple normally to its neighbors (but not usually to the OH). H C δ ppm δ ppm O H AFB QO I 2007/08 43

44 CH 2 CH 2 OH AFB QO I 2007/08 44

45 13 C NMR spectroscopy chemical shift of C OH C is δ ppm C O O is about ppm less shielded than C HC CH 3 CH 2 CH 2 CH 3 CH 3 CH 2 CH 2 CH 2 OH δ 13 ppm δ 61.4 ppm AFB QO I 2007/08 45

46 13C NMR Spectroscopy Carbons bearing an oxygen are deshielded and normally occur in the ppm region; a carbon with more than one oxygen may be further downfield. AFB QO I 2007/08 46

47 UV-VIS VIS Unless there are other chromophores in the molecule, alcohols are transparent above about 200 nm; λ max for methanol, for example, is 177 nm. AFB QO I 2007/08 47

48 Mass Spectrometry of Alcohols molecular ion peak is usually small a peak corresponding to loss of H 2 O from the molecular ion (M - 18) is usually present peak corresponding to loss of an alkyl group to give an oxygen- stabilized carbocation is usually prominent AFB QO I 2007/08 48

49 Synthesis AFB QO I 2007/08 49

50 AFB QO I 2007/08 50

51 Synthesis of Alcohols by Nucleophilic Substitution alcohols can prepared by SN2 and SN1 hydroxide and water respectively as nucleophiles. drawbacks: Elimination Rearrangements The use of polar, aprotic solvents alleviates some of these problems. AFB QO I 2007/08 51

52 Synthesis of Alcohols by Nucleophilic Substitution AFB QO I 2007/08 52

53 Synthesis of Alcohols by Nucleophilic Substitution The problem of elimination in S N 2 reactions of oxygen nucleophiles with secondary or sterically encumbered, branched primary substrates is the use of acetate as a less basic nucleophile. Step 1: Acetate formation (S N 2 reaction) Step 2: Conversion to alcohol (hydrolysis) AFB QO I 2007/08 53

54 Synthesis of Alcohols by Regiospecific Hydration of Alkenes Hydroboration/oxidation: syn, non-markovnikov hydration Oxymercuration/reduction: Markovnikov hydration AFB QO I 2007/08 54

55 Preparation of 1,2-Diols Review: Cis 1,2-diols from hydroxylation of an alkene with OsO 4 followed by reduction with NaHSO 3 In Chapter 18: Trans-1,2-diols from acid-catalyzed hydrolysis of epoxides AFB QO I 2007/08 55

56 Reduction of Aldehydes and Ketones Aldehydes gives primary alcohols Ketones gives secondary alcohols AFB QO I 2007/08 56

57 Hydride reducing agents Sodium Borohydride, NaBH 4, is not sensitive to moisture; it does not reduce other common carbonyl functional groups Lithium aluminum hydride, LiAlH 4, is more powerful, less specific, and very reactive with water. diethyl ether is most commonly used solvent H Na + H B H H AFB QO I 2007/08 57

58 Hydride Reducing Agents: AFB QO I 2007/08 58

59 From mannose to mannitol OH OH HO HO OH OH HO HO OH O O OH OH OH OH OH HO NaBH 4 HO OH OH O AFB QO I 2007/08 59 OH OH OH osmotic diuretic agent weak renal vasodilator

60 Reduction of Carboxylic Acids and Esters lithium aluminum hydride is only effective reducing agent AFB QO I 2007/08 60

61 Mechanism of hydride reduction The reagent adds the equivalent of hydride (H - ) to the carbon of C=O AFB QO I 2007/08 61

62 Catalytic hydrogenation O OH MeO H H 2 Pt/Ethanol MeO H O OH H 2 Pt/Ethanol O O H 2 Ni HO OH AFB QO I 2007/08 62

63 Hydrogenation: Selectivity O OH 1) LiAlH 4 /ether 2) H 2 O neither NaBH4 or LiAlH4 reduces isolated double bonds (90%) AFB QO I 2007/08 63

64 Grignard Reagents AFB QO I 2007/08 64

65 Grignard Reagents AFB QO I 2007/08 65

66 Grignard Reagents Ester reaction AFB QO I 2007/08 66

67 Carboxylic Acids and Grignard Reagents Grignard reagents do not add to carboxylic acids they undergo an acid-base reaction, generating the hydrocarbon of the Grignard reagent AFB QO I 2007/08 67

68 Limitations of Grignard Reagents Can't be prepared if there are reactive functional groups in the same molecule, including proton donors AFB QO I 2007/08 68

69 Mechanism of the Addition of a Grignard Reagent Grignard reagents act as nucleophilic carbon anions in adding to a carbonyl group The intermediate alkoxide is then protonated to produce the alcohol AFB QO I 2007/08 69

70 Epoxides and Grignard Reagents O 1) ether 2) H 3 O + MgBr OH AFB QO I 2007/08 70