Reactions of Alcohols I. Oxidation and Reduction according to organic chemists: A. Basics1.

Oxidation- the result of an oxidation agent being added; O or O2, halogens X2, loss of H2. 2. Reduction- the result of a reducing agent being added; H2 or H-; loss of O or O2, loss of halogens X2. 3. Neither- addition or loss of H+, H2O, HX, etc. is neither oxidation nor reduction. *Note that an alkane can be oxidized to a primary alcohol, further oxidation leads to an aldehyde, and one more round of oxidation yields a carboxylic acid. *Secondary alcohols are oxidized to yield a ketone and water. *Tertiary alcohols cannot be oxidized without breaking bonds. B. Secondary Alcohols1. Chromic acid reagent- easily oxidizes secondary alcohols to give excellent yields of ketones. Prepared by dissolving sodium dichromate in a mixture of sulfuric acid and water, or adding chromium trioxide to dilute sulfuric acid. Na2Cr2O7 / H2SO4 a. The first step of this reagent is to form a chromate ester. b. The next step is the elimination of the ester and the oxidation of the carbinol carbon. This utilizes water as a base abstracting the proton from the carbinol carbon with its lone pairs, and using the electrons from the bond to form a carbonyl bond. Refer to p 463 to see electron movement. C. Primary Alcohols1. Pyridinium Chlorochromate(PCC)- is used to perform limited oxidation of primary alcohols to aldehydes in excellent yeilds. Most other oxidizing agents are too strong and oxidize the primary alcohols all the way to carboxylic acids. Consists of complex of chromium trioxide with pyridine and HCl. Soluble in nonpolar solvents such as dichloromethane(CH2Cl2). a. Can also be used as a mild reagent to oxidize secondary alcohols into ketones. *Refer to the example on p. 464 D. Tertiary alcohols- resistance to oxidation 1. Must take place by breaking the carbon-carbon bond. Requires severe conditions and therefore, mixed products result. 2. Chromic acid test-Upon the addition of a primary or secondary alcohol to chromic acid reagent, the color goes from orange to green or blue. If it is nonoxidizable such, then there is no immediate color change. Tertiary alcohols, ketone, and alkanes

E. Additional Methods for alcohol oxidation1. Collins Reagent- a complex of chromium trioxide and pyridine. 2. Jones Reagent- milder form of chromic acid that consists of a solution of diluted chromic avid in acetone. 3. Potassium Permanganate and Nitric acid- Both strong oxidants that are less expensive than the chromium reagants, and both also give byproducts that are environmentally less hazardous than spent chromium agents. a. Strong oxidizers, therefore the primary alcohols to carboxylic acids, and secondary acids to ketones. b. So strong that they will break carbon-carbon bonds if not controlled. 4. Dehydrogenation- the least expensive method for oxidizing alcohols. Takes place at high temperatures with copper or copper oxide as a catalyst. This results in a hydrogen byproduct that can be used in other reactions or even sold. a. Not useful for a laboratory setting 5. Swern Oxidation- Uses dimethyl sulfoxide(DMSO) as the oxidizing agent to convert alcohols to ketones and aldehydes. a. DMSO and oxalyl chloride are added to the alcohol at low temperature; this is then followed by the addition of a hindered base such as triethylamine. b. Byproducts are volatile, so separation of products is easy. c. Secondary alcohols ketones; Primary alcohols aldehyde d. See ex on p. 466. 6. Biological Oxidation of alcohols- The enzyme that breaks down alcohol, oxidiation of the alcohol, is alcohol dehydrogenase. This is done by the removal of two hydrogens from the alcohol. a. Oxidizing agent is NAD; exists in two forms: i. the oxidized form, NAD+ ii. the reduced form, NADH b. ethanol is oxidized to acetylaldehyde, and NAD+ is reduced to NADH. c. See p. 467 d. Aldehyde dehydrogenase- is the enzyme that converts the acetylaldehyde and oxidizes it to acetic acid. e. Some alcohols byproducts are more toxic than the alcohol itself. i. Methanol, a toxic alcohol, is oxidized to formaldehyde and then to formic acid both of which are more toxic than the original alcohol. Blindness and death result. ii. Ethylene glycol is a toxic diol found in antifreeze that is oxidized to oxalic acid another toxic compound. Many pets are poisoned by this because of the sweet odor of this compound. When ingested the kidneys fail and death results. iii. Both poisonings are treated the same, give them diluted ethanol intravenously. The ADH enzyme is overwhelmed with ethanol, the preferred

substrate; as a result, the kidneys have time to expel the toxic elements before oxidation takes place. II. Alcohols as nucleophiles and electrophilesA. Versatility1. Alcohol can be weak nucleophile bonding to a strong electrophile such as a carbocation. a. The C-O bond is broken when alcohol acts as electrophile as in substitution reactions. b. The alcohol can make the poor leaving hydroxyl group into a good leaving group through protonation of the hydroxyl group. i. Ex: add HBr to alcohol which donates its proton to the oxygen with 2 lone pairs. This creates H2O with a positive charge on oxygen. This instability results in the formation of a good leaving group, water. This results in a carbocation which then binds Br- in classic SN2 fashion. ii. The disadvantage of using the protonated alcohol is that a strongly acidic solution is required to protonate the alcohol. This is a problem because there are few nucleophiles that are stable in strongly acidic solutions besides halide ions. Most of the nucleophiles are also basic and will abstract a proton in acid. This makes it lose its nucleophilicity. 2. Alcohol can be converted to a strong nucleophile by conversion to an alkoxide ion. This allows for an attack of a weaker electrophile. a. The O-H cond is broken when alcohol is nucleophillic as in the elimination reacton. 3. Tosylate esters the product of condensation of an alcohol with p-toluenesulfonic acid(TsOH). The tosylate is an excellent leaving group. Depending on the reagents, many SN2 products can formed when in the presence of a strong nucleophile and the Rs must be primary or unhindered secondary alkyl group. See table p. 471. Reduction of alcohols: A. Basics1. Not as common because it removes a functional group; leaving fewer options for further reactions. 2. Two step process: a. Dehyrdrate to yield alkene. b. Then hydrogenate to yield alkane. 3. Can also be achieved by converting the alcohol to a tosylate ester, then using a hydride reducing agent to displace the tosylate. a. Works best for primary and secondary alcohols

III.

IV.

Reactions of Alcohols with hydrohalic acids: A. Common Reactions to yield alkyl halides: 1. Tosylation, followed by displacement of tosylate by a halide ion alkyl halide. a. Simple one step reactions are available 2. Hydrobromic acid treatment-If an alcohol is placed in an acidic solution, the acid donates a proton to the alcohol converted to its protonated form. a. Alcohol and protonated form are in equilibrium b. The protonated(H2O+) version is a good leaving group c. Then the halide anion, a weak base(b/c the acid is so strong), will act in nucleophilic substitution 1 or 2 depending on the structure of the alcohol. i. Tertiary and secondary alcoholsa. SN1 mechanism- forms a tertiary or secondary carbocation. b. Subsequent attack of the nucleophilic halide. ii. Primary alcoholsa. Protonation as above, results in good leaving group b. Ionization to form carbocation is unfavorable iii. Must have concerted reaction with backside attack of bromide ion in SN2 fashion. 3. Hydrochloric acid treatment- reacts much like hydrobromic acid. a. Chloride ion is a weaker nucleophile than bromide ion because it is smaller and less polarizable. i. Lewis acid such as ZnCl2 is sometimes necessary to promote reactions of HCl with primary and secondary alcohols. a. The ZnCl2 will bind to the oxygen of the hydroxyl group with more efficiency and form the good leaving group. ii. Lucas reagent- HCl and ZnCl2. a. Secondary and tertiary alcohols react with SN1 mechanism. b. Primary alcohols cannot ionize to form primary carbocation because they are too unstable. i. Therefore, a concerted 1 step SN2 mechanism is required. This is much slower than the secondary and tertiary reactions, that use SN1 mechanism, due to the fact of rate of the SN1 reactions are dependent only on the concentration of the alkyl halide; however, both the nucleophile and alkyl halide concentrations affect the rate in SN2 mechanisms. (Inc the nucleophile speeds up kinetics in the 2s)

ii.

Lucas test- A test that is used to determine the structure of an alcohol, primary, secondary, or tertiary. Alcohols react with lucas reagent at fairly predictable rates. The rates can be used to distinguish which alcohol is present. a. Add Lucas reagent to an unkown alcohol to form one phase. i. The very polar HCl dissolves the alcohol-zinc chloride complex to yield the alkyl halide, a nonpolar substance. ii. This will cause a second phase to emerge. a. Primary- very slow (10min-sev days) b. Secondary- 1 to 5 minutes c. Tertiary- almost instantaneous

B. Limitations on the use of Hydrohalic Acids with Alcohols1. Poor yields of alkyl chlorides from primary and secondary alcohols. a. side reactions prevent good yields 2. Elimination is preferred when an alcohol is heated in concentrated acid such as HCl or HBr. Protonation is achieved making the hydroxyl group is then protonated resulting in a good leaving group, can undergo elimination or substitution. 3. Rearrangements of carbocations intermediates are always prone to rearrangenments to increase the stability of a carbocation. 4. Limited ability to make alkyl iodides due to the reactivity of alkyl iodides.

C. Reactions of alcohols with Phosphorous Halides1. PCl3, PBr3, PCl5 all react to yield primary and secondary alkyl halides. 2. Doesnt work as well for PClides. 3. Phosphorous trihalides, strong electrophiles, have rearrangements that are uncommon, and tertiary alcohols are unlikely to react. a. the first step is for the alcohol will react with the electrophillic Phosphorous trihalide to make the cationic oxide ion, a good leaving group, and the halide anion. b. The halide ion then displaces the leaving group in a backside attack. c. No carbocation, therefore, no rearrangements are likely d. Because of the SN2 backside attack, the tertiary alcohols are sterically hindered. e. For a tertiary alcohol, ionization must occur to form the carbocation. i. too slow; invites side reactions.

D. Thionyl Chloride1. The best reagent for converting an alcohol into an alkyl chloride. a. Byproducts, SO2 and HCl, are gaseous so they leave the mixture preventing a reverse reaction. b. Steps: i. First, nonbonding electrons of the hydroxyl oxygen atom attack the electrophilic sulfur atom of thionyl chloride. ii. Second, a chloride ion is displaced which then comes and removes the hydrogen that is on the hydroxyl group to yield a chlorosulfite ester(great leaving group) iii. Then, provided secondary or tertiary, SN2 mechanism. iv. Primary undergoes the concerted reaction of SN1 forming a chloride bond with the carbon and breaking the C-O bond. E. Formation of Alkenes1. Protonate alcohol, a slightly exothermic step, to convert the hydroxyl to a water cation, an excellent leaving group. 2. Water leaves to form a carbocation in the rate limiting step 3. Water acts as a base and abstract the hydrogen from the carbon bonded to the carbocation. 4. Must be in acidic conditions to promote protonation of hydroxyl. 5. Equilibrium can be driven to the right by the removal of the products: a. Can be achieved by the distilling the products out of the reaction mixture or by adding a dehydrating agent to remove the water. i. The alcohol is mixed with the dehydrating acid, and the mixture is heated to boiling. The alkene boils at lower temperature than the alcohol, due to h-bonding, and the alkene distills out of the mixture. *Note Classic E1 mechanism so the reactivity depends on the stability of the carbocation, tertiary>secondary>and primary with rearrangements are common. F. Bimolecular dehydration to Form Ethers1. Sometimes protonated primary alcohols can be attacked by another molecule of the alcohol. The molecule can then undergo SN2 displacement. 2. The two joined molecules have an oxygen molecule that is positively charged and unstable. a. a water molecule comes and abstracts the remaining hydrogen to yield an ether and H3O+ . 3. Used to synthesize symmetrical dialkyl ethers, diethyl ether and dimethyl ether, form unhindered primary alcohols.

4. Under acidic conditions, competition occurs: a. Substitution to give ether, bimolecular dehydration b. Elimination to give the alkene, unimolecular dehydration. *Control can be achieved by controlling the temperature: the higher the temp the more favorable the elimination path becomes favorable. 40 degrees Celsius and below for ether formation, and 80 degrees and above for alkene formation. G. Unique Reactions of Diols1. Pinacol Rearrangement- a dehydration reaction that is catalyzed by an acid. The steps are as follows: a. protonation of the hydroxyl group to yield unstable cationic water, good leaving grp. b. methyl group migrates to the cationic carbon, thereby moving the charge to the carbon that has the remaining hydroxyl group. i. the oxygens lone pair helps to stabilize the positive charge on the carbon. This is what drives the rearrangement. c. Deprotonation of the resonance stabilized cation gives the product pinacolone.

H. Periodic Acid Cleavage of Glycols1. Periodic acid(HIO4)- 1,2 diols(glycols) are cleaved by this acid to yield ketones and aldehydes. Steps: a. Hydroxylation of the alkene to yield a glycol, using OsO4 and H2O2. b. Periodic acid subsequently cleaves the glycol using a cyclic periodate intermediate. *The resulting products that would be formed are the same as the products formed by the reduction of the alkenes, ozonlysis. Useful for determining the structures of surgars. I. Fischer esterification1. a process in which the hydroxyl group of a carboxylic acid with the OR of an alcohol to yield an ester. a. unfavorable equilibrium, so to achieve good yields an excess of alcohol or acid is used b. adding a dehydrating agent so that water, a product, is removed also helps. c. combining an alcohol with an acid chloride is highly favorable(exothermic)

J. Esters of Inorganic acids1. Inorganic esters when the alcohol is bonded to an inorganic acid, such as nitric, sulcuric, or phosphoric acid, the product is an inorganic ester. Each still undergoes a dehydration reaction in which the hydroxyl of the acid is replaced by the alkoxy, -OR, group of the alcohol. a. Sulfate esters are analogous to tosylate esters. i. alkoxy groups are bonded to the sulfur atom through oxygens. ii. Sulfate ions are excellent leaving groups and good electrophiles. iii. Nucleophiles react with sulfate esters to give alkylated products. b. Nitrate esters are famous due to nitroglycerine. c. Phosphate esters react with 1, 2, or 3 moles of an alcohol. i. play an important role in the formation of backbones of nucleic acids of RNA and DNA.

I.

Alkoxide ion reactions1. The reduction of alcohol by reduction with an active metal such sodium or potassium yields a salt of the alkoxide ion and hydrogen gas. 2. Reactivity: methyl > primary > secondary > tertiary. 3. Sodium reacts quickly with primary and secondary alcohols. 4. Potassium is more reactive than sodium and is commonly used with tertiary and some secondary alcohols. 5. If the alcohol isnt as reactive, then sodium hydride is used in a tetrahydofuran(THF) solution. 6. Alkoxide ion is very reactive as a strong nucleophile, and also as a powerful base. 7. Alkoxide ion, unlike alcohols, can bond with primary alkyl halides, no steric hinderance, and tosylates to form ethers in a SN2 reaction known as Williamson Ether Synthesis. a. If not primary, elimination reaction takes place.