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2 xidation of Alcohols with Chromium (VI): Jones xidation 2 Alcohols are oxidized by a solution of chromium trioxide in aqueous acetone (2), in the presence of an acid such as 2 S 4. This is called the Jones reagent, and the reaction of this mixture with an alcohol is called Jones oxidation. The acetone moderates the reaction and helps to solubilize the various reactions found in this oxidation. In a typical experiment using Na 2 Cr 2 7 in sulfuric acid, 3-pentanol (9) is converted to 3-pentanone (12) in 57% yield. Recognition that in aqueous solution Cr 3 is in equilibrium with Cr 3 7 2, allows the use Cr 3 as the active oxidizing agent to look at a simplified mechanism. 9 Na 2 Cr 2 7, acetone +, water 12

The acetone moderates the reaction and helps to solubilize the various reactions found in this oxidation.

3 xidation of Alcohols with Chromium (VI): Jones xidation 3 The oxygen of the alcohol (a Lewis base) donates two electrons to chromium (Cr is a Lewis acid) to form oxonium salt 10. Transfer of the acidic proton of the oxonium salt in 10 to the chromate oxygen (the base) leads to a so-called chromate ester, 11. Formation of the chromate ester makes the hydrogen atom on the α-carbon acidic (marked in red in 11). Removal of that hydrogen by water is an acid-base reaction that leads to loss of the chromium(iii) leaving group, which is an elimination reaction that forms a new π-bond; a carbonyl (C=). If the chromium unit is viewed as a leaving group, then the hydrogen α- to the oxygen is lost to water and the leaving group is Cr 3. This mechanism predicts that the secondary alcohol (9) will be converted to 3-pentanone (12), which is an oxidation. Note the similarity of the oxidation of an alcohol to the elimination reaction of 11 via an E2 reaction (shown in the box) for conversion of an alkyl halide to an alkene. Cr Cr Cr 3 - Cr Br E2 reaction + + Br

Formation of the chromate ester makes the hydrogen atom on the α-carbon acidic (marked in red in 11).

4 xidation of Alcohols with Chromium (VI): Aldehydes 4 Jones oxidation is such a powerful oxidizing medium that unwanted products are possible due to over-oxidation. When a primary alcohol such as 1-pentanol (15) reacts with chromium trioxide and aqueous sulfuric acid, it follows the same mechanistic pathway as 9, with formation of chromate ester 16. Experiments show that the yields of aldehyde from primary alcohols can be very low. 1-Propanol is oxidized to propanal, for example, in only 49% yield, and to obtain the product requires a short reaction time. Very often, a carboxylic acid is formed as a second product or even the major oxidation product rather than the aldehyde. It is known that aldehydes are easily oxidized to carboxylic acids, even by oxygen in the air.

Experiments show that the yields of aldehyde from primary alcohols can be very low.

5 xidation of Alcohols with Chromium (VI): Aldehydes 5 Formation of an aldehyde such as 17 in the presence of a powerful oxidizing agent such as chromium(vi), is usually followed by rapid oxidation of 17 to the corresponding carboxylic acid, pentanoic acid (18). In general, Jones oxidation of simple aldehydes usually gives the carboxylic acid as the major product. If the reaction mixture is heated, over-oxidation to the carboxylic acid is even more rapid. Cr 3 Cr 3, aq. + - Cr 3 Cr 3, aq heat

(18). In general, Jones oxidation of simple aldehydes usually gives the carboxylic acid as the major product.

6 xidation of Alcohols with Chromium (VI): Aldehydes 6 When acetone is used as a solvent the rate of oxidation of aldehyde to acid is relatively slow. Acetic acid (ethanoic acid) serves a similar role in many oxidations. This means that cold temperatures and short reaction times favor the aldehyde, but long reaction times and heat favor formation of the acid. The reaction of 19 with Cr 3 in sulfuric acid and aqueous acetic acid for several hours and then heated to 100 C gives carboxylic acid 20 was isolated in 82% yield. If the number molar equivalents of oxidizing agent is diminished, and the temperature is keep low with a short reaction time, aldehyde 21 is isolated in 59% yield. 3 In general, assume that oxidation of a secondary alcohol with chromium (VI) leads to a ketone and oxidation of a primary alcohol leads to an aldehyde if temperature and time are controlled. C 1.3 Cr 3, 2 S Cr 3, 2 S 4 C aq. C 3 C aq. C 3 C 59% 0-5 C 25 C (overnight) C (1 h) heat (10 minutes) %

This means that cold temperatures and short reaction times favor the aldehyde, but long reaction times and heat favor formation of the acid.

7 xidation of Alcohols with Chromium (VI): Steric Effects 7 Alcohol 22 (2-methyl-3-pentanol) is oxidized faster than alcohol 24 (2,2,4,4-tetramethyl-3-pentanol). If both alcohols are converted to the corresponding chromate ester (23 and 25 respectively), the α-hydrogen (marked in red) must be removed in each case to give the ketone. The surrounding methyl groups in 25 create significant steric hindrance around the α-hydrogen, so it is more difficult for the base (water) to approach that hydrogen. The α-hydrogen in 23 is relatively unhindered and is easily removed by the base, so the rate of oxidation is relatively fast for 23 but slower for 25 due to steric hindrance in the chromate ester. The steric hindrance in the chromate ester makes it more difficult for the water to react with the α- proton. Note that the chromate ester is formed in both cases, and the steric hindrance to oxidation occurs in the chromate ester and not in the alcohol. Cr 3 FAST Cr 3 SLW very sterically hindered so it is difficult for 2 to collide with

The surrounding methyl groups in 25 create significant steric hindrance around the α-hydrogen, so it is more difficult for the base (water) to approach that hydrogen.

8 xidation of Alcohols with Chromium (VI): PCC & PDC 8 The reaction of chromium trioxide (5) with pyridine, in aqueous Cl generates a specific compound known as pyridinium chlorochromate (PCC, 31) that is isolated and purified. The Cr 3 forms Cr 4 (6) in dilute aqueous acid, which reacts with Cl to form CrCl 3. Pyridine then reacts as a base with this acidic proton to form PCC. If the reaction conditions are modified to increase the amount of pyridine in the water solution. and the Cl is omitted, the reaction generates pyridinium dichromate (PDC, 32), presumably by reaction of an excess of pyridine with 2 Cr 2 7. In dilute solution, Cr 3 is in equilibrium with 2 Cr 2 7, and pyridine reacts with both acidic hydrogen atoms to produce PDC. Cr 3 Cl N N Cr 2 7

If the reaction conditions are modified to increase the amount of pyridine in the water solution.

9 xidation of Alcohols with Chromium (VI): PCC & PDC 9 Both PCC and PDC are less reactive than chromium trioxide in the Jones reagent, but they are very effective for converting primary alcohols to the aldehyde, in good yield and under mild conditions. Secondary alcohols are readily converted to ketones by both reagents. Dichloromethane is typically used as the solvent with both reagents. An example is the reaction of 2-cyclopentylethanol (33) and PCC in dichloromethane gave 1- cyclopentylethanal, 34 in 72% yield. The reaction of 4-propylcyclohexanol (35) and PDC, gives 4-propylcyclohexanone (36) in 97% isolated yield. PCC, C 2 Cl 2 C 72% PDC, C 2 Cl %

Dichloromethane is typically used as the solvent with both reagents.

10 xidation of Alcohols with DMS: Swern xidation 10 An oxidation reagent is derived from the reaction of dimethyl sulfoxide (DMS, 37) and oxalyl chloride (38). When 2-butanol is mixed with these reagents at 60 C, dimethyl sulfide (MeSMe) is observed as a product and 2-butanone (43) is isolated in 78% yield. This particular oxidation of an alcohol to a ketone or aldehyde is called the Swern oxidation. 3 C S 3 C + Cl Cl C Me 41 3 C 3 C S + Me 43

When 2-butanol is mixed with these reagents at 60 C, dimethyl sulfide (MeSMe) is observed as a product and

11 xidation of Alcohols with DMS: Swern xidation 11 The mechanism proposed to explain these observations shows that the oxygen of DMS must attack the acyl carbon of oxalyl chloride in an acyl substitution reaction (chapter 19, section 19.2) to form an acyl-sulfonium derivative, 39. This intermediate decomposes with loss of carbon dioxide (C 2 ) and carbon monoxide (C) to give a chlorosulfonium salt, 40. Sulfonium salt 40 has an electrophilic sulfur that it attacked by the nucleophilic oxygen of an alcohol such as 2-butanol (41), at low temperatures (less than 60 C), to give 42. Intermediate 42 is related to intermediate 16 (the chromate ester of 19 discussed in section 17.2.B) in that a leaving group (Me 2 S) is lost and a hydrogen atom (in red in 42) is removed. Me 3 C 3 C - C 2 3 C S Cl Cl -60 C S - C Cl - 3 C S 41 3 C 3 C Cl Cl =SMe 2 Me 3 C 3 C + S S 3 C 42 3 C 43 +

This intermediate decomposes with loss of carbon dioxide (C 2 ) and carbon monoxide (C) to give a chlorosulfonium salt, 40.

12 xidation of Alcohols 12 Cr 3, 2 S 4 aq. acetone C 2 PDC C 2 Cl 2 C PCC C 2 Cl 2 C 2 DMS, -78 C oxalyl chloride C

13 xidation of Alkenes: Dihydroxylation 13 Cyclohexene was treated with s 4 (osmium tetroxide) in anhydrous 2-methyl-2-propanol (tert-butyl alcohol) at 0 C. After standing overnight, a 45% yield of cis-1,2cyclohexanediol (44) was isolated. This reaction is a dihydroxylation and the two units have a cis- relationship. Alkenes also react with dilute aqueous potassium permanganate to give a cis-diol. s 4, t-bu, 0 C 44 45%

After standing overnight, a 45% yield of cis-1,2cyclohexanediol (44) was isolated.

14 xidation of Alkenes: Dihydroxylation 14 Both potassium permanganate (KMn 4 ) and osmium tetroxide (s 4 ) react with an alkene via 1,3-dipolar addition to give what is known a manganate ester (45) or an osmate ester (47). In the presence of aqueous hydroxide, 45 reacts to give 1,2-diol 46. In the osmium tetroxide reaction, aqueous sodium thiosulfite (NaS 3 ) or tert-butanol is used to convert 47 to diol 44. The conversion of an alkene to a diol is a formal oxidation Mn Mn aq. NaS 3 s s 47 44

In the presence of aqueous hydroxide, 45 reacts to give 1,2-diol 46.

But in organic terms: Oxidation: loss of H 2 ; addition of O or O 2 ; addition of X 2 (halogens).

But in organic terms: Oxidation: loss of H 2 ; addition of O or O 2 ; addition of X 2 (halogens). Reactions of Alcohols Alcohols are versatile organic compounds since they undergo a wide variety of transformations the majority of which are either oxidation or reduction type reactions. Normally: Oxidation