Alcohols and Phenols Alcohols possess a hydroxyl group

Alcohols and Phenols • Alcohols possess a hydroxyl group (-OH) • Hydroxyl groups are extremely common in natural compounds 13 -1

Alcohols in Nature • Hydroxyl groups in natural compounds 13 -2

Phenols in Nature • Phenols possess a hydroxyl group directly attached to an aromatic ring 13 -3

Alcohols Nomenclature • Alcohols are named using the similar procedure to alkenes with minor modifications 1. Identify the parent chain, which should include the carbon that the –OH is attached to 2. Identify and Name the substituents 3. Assign a locant (and prefix if necessary) to each substituent. Give the carbon that the –OH is attached to the lowest number possible 4. List the numbered substituents before the parent name in alphabetical order. Ignore prefixes (except iso) when ordering alphabetically 5. The –OH locant is placed either just before the parent name or just before the -ol suffix 13 -4

Alcohols Nomenclature 1. Identify the parent chain 13 -5

Alcohols Nomenclature 3. Assign a locant (and prefix if necessary) to each substituent. Give the carbon that the –OH is attached to the lowest number possible taking precedence over C=C double bonds 13 -6

Alcohols Nomenclature 5. The –OH locant is placed either just before the parent name or just before the -ol suffix • R or S configurations should be shown at the beginning of the name 13 -7

Cyclic alcohol Nomenclature • For cyclic alcohols, the –OH group should be on carbon 1, so often the locant is assumed and omitted • Common names for some alcohols are also frequently used 13 -8

Diol Nomenclature • Diols are named using the same method as alcohols, except the suffix, “diol” is used 13 -9

1/2/3 Alcohols • Like halides, alcohols are often classified by the type of carbon they are attached to 13 -10

Phenol Nomenclature • The –OH group is position as #1 in benzene ring • When there is only one other substituent, use ortho/meta-/para- to locate the other substituent: • o-methylphenol, m-bromophenol, p-isopropylphenol 13 -11

Methanol, Ethanol, Isopropyl alcohol • • Methanol (CH 3 OH) is the simplest alcohol, ~2 billion gallons made industrially from CO 2 and H 2 every year Methanol is poisonous, but it has many uses solvent, precursor for chemical syntheses, or fuel • Ethanol used as Solvent, precursor for chemical syntheses, fuel, also Human consumption • Isopropanol is made industrially from acid-catalyzed hydration of propylene Isopropanol is poisonous, but many uses as Industrial solvent, Antiseptic, Gasoline additive • 13 -12

2. Physical Properties of Alcohols • The –OH of an alcohol can have a big effect on its physical properties as very polar, H-bonding group boiling points • Small alcohol miscible with water. • Solubility of alcohols (> 3 carbon) decreases as the size of hydrophobic group increases • 13 -13

Alcohols as Anti-bacterial Agent • An alcohol’s potency as an anti-bacterial agent depends on the size of the hydrophobic group • To kill a bacterium, the alcohol should have some water solubility, as well as significant hydrophobic region. 13 -14

Acidity of Alcohols and Phenols • A strong base or alkali metals is usually necessary to deprotonate an alcohol, forming alkoxide ion. • Phenol is much more acidic due to resonance with benzene ring, can be deprotonated by Na. OH 13 -15

Induction affects Acidity of Alcohols Induction: high electronegative group increase the acidity of alcohol 13 -16

Solvation affects Acidity • Smaller alkoxide ion is better stabilized by polar solvent. 13 -17

3 Preparation of Alcohols • From Nucleophilic Substitution: Nucleophile such as water or OH-, either SN 1 or SN 2 mechanism. Either. • From Hydration of alkene (Electrophilic Addition) 13 -18

Alcohols from Alkyl halide • The SN 1 process generally uses a weak nucleophile (H 2 O), which makes the process relatively slow 13 -19

Alcohols: Hydration of Alkene • Regioselectivity of hydration: Markovnikov or anti. Markovnikov • Acid-catalyzed hydration proceeds through a carbocation intermediate that can possibly rearrange Oxymercuration-demercuration avoid rearrangement. • 13 -20

4: Alcohol from Reduction of C=O • • • A third method to prepare alcohols is by the reduction of a carbonyl (C=O) Reductions involve a change in oxidation state Two methods: Catalytic Hydrogenation or Hydride (Nucleophilic addition) 13 -21

Catalytic Hydrogenation • Similar to alkene and alkyne, catalytic Hydrogenation reduces C=O (ketone or aldehyde) to alcohol – Forceful conditions (high temperature and/or high pressure) 13 -22

Reduction by Hydride (H-) A. Sodium borohydride (Na. BH 4) 13 -23

Hydride Reduction by LAH B. Lithium aluminum hydride (LAH) 13 -24

LAH more reactive than Na. BH 4 • • Note that LAH is significantly more reactive that Na. BH 4 LAH reacts violently with water, producing hydrogen gas. • Thus LAH can not be used with water. Water is used AFTER LAH treatment for protonation of alkoxide ion. 13 -25

Hydride more selective than Hydrogenation • Hydride delivery agents will somewhat selectively reduce carbonyl compounds (without affect C=C) 13 -26

Variety of Hydride Reagent • The reactivity of hydride delivery agents can be finetuned by using derivatives with varying R-groups – – – Alkoxides Cyano Sterically hindered groups 13 -27

LAH converts RCO 2 H and Ester to ROH • LAH is strong enough to also reduce esters and carboxylic acids, whereas Na. BH 4 is generally not 13 -28

LAH reduction of Ester: Mechanism • To reduce an ester, 2 hydride equivalents are needed 13 -29

Practice: Alcohol Prep via Reduction • Predict the products for the following processes 13 -30

5 Diol from Reduction of C=O • If two carbonyl groups are present, and enough moles of reducing agent are added, both can be reduced 13 -31

Vicinal Diol from Epoxide or Oxidation • Note the different stereochemistry 13 -32

6 Grignard Reactions • • Grignard reagents are often used in the synthesis of alcohols To form a Grignard, an alkyl halide is treated with Mg metal 13 -33

Grignard Reagent as Nucleophile • The electronegativity difference between C (2. 5) and Mg (1. 3) is great enough that the bond has significant ionic character • The carbon atom is not able to effectively stabilize the negative charge it carries, strong tendency as nucleophile. 13 -34

Grignard Reaction: Nucleophilic Addition • If the Grignard reagent reacts with a carbonyl compound, an alcohol can result • Note the similarities between the Grignard and LAH mechanisms 13 -35

Grignard Reactions Require Moisture Free • Because the Grignard is both a strong base and a strong nucleophile, require protection from moisture or other protic solvent. • Polar aprotic, non carbonyl solvent like ether are used. Such as tetrahydrofuran (THF) and diethyl ether. 13 -36

Grignard Reactions for Alcohol • Grignard examples • With an ester substrate, excess Grignard reagent is required. Functional groups that are NOT compatible (also electrophilic) with the Grignard: O-H, C=O, C=N, C≡N • 13 -37

Practice: Grignard Rxn for Synthesis • Design a synthesis for the following molecules starting from an alkyl halide and a carbonyl, each having 5 carbons or less 13 -38

7 Protection of Alcohols • Grignard reagent can not has protic functional groups • The alcohol can act as an acid, especially in the presence of reactive reagents like the Grignard reagent The alcohol can be “protected” to prevent it from reacting • 13 -39

Scheme for Protection of Alcohols • A three-step process is required to achieve the desired overall synthesis 13 -40

TMS for Protection of Alcohols • One such protecting group is trimethylsilyl (TMS) • The TMS protection step requires the presence of a base such as tertiary amine, by an SN 2 mechanism 13 -41

De. Protection of Alcohols • • The TMS group can later be removed with H 3 O+ or F- , because strong Si-F bond TBAF is often used to supply fluoride ions 13 -42

Example: Complete Process involving Protection/Deprotection of Alcohols • Practice with conceptual checkpoint 13. 18 13 -43

8 Preparation of Phenols • 2 million tons of phenol is produced industrially yearly • • Acetone is a useful byproduct Phenol is a precursor in many chemical syntheses – – Pharmaceuticals Polymers Adhesives Food preservatives, etc. 13 -44

9 Reactions of Alcohols: 3°Alcohol Alkyl Halide with HX (SN 1) • Recall tertiary alcohol ROH RX via SN 1 reaction, with carbocation as intermediate 13 -45

1°Alcohols Alkyl Halide with HX (SN 2) • HBr reacts with primary alcohols to form alkyl bromide: • Rxn of primary alcohol with HCl requires Zn. Cl 2 (catalyst) 13 -46

ROH to ROTs (SN 2) • • Tosyl group (OTs) is excellent leaving group Reaction of alcohol with Tosyl chloride (Ts. Cl) in pyridine (weak base as solven) converts –OH group into –OTs/OMs/-OTMS 13 -47

Alcohols to Alkyl Halides with SOCl 2 in pyridine can be used to convert an alcohol to an alkyl chloride. Note the protonated intermediate as good leaving group, allowing SN 2 attack by chloride ion. 13 -48

Alcohols to Alkyl Halides with PBr 3 can be used to convert an alcohol to an alkyl bromide • Note that the last step of both SOCl 2 and PBr 3 as SN 2 mechanisms 13 -49

Practice: Reactions of Alcohols • Fill in the necessary reagents for the conversions below 13 -50

Elimination of Alcohols to Alkene (E 1) • Elimination : an acid can promote E 1 of alcohol. Concd H 2 SO 4 help shift equilibrium to alkene. Possible rearrangement • Regioselectivity: Elimination generally produces the more substituted alkene product (Zaitsev) 13 -51

ROH ROTs Elimination • If the alcohol is converted into a better leaving group such as Ots, then a strong base can be used to promote E 2 • Advantage of E 2 over E 1 elimination: E 2 reactions do not involve rearrangements. When applicable, E 2 reactions also produce the more substituted product (Zaitsev) • 13 -52

10 Oxidation of Alcohols • • Recall: alcohols can be formed by the reduction of a carbonyl (Na. BH 4, LAH) For alcohol with -H (1 or 2 ), the reverse process is also possible with the right reagents 13 -53

Oxidation of 1 /2 Alcohols • From 1 alcohols: an aldehyde (intermediate) and eventually to carboxylic acid – • Very few oxidizing reagents will stop at the aldehyde From 2 alcohols: to ketone – Very few agents are capable of oxidizing the ketone 13 -54

Oxidizing Agent of Alcohols: H 2 Cr. O 4 • 3 alcohols generally no oxidation (no -H). • • Most common oxidizing agent: chromic acid, H 2 Cr. O 4 Two main methods to produce chromic acid 13 -55

Mechanism of Oxidation of Alcohols • Chromate ester as reaction intermediate 13 -56

Oxidation of Alcohols to Aldehyde: PCC • Recall: Chromic acid will generally oxidize a primary alcohol to a carboxylic acid • PCC (pyridinium chlorochromate) can be used to stop at the aldehyde. PCC can be prepared as follows: 13 -57

Use of PCC for Alcohol oxidation Methylene chloride (CH 2 Cl 2, dichloromethane, DCM) is generally used as solvent for PCC • Both PCC and Chromic acid will work with secondary alcohols, yielding ketones. 13 -58

Practice: Oxidation of Alcohols • Predict the product for the following reaction 13 -59

11 Biological Redox Reactions • • • Nature employs reducing and oxidizing agents They are generally complex and selective. NADH is one such reducing agent 13 -60

Biological Reducing Agent: NADH • The reactive site of NADH acts as a hydride delivery agent • This is one way nature converts carbonyls into alcohols 13 -61

NADH regenerated by alcohol • NAD+ can undergo the reverse process • The NADH / NAD+ interconversion plays a big role in metabolism 13 -62

12 Oxidation of Phenol • • • Recall that tertiary alcohols do not undergo oxidation, because they lack an alpha proton You might expect phenol to be similarly unreactive Phenol is even more readily oxidized than primary or secondary alcohols 13 -63

Oxidation of Phenol yield Quinone • Phenol oxidizes to form benzoquinone, which in turn can be reduced to hydroquinone • • Quinones are found everywhere in nature They are ubiquitous 13 -64

Quinones in biology • Ubiquinones act to catalyze the conversion of oxygen into water, a key step in cellular respiration 13 -65

Biochemistry of Ubiquinone • Ubiquinone catalysis: 13 -66

More “Tools”, More on Synthesis • Recall some functional group conversions we learned 13 -67

Redox in Synthetic Strategies • Classify the functional groups based on oxidation state 13 -68

Synthetic Strategies (A-Maze-ing! ) 13 -69

Practice: Develop Synthetic Strategies • Give necessary reagents for the following conversions • • L: only RCH 2 OH gives the final product (via PCC); SN not feasible from RBr to ROH, thus RBr C=C ROH. • R: RCH 2 OH gives the final product (via chromic acid); 13 -70

Synthetic Strategies for 3 Alcohol • Recall the C-C bond forming reactions we learned 13 -71

Interesting Tricks • From an aldehyde to a ketone? • Apply: How to achieve the following conversion? 13 -72

Additional Practice Problems • Predict the products for the following processes 13 -73

Additional Practice Problems • Design a synthesis for the following molecule starting from an alkyl halide and a carbonyl, each having 5 carbons or less 13 -74

Additional Practice Problems • Give necessary reagents for the multi-step synthesis below 13 -75

Additional Practice Problems • Name the following molecule • Draw (1 R, 2 R)-1 -(3, 3 -dimethylbutyl)-3, 5 -cyclohexadien 1, 2 -diol 13 -76

Additional Practice Problems • Use ARIO and solvation to rank the following molecules in order of increasing p. Ka 13 -77

Practice: Alcohol Prep via Reduction • Predict the products for the following processes 13 -78

Mechanism to form OTMS • • Evidence suggests that substitution at the Si atom occurs by an SN 2 mechanism Because Si is much larger than C, it is more open to backside attack where alcohol is the nucleophile. 13 -79