SUMMARY General Information Synthesis of Alcohols + From Alkenes via Oxymercuration-Demercuration * From Alkenes via Hydroboration-Oxidation * From Alkenes via Hydroxylation with OsO4 ‘* From Aldchydes/Ketones via Reduction with NaBHy * From Carbonyl Compounds via a Grignard Reaction * From Esters via Reduction with LiAlH Reactions of Alcobols * Preparation of Alkenes via Acid-Catalyzed Dehydration * Preparation of Alkyl Halides from 3° Alcohols + Preparation of Alkyl Halides from 1° and 2° Alcohols + Preparation of Aldchydes/Ketones from 1° and 2° Alcohols Aleobols 1 Alcohols 2 Alcohols 3 Alcohols 4 Alcohols 5 Alcohols 6 Alcohols 7 Alcohols 8 Alcohols 9 Alcohols 10 Alcohols 11 AlcoholsGENERAL INFORMATION Alcohols 1 Alcohols (R-OH) Introduction: Alcohols are compounds with a hydroxyl group (-OH) as their main functional group. They are rather abun- dant in nature and widely used in the chemical industry. Some common alcohols are listed below: 1. Ethanol is produced from fermentation of sugar by yeast (e.g., beer). Itis also industrially synthesized from ethylene. 2. Isopropyl alcohol, commonly known as rubbing alcohol, is prepared from propene. It has antibacterial properties. * Alcohols have higher melting and boiling points than alkanes of comparable molecular weight because of their ability to form intermolecular hydrogen bonds. * Only low-molecular-weight alcohols (fewer than 5 carbons) are soluble in water. Chemical Properties: * The bond angle formed by C-O-H is slightly /ess than 109. has tetrahedral geometry. * Alcohols have both very weak acid (pK, ranges from 16 to 19) and very weak base properties. 1. An increase in alkyl substitution results in decreased acidity because bulkier groups sterically hinder water from stabilizing RO™ (e.g., methanol is more acidic than tert-butyl alcohol). 2. An increase in halogen substitution results in increased acidity because halogens are electron-withdrawing and can stabilize the negative charge on RO™ (this is known as the inductive effect). * Alcohols react vigorously with verystrong bases (e.g., NaH, NaNH), alkali metals, and Grignard reagents, but less so with hydroxide, to yield alkoxide ions. However, they do not react witheweak bases such as amines and HCO3~. ‘The hydroxyl group is sp3 hybridized andNomenclatus Alcohols can be named in a similar manner as alkanes but with two differences: (1) the last -e of the alkane is replaced with -ol, and (2) the -OH is assigned the lowest possible number on the carbon chain. om Wie GH—cH— cre on 3-Methyl-2-batanol Spectroscopy: H NMR: Hydrogen attached to the carbon atom has a characteristic peak at 6 = 3.5 ppm. Hydrogen attached to the oxygen atom has a characteristic peak at 2-8 ppm. C NMR: Characteristic peak at 8 = 60ppm for carbon-bearing OH group. IR: The hydroxyl group (OH) has characteristic absorption in the range 3300-3600cm™1 . {782-6 ppm (usually broad), nooo 93545 ppm UUSYNTHESIS OF ALCOHOLS Alcohols 2 FROM ALKENES VIA OXYMERCURATION-DEMERCURATION "52 omoreaita buroreno, OS, oxenor ET Prope 2 ropa (in) ‘akon Keys: 1. The regiochemistry of this complex reaction obeys Markovnikov’s rule: The -OH group attaches to the more substituted carbon (the one with fewer H atoms), while the -H attaches to the less substituted carbon (the one with more H atoms). 2. This reaction has two steps: oxymercuration and demercuration (see Mechanism). 3. The first step of the reaction proceeds through a mercurinium ion intermediate. 4. The -OH on the product comes from HO; the -H comes from sodium borohydride (NaBH4). Note: A direct hydration reaction also exists but is used only in the industrial synthesis of alcohols; poor yields occur in laboratory synthesis. me OM CH \< DEP, ‘ nan 210 al Propene 2-Propanol (alkene) (alcohol) -- ‘This reaction proceeds through a carbocation intermediate. Faster hydration reactions are observed with more stable carbocations.‘Mechanism: I. Oxymercuration 1, Electrophilic addition of mercuric acetate [Hg(OAc)y] to the alkene yields a mer- curinium ion. Note that mercury is bonded to both carbon atoms. 2. Nucleophilic attack by HO on the more substituted carbon atom of the mercurinium ion occurs (Markovnikov addition step). 3, Free acetate (“OAc) abstracts a proton from the newly substituted HO to produce an organomercury compound. I Demercuration 4. The organomercury compound reacts with sodium borohydride (NaBH) to produce the final alcohol product. Onn R He Hgore Organomercury ‘compound, On @NaBHs Aa AlcoholSYNTHESIS OF ALCOHOLS Alcohols 3 FROM ALKENES VIA HYDROBORATION-OXIDATION. Hon 1 1) BH THE mononmo?” wyeT kn, 2)103,08,H0 YY Hew Propene |: Propane! (alkene) (aleoho) Keys: 1. The regiochemistry of this reaction is opposite Markovnikov’s rule, The -OH group attaches to the less substituted carbon (the one with more H atoms), while the -H attaches to the more substituted carbon. This is partly due to steric hindrance effects (see Mechanism). 2. Syn addition of the ~OH and -H groups is observed (i-e., both groups are attached to carbon atoms on the same side of the double bond). 3. The reaction proceeds thru alkylborane intermediates (see Mechanisin). 4. The reaction has two stages: hydroboration and oxidation (see Mechanism). The hycroboration stage leads toa trialkylborane product which subsequently undergoes oxidation to form the desired alcohol.‘Mechanism: 1. Hydroboration 1. For both steric and electronic reasons, the electrophile (boron) adds to the less substituted carbon, while the more nucleophilic atom (hydrogen) adds to the more substituted carbon of the double bond. 2. The reaction occurs via a cyclic transition state, which results in syn addition of the B and H atoms {both on the same side of the double bond). An alkylborane intermediate is formed. 3. This monoalkylborane reacts with two more alkene molecules to form a trialkylborane product. IL. Oxidation 4, Hydroperoxide anion (HOO™), which is formed from hydrogen peroxide (HO) in basic solution, attaches readily to the boron of the trialkylborane. 5. A rearrangement occurs, which shifts an alkyl group of the trialkylborane from the boron to the oxy- gen and expels a hydroxyl group. 6, Repetition of steps 4 and 5 occurs until a trialkylborate ester is formed. 7. Hydrolysis of the trialkylborate ester yields 3 mol of the desired alcohol product and one B(OH)4~ molecule. ‘ noi? cmc © Be Sh we vB Bk, 2C=C " RcH:CHY ~cH:CHAR wen ty tc Tai boane vnaston tte eo oho aroncnon <2 wenonont <8 Sheen + BOM “Tralkylborate ester we ReatrangementSYNTHESIS OF ALCOHOLS Alcohols 4 FROM ALKENES VIA HYDROXYLATION WITH OsO4 (OR KMnO4) " " a 1) 0504, pyridine “A / Doma ase 2)NaHSO,H0 HS “mn neon Propene is-12.Diol (alkene) {alcohol Keys: 1, This reaction generates high yields of cis-diols. 2. Syn addition of the OH groups is observed (i.e., both groups are attached to carbon atoms on the same side of the double bond). 3. This reaction proceeds through a cyclic osmat cermediate (see Mechanism). Note: Potassium permanganate (KMnO4) is another reagent used to oxidize alkenes. As with OsO4, syn addition is observed, a cyclic manganate intermediate is formed, and cis-diols are produced (albeit in lower yields). " me 1) KMn0, “ / 1:0 aN / Sven enat a Ca a DMOHMO” M " oy Xin < nt Now Sun 1,2-Diol of No alcohol), (Cyclic manganate intermediate =1. Syn addition of OsO4 to the alkene yields a cyclic osmate intermediate. 2. Bisulfite ion (HSO3-) reduces the cyclic osmate intermediate to generate the cis-diol. It should be noted that if KMnOg is used instead, bisulfite is not required because of the rapid hydrolysis of the manganate intermediate. R R RoR RoR J 100. Nee msn ome iy tery, wos ww om Ws gy <>» wh Yon Alene 0s, cis Diol oS (alcoho!) (Cyclic osmate intermediateSYNTHESIS OF ALCOHOLS Alcohols 5 FROM ALDEHYDES/KETONES VIA REDUCTION WITH NaBH i ” i * oda ES oy oa e€ect ‘CHOW { cHhOH i Ethanal Ethanot Acetone 2-Propanol (aldehyde) (1 aleohob (ketone) ( alcohol) Keys: 1, Sodium borohydride (NaBH4) rapidly reduces both aldehydes and ketones. 2. Reduction of aldehydes yields 1° alcohols, whereas reduction of ketones yields 2° alcohols. 3. In this reaction, NaBHy acts as a source of hydride ion (H:~) which does not exist as a discrete species in solution. It should be noted that NaBHq adds its hydride on the carbonyl carbon and not on the carbonyl oxygen. Note: An acidic workup is not required because the carbonyl oxygen abstracts a proton from the alcoholic solvent (see Mechanism). 4. Stoichiometry: One mole of borohydride ion reduces four carbonyl groups to alcohols.jum aluminum hydride (LiAlHg, LAH) is another, much more reactive, reducing agent. Unlike NaBH reactions, LAH reactions are run in ether and require an acidic workup. Many functional groups (e.g., esters, amides, acyl halides, and alkyl halides) are readily reduced by LAH but not by NaBH. Although more reac- tive, LAH can still be used in the reduction of a.B-unsaturated ketones to unsaturated alcohols: Note that if NaBH, is used instead, a mixture of saturated and unsaturated alcohols will be generated. See Aleobols 7 for additional reactions in which LAH is used as a reducing agent. ° on 1 1) LiAIHy/E130 Hy —6—cn=cn— cH, DUAUEHO oy c= chem 20" t 4 aB-Unsaturated Unsaturated (allylic) ketone alcohol ‘Mechanism: Exact details of the mechanism are complex. Briefly, NaBHq [the equivalent of the nucleophilic hydride ion (H:")), attacks the carbonyl carbon of the aldehyde (or ketone), while at the same time the carbonyl oxygen atom abstracts a proton from the alcoholic solvent (e.g., CH3OH), thereby producing an alcohol. ° ( OH “tt t e SSB BOW + cH wha wt ‘Aldehyde: Z =H Ketone: Z=alkylSYNTHESIS OF ALCOHOLS Alcohols 6 FROM CARBONYL COMPOUNDS VIA A GRIGNARD REACTION MX Giga reagent fo onwecno, _f" BMES Gime A ae it I Caton compound Aeoet 1. This is a nucleophilic addition reaction in which the Grignard is the nucleophile. It is a reaction that is widely used to extend a carbon chain. 2. Depending on the starting carbonyl compound, different types of alcohols can be generated. Starting Carbonyl Compound __ Alcohol Product Formaldehyde 1° Alcohol Aldehyde 2° Alcohol Ketone 3° Alcohol Ester 3° Alcohol 3. In order to fully convert an ester to a 3° alcohol, two moles of Grignard reagent are needed to react with ‘one mole of ester. 4. Of all the carbonyl compounds, only carboxylic acids do nor react with Grignard reagents to produce alco- hols because the Grignard reagents are destroyed in the reaction.Note: 1, Preparation of the Grignard reagent (see Alkyl Halides 4 for more details). ° on i Ist MEX, i 2nd RMB, i n—e—ocr —AEMENS cHomox + a—e—e# SEMEN, pcan k Ester Methoxymagnesium Ketone 3° Alcohol halide Beware: Grignard reagents cannot be formed if the reacting alkyl halide also contains another functional group (specifically a ketone, alcohol, carboxylic acid, or amine). 2. Since it is chemically similar to the Grignard reagent, an organolithium (RLi) can also be used to convert carbonyl compounds to alcohols (see Ally! Halides 5 for the synthesis of RLi). Mechanism: 1. The R group of the Grignard reagent is nucleophilic; it attacks the carbonyl carbon to form a tetrahedral alkoxide. 2. The negatively charged oxygen abstracts a proton from a hydronium ion (H30*) to form the alcohol prod- uct with a longer carbon chain. compound intermediateSYNTHESIS OF ALCOHOLS Alcohols 7 FROM ESTERS VIA REDUCTION WITH LiAlH4 ° on t 1) LAI, ether t cnscH,—C—0— ON cia —C—H + CHOW Hic oo ° c Hs ‘Methyl propranoate L-Propanol Methanol (ester) (2° alcohol) Keys: 1, LiAlHy is the preferred choive for ester reduction because reaction with NaBHg is too slow. NaBHy can be used to reduce aldehydes and ketones while leaving esters unchanged. 2. The reaction forms two alcohols: The carbonyl group yields a 1° alcohol, while the -OR group yields ROH (see Mechanism). 3. Two moles of LiAIHy reduce one mole of ester, 4. In this reaction, LiAIHy acts as a source of hydride ion ( solution. , which does nor exist as a discrete species in Note: Reduction of other carbonyl compounds via LiAIHy ° i D LialHietber neon DLAI Resor 2) HO" hoi Carboxylic acid 1° Alcohol ‘ . pate LAME Reon HO Acid chloride 1° Aleobot iit Lally ether n—c-0-c-n LAS apcton fa ue 0 Acid anhydride 1° AlcoholMechanism: 1. The hydride ion (H:~) from LiAIHg nucleophilically attacks the carbonyl carbon of the ester to form a tetrahedral anion intermediate. 2. This intermediate then expels an alkoxide ion (~OR), giving an aldehyde. 3. The aldehyde is reduced by a second hydride ion (from LiAIH4) to form the alkoxide of the 1° alcohol. 4, Alkoxide ions are neutralized by added acid (i.e., acid workup) to form the alcohols. Note that the alkyl groups (R and Ry) of the ester are not changed. Gm ge o we Be eon MOS Reon Cm a aus " a rl oy Eu < chy 1° Alcohol 4 ©, Son 180" . . won BoREACTIONS OF ALCOHOLS Alcohols 8 PREPARATION OF ALKENES VIA ACID-CATALYZED DEHYDRATION _ a oven fno YESS reno t em Bed 5 2 Mayenne 2 sty gee Keys: 1, Dehydration of 2° and 3° alcohols, but ot 1° alcohols proceeds via an E1 mechanism (see Alky! Halides 9 for details on El). 2. The reaction involves a carbocation intermediate. Because 3° carbocations are the most stable, 3° alcohols are the most reactive and readily produce alkenes. The following rule is handy: Alcohol: 19 ec BP Reactivity: Least a Most Only 2° and 3° alcohols are reactive enough to form alkenes. Under similar conditions, 1° alcohols form ethers instead. However, under conditions of stronger acidity and higher temperatures, 1° alcohols can yield alkenes via an E2 mechanism (see Alkyl Halides 8 for details on E2), 3. The reaction may yield a mixture of alkenes. If it does, the most substituted alkene is the major product (Zaitsev’s rule). [In the example above, 2-methyl-2-pentene is the major product, while 2-methyl-I-pentene (the less substituted alkene) is the minor product.} Reasons: (a) The transition state for the formation of the more substituted alkene has a lower activation energy, and therefore it forms faster. (b) In the presence of acid, the less substituted alkene may isomerize to the more substituted, more stable, alkene. 4. This reaction is catalyzed by strong acid (e.g., HySOq). -Mechanism: 1. The oxygen on the alcohol abstracts a proton from the acid (e.g., HySOq) to form a protonated alcohol. 2. Spontaneous loss of H3O from the protonated alcohol yields a carbocation intermediate. It should be noted that this is the rate-limiting step. 3. A base (e.g,, bisulfate ion) abstracts a proton from the carbocation intermediate, thereby forming an alkene and regenerating the acid catalyst. The more substituted alkene forms faster because of a lower energy of activation. 4. The alkenes produced in step 3 may also isomerize to form the more substituted, more stable alkene as the ‘major product (a step not shown in the figure). e e ' ome 2+ cy —G—ch—R i " | \nSdson HOs0.H Protonated alcohol Carbocation Alkene intermediateREACTIONS OF ALCOHOLS Alcohols 9 PREPARATION OF ALKYL HALIDES FROM 3° ALCOHOLS ms om odo Sc, —b or To Ho i on Br 2-Methyl-2-propanol _ 2-Bromo:2-methylpropane (3 alconol) (alkyl halide) Keys: 1. This is a good reaction for converting 3° alcohols to alkyl halides. Primary and secondary alcohols do not work well here (refer to Alcohols 10 for reactions involving 1° and 2° alcohols}. 2. The reaction proceeds through an Syy1 mechanism (see Ally! Halides 7 for more details on Spy).Mechanism: 1. The oxygen on the alcohol abstracts a proton from the hydrogen halide (HX). 2, Spontancous loss of HO from the protonated alcohol yields a carbocation intermediate. This is the rate- limiting step. 3. The nucleophilic halide ion (I > Br~ > CI") reacts with the carbocation to produce an alkyl halide ® ml L ® L noe Dy near oH x Alcohol yy Hydrogen Alkyl halide halideREACTIONS OF ALCOHOLS Alcohols 10 PREPARATION OF ALKYL HALIDES FROM 1° AND 2° ALCOHOLS crrcrcricHon 225 cHcHcHichier |-Butanol 1-Bromobutane (1° alcohol) (1° alkyl bromide) Keys: 1. The reaction proceeds through an Syq2 mechanism (see Alky! Halides 6 for more details on Sy2). 2. This is a good reaction for converting 1° and 2° alcohols to alkyl halides. Tertiary alcohols do not work well in this reaction (refer to Alcohols 9 for the reaction involving 3° alcohols.) 3. Phosphorus tribromide (PBr3) is exclusively used with 1° and 2° alcohols (but not with 3° alcohols) to make the hydroxyl group a better leaving group (see Mechanism). 4, One mole of PBr3 converts 3mol of ROH to 3mol of RBr (see Mechanism). Note: PBr3 is specifically used for the production of alkyl bromides. If an alkyl chloride is desired instead, SOCl should be used as the reagent. This reaction also proceeds through an Sjy2 mechanism. crscricner, OC, crcrcner + 80; + He! Pie dine i ox & L-Batanol 2-Chlorobutane (2 alcohol) (2° alkyl chloride)‘Mechanism: 1. The alcohol reacts with PBr3, thereby transforming the -OH from a poor to a better leaving group (HOPBry). 2. A nucleophilic bromide ion attacks the carbon from the back and expels the leaving group (HOPBry), forming the alkyl bromide product. It should be noted that the stereochemistry of the product is inverted (e.g., from the R configuration in the starting material to an S configuration in the product). 3. The HOPBr formed reacts with two more alcohol molecules by a similar mechanism, ultimately yielding P(OH)3 and three alkyl bromide molecules for each PBr3 used (a step not shown in the figure). fl . . @ @ ws Pe eae Poe Be by, + HOPE ww Peer wok Aw " 2° Alkyl bromideREACTIONS OF ALCOHOLS Alcohols 11 PREPARATION OF ALDEHYDES/KETONES FROM 1° AND 2° ALCOHOLS ° on ° Pec u NaxCh0; i crycrcricron “<5 cnycnscncr enscreencrs SECOy cnycrcery cic 10" 1-Butanol Butanal 2-Butanol 2-Butsnone (AP alcohol) (solvent) (aldehyde) (2° aleohot (kewone) Keys: 1. The reaction proceeds through an E2-like oxidation/reduction reaction of a preformed chromate ester (see Mechanism: for more details). 2. This is a good reaction for converting 1° alcohols to aldehydes and converting 2° alcohols to ketones. Tertiary alcohols cannot undergo this reaction, as there is no o-hydrogen atom, 3a. Conversion of 1° alcohols to aldehydes: i. Depending on the oxidizing reagent, 1° alcohols can be converted to aldehydes ot further oxidized to form carboxylic acids (see Note for 1° alcohol to carboxylic acid oxidation). 1° alcohols — aldehydes > carboxylic acids ii, Pyridinium chlorochromate (PCC, CsHsNCrO3Cl) in an organic solvent (CHCly) is the preferred oxidizing reagent. Reason: Oxidation of 1° alcohols to aldehydes in aqueous solution would proceed further to yield carboxylic acids (see Note). 3b. Conversion of 2° alcohols to ketones: The preferred reagent is sodium dichromate (NayCr707) or chromic acid (HyCrO4) in aqueous acid solution.Now Primary alcohols are usually converted to carboxylic acids with aqueous solutions of these chromium reagents (e.g., NayCr707, HyCrO4) ° NasCr0y 1 cryoricryorhon —T > ctcrycHCon 1-Butanol Butanoic acid (1° alcohol) (carboxylic acid) Mechanism: 1, The chromium-based oxidizing agent reacts with the alcohol to yield a chromate ester intermediate. 2. A base (e.8., HzO, pyridine) abstracts a proton from the chromate intermediate, eliminating, (and reducing) the Cr and generating an aldehyde or ketone. It should be noted that 3° alcohols cannot be oxidized because they lack the o-hydrogen necessary for this elimination reaction. al z 4 i Reon + xox Py n-eyoctax —B> nem He alcohot Pyridine : Aldehyde: Z=H = Ketone: Z = alkyl Z=H, 1° alcohol X= OH, CL ‘Chromate ester “ ally kyl, 2° aleohol intermediate