Chem HH W13-Notes Dr. Masato Koreeda - Page 1 of 13 Date: February 20, 2013

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1 hem W13-otes Dr. Masato Koreeda - Page 1 of 13 Date: February 20, 2013 hapter 13. Alcohols, Diols, and Ethers verview: hemistry and reactions of sp 3 oxygen groups, particularly oxidation of an alcohol, ether formation, and reactions of oxirane (epoxide) groups. I. What are alcohols, phenols, and ethers? Alcohols (-) Primary alcohols (1 -alcohols) pka ~16-17 IUPA names ommon names 3 methanol methyl alcohol 3 2 ethanol ethyl alcohol propanol n-propyl alcohol methyl-1-propanol isobutyl alcohol ,2-dimethyl-1-propanol neopentyl alcohol 3 3 econdary alcohols (2 -alcohols) pka ~ propanol 2-butanol isopropyl alcohol sec-butyl alcohol Tertiary alcohols (3 -alcohols) pka ~ methyl-2-propanol tert-butyl alcohol Phenols (Ph-) pka ~10-12 Ethers (--') diethyl ether 3 Ph--= 2 phenyl vinyl ether -: alkoxy Ar-: aryloxy Ph methoxy ethoxy phenoxy II. xidation xidation historical use of the term: (1) oxide (oxyd/oxyde) the acid form of an element; e.g., air oxide of (acid of sulfur) (2) oxidation or oxidize to make such an acid, to make the oxide (3) oxygen Lavoisier: substance in the air that makes acids; the bringer of acids = oxygen (4) oxidation or oxidize to increase the % oxygen in a substance (reduction: to reduce the % oxygen) More modern definition: oxidation or oxidize loss of electrons (coupled with reduction as gain of electrons) ote: The loss of electrons (oxidation) by one atom or compound must be matched by the gain of electrons (reduction) by another.

2 hem W13-otes Dr. Masato Koreeda - Page 2 of 13 Date: February 20, 2013 III. xidation state (or number) counting (see: pp of the textbook) e ep "the contribution of an to the oxidation number of the is -1" "the contribution of a to the oxidation number of the is 1" Therefore, The oxidation number of this is ther examples of oxidation numbers: "reducing agent" "oxidizing agent" Zn Zn -1-1 An atom with a formal charge: incorporate its charge # to its oxidation number. mely, if an atom has a 1 charge, add 1 to its oxidation number. Example: For 3 x (- 1) from 3 carbon atoms = -3 1 from oxygen atom = 1 1 from the charge = 1 For -1 from nitrogen atom = -1-1 from the charge = -1 overall: -2 overall: -1 ================================================================== ydrocarbon oxidation-reduction spectrum: "reduction" (hydrogenation) methane methanol formaldehyde (methanal) formic acid (methanoic acid) carbonic acid 4 2 "oxidation" (oxygen insertion) "oxidation" (also: dehydrogenation) increasing %; decreasing % decreasing %; increasing % "oxidation" "reduction" note: used in biochem.: oxidase = dehydrogenase enzyme

3 hem W13 - otes Dr. Masato Koreeda - Page 3 of 13 Date: February 20, 2013 IV. xidation of alcohols 1 -alcohol [ox] [ox] 2 -alcohol [ox] - 2 aldehyde - carboxylic acid ' - 2 ' ketone 3 -alcohol " not easily oxidized ' xidation methods: There are hundreds that differ in experimental conditions, but these follow basically the process shown below. difficult to remove as LG X B LG "E2 - type" reaction B ' - ' - LG ' "converting this to a leaving group" LG: leaving group istorically, most common reagents involve high-valency metals. 1. r (VI)-based reagents - all r(vi) reagents have toxicity problems 6 r 3 r chromium trioxide (chromic anhydride) "to be oxidized" Balancing the oxidation-reduction reaction "to be reduced" 2 r 3 oxidizing agent r 3 3 x e ("two-electron" oxidation) 2 x r 6 3e r 3 verall, r r 3 "stoichiometry"

4 hem W13 - otes Dr. Masato Koreeda - Page 4 of 13 Date: February 20, a hromic acid [ r r 4 ] (hydrous conditions) r 6 problems: 1. acidic conditions 2. can't stop at the stage of an aldehyde because of the presence of water Jones reagent: r 3 / 2 4 / 2 historically, one of the most commonly used chromium 6-based reagents for the oxidation of alcohols hromate: Dichromate: 2 r 4 (sodium chromate)/ 2 4 / 2 2 r 2 7 (sodium dichromate)/ 2 4 / 2 2 r 2 7 r r 1b. Anhydrous r 6 r 3 pyridine pyridinium chlorochromate (P): one of the most widely used oxidants! pyridinium dichromate (PD) [(py ) 2 r ] r 6 pyridinium chlorochromate (P) prepared from pyridine,, and r 3 xidation reactions of alcohols using these reagents are carried out in anhydrous organic solvents such as dichloromethane and, thus, the oxidation of a primary alcohol stops at the stage of an aldehyde. Mechanism for the oxidation with P: - ' more electrophilic than the r in r 3 because of r ' r r 4 (chromium is reduced!) oxidation step ' r 4 becomes r 3 through redox-disproportionation. B: often referred to as "hromate" ester r still r 6 r ' - B: ' extremely acidic! r still r 6

5 hem W13 - otes Dr. Masato Koreeda - Page 5 of 13 Date: February 20, 2013 The oxidation of primary alcohols with Jones reagent: 1 -alcohol r 3, acetone (solvent) more than 2 mol equiv. of the reagent needed aldehyde not isolable faster step carboxylic acid ften, an ester -(=)- is a by-product. Mechanism: 6 r A -A r 2 r A r B r 6 "chromate ester" oxidation step aldehyde: doesn't stop here! A r 4 r 3 r 6 "chromate ester" B r oxidation step! A r r A -A 2 A carboxylic acid r 4 2 r 4 r 3 r5, etc.

6 hem W13 - otes Dr. Masato Koreeda - Page 6 of 13 Date: February 20, on chromium-based xidation eactions: greener methods i) wern oxidation: usually using dichloromethane ( 2 2 ) as the solvent anhydrous (i.e., no water present!), non-acidic conditions 1 -alcohol: stops at an aldehyde; 2 -alcohol: gives a ketone Mechanism: dimethyl sulfoxide oxalyl chloride 3 This is the species in the solution after step 1. 3 B ( 2 3 ) 3 triethylamine 3 B 3 3 2,, 3 3 highly acidic s! ( 2 3 ) 3 pk a ~ ( 2 3 ) 3 3 xidation step! "intramolecular process" 3 ote: D ( 2 3 ) D

7 hem W13 - otes Dr. Masato Koreeda - Page 7 of 13 Date: February 20, 2013 IV 2. on chromium-based xidation eactions: greener methods ii) odium hypochlorite (): Bleach Usually under acidic conditions (e.g., in acetic acid); (hypochlorous acid) is the actual oxidant. As is not stable, it has to be generated in situ in the reaction medium. V. eactions of alcohols: Direct conversion of alcohols to alkyl halides With 2 (thionyl chloride) or P 3 (phosphorus tribromide) Mechanism for an alcohol to the chloride with 2 /pyridine highly electrophilic or B or B Alternatively, that can be formed from 2 and pyridine may be the reagent that puts (=) onto the group. 2 product 2 (gas) *imilar reactions and mechansims for the formation of bromides from alcohols with P 3.

8 hem W13 - otes Dr. Masato Koreeda - Page 8 of 13 Date: February 20, 2013 VI. Ethers ( ) 1. ynthesis a.williamson synthesis ' X ' ether X 2 reaction - X: alkyl halides (usually bromide and iodide, sometimes chloride) or tosylates : usually primary; methyl, allyl ( 2 =- 2 - ), benzyl (Ph 2 -). Mechanism: (gas) (1 mol equiv) I 2 3 (excess; typically, 1.5 mol equiv) sodium alkoxide 2 3 odium alkoxides can also be prepared by the treatment of alcohols with. Mechanism: e I anion radical 2 I I (gas) pk a ~40 M interpretation: a strong base This in - has no nucleophilicity. σ* σ - bond of the anion radical anti-bonding orbital bonding orbital 3 electrons in the - bond! 2 -alkyl halides and tosylates are occasionally used in the Williamson synthesis, but elimination (E2) competes or dominates, and yields of the ether products are often quite low. 3 -alkyl halides: exclusive elimination (E2). 3 3 E2! ot formed! Then, how do you make this t-butyl n-propyl ether? Phenyl ethers: More acidic than alcohol s. A milder base such as can be used to generate phenoxides (Ph ) I 80%

9 hem W13 - otes Dr. Masato Koreeda - Page 9 of 13 Date: February 20, 2013 VI 2. eavage of ethers, pp In general, difficult to cleave ether - bonds (for exceptions, see VIII, pp 10-13). an be cleaved by heating with I (more common) or. eed a strong önsted or Lewis acid and a strong nucleophile. Usually, methyl ether - and benzyl ether - are those that can be cleaved. Modern methods for cleaving ethers include the use of B 3 and Al I Δ (heat) VII. Intramolecular ether formation 3 yclic ethers: by an intramolecular 2 reaction of an alkoxide 2 I 2 5- and 6-membered cyclic ether formation: fast In general, intramolecular reactions are faster than the corresponding intermolecular (bi-molecular) reactions. An intermolecular 2 reaction of an alkoxide or slow! hydroxide ion with an alkyl chloride is slow. 95% Geometrical and stereochemical effects on cyclic ether formation: Which of the two diastereomeric hydroxy-bromide could form its cyclic ether derivative? cis trans trans 3 I A The alkoxide from A can't undergo an 2 reaction with the -. B 2 2 reacton possible! equatorial axial too far away no 2! more favored/stable conformer axial equatorial o cyclic ether formation

10 hem W13 - otes Dr. Masato Koreeda - Page 10 of 13 Date: February 20, 2013 VIII. Epoxides (or xiranes): pecial kind of cyclic ethers (3-membered ethers) epoxides (or oxiranes): The ring is strained; more polarized - bonds ethers: unstable and reactive! stable a. Formation: (1) Epoxidation of alkenes with peroxyacids (e.g., m-chloroperoxybenzoic acid; see h. 8 ) (2) From halohydrin with a base 2 25, 1 hr more favored/stable conformer - and - bonds are not oriented for an 2 process to take place. 2 70% b. ing-opening reactions of epoxides: Epoxides are highly strained and easily undergo ring-opening reactions under both acidic and basic conditions. Acidic conditions: ring-opening reactions proceed rapidly at low temperatures (usually at room temp or below); elongated - bonds of the protonated, highly strained epoxides believed to be the origin of high reactivity. Acyclic epoxides 3 3 meso 0 3 (2,3) 3 racemic mixture 3 (2,3) 3 2-like inversion of stereochemistry here! like inversion of stereochemistry here! yclic-fused epoxides 3 3 inversion of stereochemistry 3 3 or simply B 3 enantiomer transproduct

11 hem W13 - otes Dr. Masato Koreeda - Page 11 of 13 Date: February 20, 2013 ote: The mechanism for the ring-opening of epxodies under acidic conditions is quite similar to that of bromination of alkenes. bromonium ion intermediate inversion of stereochemistry enantiomer trans-product tereochemical/regiochemical issues: 3 D stereochemical inversion observed here! 3 D retention regiochemically, stereochemically clean formation of this diol. pecific incorporation of 18 here! Mechanistic interpretation on the stereochemical/regiochemical outcome under acidic conditions: more elongated -- bond; -charge delocalized because this more substituted can better stalilize the postive charge 3 D D D 3 3 In the transition state for the attack of 2 ( 2 18 in this case), the nucleophile attacks preferentially the carbon center that can better stabilize a positive character (i.e., the more substituted carbon). stereochemical inversion observed here! 3 D retention pecific incorporation of 18 here! an accommodate charge better here! 3 D an 2-like stereochemical inverstion at a more substituted carbon center

12 hem W13 - otes Dr. Masato Koreeda - Page 12 of 13 Date: February 20, 2013 Epoxide-ring opening under basic conditions A straight 2 process at the less-substituted carbon with a stereochemical inversion. 3 3 D D D less-substituted ; 2 reaction here! ummary of epoxide-ring opening reactions: D 2 3 Acidic conditions: 2 like in term of the stereochemical inversion, but at the more substituted. ing opening at the more substituted with the inversion of stereochemistry. Basic conditions: pure 2 ing opening at the less substituted with the inversion of stereochemistry. 1,2-Diaxial opening of cyclohexene oxides 1) 3 more stable conformer 2) 2 axial-like axial-like only 1,2-diaxial transition state feasible for an 2 like process to occur axial axial thermodynamically less favored conformer This is the conformer produced first, then it inverts to the more stable diequatorial conformer shown above. Because these are transfused decalins, these diaxial diols can't invert conformations to become diequatorial diols.

13 hem W13 - otes Dr. Masato Koreeda - Page 13 of 13 Date: February 20, 2013 The above examples are quite similar to the bromination reaction of cyclohexene systems. 2 Problems: how the structure of the expected major product for each of the following reactions. (1) 2 1. MPBA 2. aq 4 (2) 3, 3 3