Presentation on theme: "Reactions of Alcohols oxidation tosylation and reactions of tosylates substitutions to form alkyl halides dehydration to form alkenes and ethers."— Presentation transcript:
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 - 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 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