Reactions of Alcohols  oxidation  tosylation and reactions of tosylates  substitutions to form alkyl halides  dehydration to form alkenes and ethers  pinacol rearrangement  esterification  cleavage of glycols  ether synthesis

Classification of Reactions  Oxidations addition of O or O 2 addition of X 2 loss of H 2  Reductions loss of O or O 2 loss of X 2 addition of H 2 or H -

Classification of Reactions  Neither an oxidation nor a reduction Addition or loss of H + Addition or loss of OH - Addition or loss of H 2 O Addition or loss of HX

Classification of Reactions  Oxidations count C-O bonds on a single C the more C-O bonds, the more oxidized the C increasing level of oxidation

Reactions of Alcohols - Oxidation  For alcohols, the oxidation comes from the loss of H 2.  Oxidation of a 2° alcohol gives a ketone.  Chromic acid reagent used in lab oxidations. Na 2 Cr 2 O 7 + H 2 SO 4 + H 2 O  2H 2 CrO 4 + 2NaHSO 4 CrO 3 + H 2 O (dil H 2 SO 4 )  H 2 CrO 4

Reactions of Alcohols - Oxidation  Oxidation of a 1° alcohol gives a carboxylic acid if chromic acid reagent is used. an aldehyde if pyridinium chlorochromate (PCC) is used.

Reactions of Alcohols - Oxidation  Two other reagents behave like the chromic acid reagent: KMnO 4 (will attack C=C, too) HNO 3  These two oxidizing agents are so strong that C-C bonds may be cleaved.  Bleach (OCl - ) also oxidizes alcohols.

Reactions of Alcohols – Swern Oxidation  Uses dimethyl sulfoxide (DMSO), oxalyl chloride (COCl) 2 and a hindered base. The reactive species is (CH 3 ) 2 SCl +. The result is a ketone or an aldehyde (the same as for PCC).

Reactions of Alcohols – Swern Oxidation  Uses dimethyl sulfoxide (DMSO), oxalyl chloride (COCl) 2 and a hindered base.

Reactions of Alcohols – Oxidation with DMP  Uses Dess-Martin periodinane (DMP). Mild conditions: room temperature and neutral pH with excellent yields The result is a ketone or an aldehyde (the same as for PCC and the Swern oxidation).

Reactions of Alcohols – Oxidation with DMP  Uses Dess-Martin periodinane (DMP).

Reactions of Alcohols - Biological Oxidation  Ethanol is the least toxic alcohol, but it is still toxic.  The body detoxifies ethanol with NAD catalyzed first by alcohol dehydrogenase (ADH) and second by aldehyde dehydrogenase (ALDH): ethanol  acetic acid  The reason methanol and ethylene glycol are so toxic to humans is that, when they react with NAD/ADH/ALDH, the products are more toxic than the original alcohols. methanol  formic acid ethylene glycol  oxalic acid

Reactions of Alcohols - Oxidation  3° alcohols will not oxidize, because there is no H on the carbinol C atom.  The chromic acid test capitalizes on this fact: orange chromic acid reagent turns green or blue (due to Cr 3+ ) in the presence of 1° or 2° alcohols, but doesn’t change color in the presence of a 3° alcohol.

Reactions of Alcohols - Tosylation  In order to perform an S N 2 reaction on an alcohol, i.e., with the alcohol as the substrate, the -OH group must leave the alcohol: R-OH + Nuc: -  R-Nuc + OH -  OH - is a poor leaving group  H 2 O is a better leaving group, but this requires protonation of the alcohol which, in turn, requires an acidic solution. Most nucleophiles are strong bases and cannot exist in acidic solutions.  We need to convert the alcohol to an electrophile that is compatible with basic nucleophiles.

Reactions of Alcohols - Tosylation  Converting the alcohol to an alkyl halide (already discussed) or an alkyl tosylate lets it act as an electrophile. Stereochemical configuration of alcohol is retained.

A Tosylate Ion is an EXCELLENT LEAVING GROUP  As good as or better than a halide.

A Tosylate Ion is an EXCELLENT LEAVING GROUP  As such, tosylates (just like halides) are candidates for S N 2 reactions E2 reactions S N 1 reactions E1 reactions  Just like the halides

S N 2 Reactions of Tosylates R-OTs + OH -  ROH (alcohol) + - OTs R-OTs + CN -  RCN (nitrile) + - OTs R-OTs + Br -  RBr (alkyl halide) + - OTs R-OTs + R’O -  ROR’ (ether) + - OTs R-OTs + NH 3  RNH OTs (amine salt) R-OTs + LiAlH 4  RH (alkane) + - OTs

S N 2 Reactions of Tosylates - Mechanism  Single step  Inversion of configuration

Alcohols to Alkyl Halides: Hydrohalic Acids (HX)  Hydrohalic acids are strong acids, existing in aqueous solution as H + and X -. Recognize a hydrohalic acid: NaBr/H 2 SO 4  The H + is need to convert the -OH of the alcohol into a good leaving group (H 2 O). The reaction mechanism, S N 1 or S N 2, depends on the structure of the alcohol.

Alcohols to Alkyl Halides: Hydrohalic Acids (HX)  The structure of the alcohol dictates whether the mechanism is S N 1 or S N 2.

 Cl - is a weaker nucleophile than Br -.  ZnCl 2 coordinates with the -OH of the alcohol (like H + does) to form a better leaving group (HOZnCl 2 - ) than water. ZnCl 2 is a better Lewis acid than H +.  This promotes the S N 1 reaction between HCl and 2° and 3° alcohols.  HCl/ZnCl 2 is called the Lucas reagent. Alcohols to Alkyl Chlorides: The Lucas Reagent

 Add the Lucas reagent to a solution of the unknown alcohol and time the formation of a second phase.  3° alcohols react immediately.  2° alcohols take 1-5 minutes.  1° alcohols take >6 minutes. Alcohols to Alkyl Chlorides: The Lucas Test

 This reaction does not always give good yields of RX. 1° and 2° alcohols react slowly with HCl, even with ZnCl 2 added. Heating an alcohol with HCl or HBr can give the elimination product, an alkene. Rearrangements can occur with S N 1 (this is not necessarily bad). HI does not give good yields of alkyl iodides, a valuable class of reagents. Alcohols to Alkyl Halides: Limitations of Using HX

 Can give good yields of 1° and 2° alkyl bromides and iodides without the acidic conditions that go with HX. 3 R-OH + PBr 3  3RBr + P(OH) 3  PI 3 is unstable and must be made in situ: 6 R-OH + 2P + 3I 2  6RI + 2P(OH) 3  PBr 3 and P/I 2 do NOT work well with 3° alcohols. Alcohols to Alkyl Halides: PBr 3 and P/I 2

A double S N 2 mechanism, which is why it does not work on 3° alcohols. Inversion of configuration, but no rearrangements. Alcohols to Alkyl Halides: PBr 3 Mechanism

Alcohols to Alkyl Halides: Thionyl Chloride, SOCl 2  Often the best way to make an alkyl chloride from an alcohol. ROH + SOCl 2  RCl + HCl(g) + SO 2 (g)  Gaseous by-products keep the equilibrium well to the right. heat dioxane

Alcohols to Alkyl Halides: Best Reagents AlcoholAlkyl chloride Alkyl bromide Alkyl iodide 1°SOCl 2 PBr 3 P/I 2 2°SOCl 2 PBr 3 (P/I 2 ) 3°HClHBr(HI)

Alcohols to Alkenes: Acid-Catalyzed Dehydration  We studied this in the formation of alkenes.  E1 elimination of a protonated alcohol  Best for 3° and 2° alcohols  Rearrangements common for 1° alcohols due to the carbocation intermediate  Zaitsev product predominates.

 Step 1: protonation of the alcohol  Fast equilibrium  Converts OH to a good leaving group Alcohols to Alkenes: Acid-Catalyzed Dehydration

 Step 2: ionization to a carbocation  slow, rate-limiting  leaving group is H 2 O Alcohols to Alkenes: Acid-Catalyzed Dehydration

 Step 3: deprotonation to give alkene  fast  The carbocation is a strong acid: a weak base like water or bisulfate can abstract the proton. Alcohols to Alkenes: Acid-Catalyzed Dehydration

 Competes with alkene formation.  Lower temperatures favor ether formation, a ΔS thing.  After protonation, the alcohol can undergo an S N 2 attack by another alcohol molecule to form a symmetric ether. Alcohols to Symmetric Ethers: Bimolecular Dehydration

3° Vicinal Diols to Ketones: The Pinacol Rearrangement  Acid-catalyzed dehydration of a 3° vicinal diol to form a ketone.  Involves a methyl migration, ~CH 3

3° carbocation resonance-stabilized carbocation 3° Vicinal Diols to Ketones: The Pinacol Rearrangement

Vicinal Diols to Carbonyls: Periodic Acid Cleavage of Glycols  Periodic acid is HIO 4.  Products are aldehydes and ketones.  Products the same as for ozonolysis. HIO 4

Alcohols to Esters: Acids  When the acid is a carboxylic acid, the reaction is called Fischer esterification.  This is an equilibrium, and it does not always favor the ester.

 When the acid is sulfuric acid, the product is a sulfate ester. Alcohols to Esters: Acids

 When the acid is nitric, and propane- 1,2,3-triol (glycerine) is the alcohol, what is the product?  When the acid is phosphoric acid, the product is a phosphate ester.  Phosphate esters are the links between nucleotides in RNA and DNA. Alcohols to Esters: Acids

DNA image from Wikipedia

Oxidation or Reduction?

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As opposed to 180°C.

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Conversions