CHEM 4113 ORGANIC CHEMISTRY II LECTURE NOTES CHAPTER 17

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1 EM 4113 GANI EMISTY II LETUE NTES 1 APTE 17 Alcohols and Thiols I. Introduction Alcohols are compounds that have hydroxyl groups (-) bonded to saturated, SP 3 - hybridized carbon atoms. This definition excludes phenols and enols. Alcohols can be considered as organic derivatives of water in which one of the hydrogens of water is replaced by an alkyl group. Alcohols are classified as primary (1 ), secondary (2 ), or tertiary (3 ) depending on the number of carbon groups bonded to the hydroxyl bearing carbon. methyl primary secondary teriiary 3 2 a. Nomenclature of alcohols and thiols Simple alcohols are named by the IUPA system as derivatives of the parant alkane, using the suffix -ol. 1. Select the longest chain containing the hydroxyl group as the parant name; drop the -e and add -ol. 2. Number the alkane from the end nearest the hydroxyl group 3. Number other substituents according to position on chain, and write in alphabetical order Benzyl alcohol Allyl alcohol tert-butyl alcohol Ethylene glycol Glycerol Non-IUPA Alcohol Names

2 2 Alcohols are named from the parent alkane: 1. drop the -e and add -ol 2. hydroxyl has priority and gets lowest possible no. 2,6-octanediol (not 3,7-octanediol) NTE: polyalcohols retain the -e ending. trans-4-hexen-3-ol NTE: higher priority than olefin. 3 trans-2-methylcyclohex-4-en-1-ol Thiols are named from the parent alkane with the suffix thiol S S 5-methyl-2-heptanethiol 7-mercapto-4-decanol NTE: higher priority than S; mercapto is the designator of S substituent. Nomenclature of alcohols and thiols. b. Properties of alcohols Alcohols are different from hydrocarbons and alkyl halides. ne example of quite different physical properties is boiling point. Alcohols have much higher boilong points than other compounds of similar molecular weight.

3 F ethanol propane dimethyl ether ethyl flouoride bp degrees ydrogen Bond: An interaction of an unshared pair on one molecule with the polarized bond of another. δ +δ +δ δ The Boiling Point of Alcohols is due to ydrogen Bonding The reason for the higher boiling points is that alcohols, like water, are highly associated in solution because of ydrogen bonding. Although -bonds have typical strengths of 5 Kcal/mole, this means that extra energy must be added to break them during the boiling process. Alcohols as show significant solubility in water solutions. Alcohol, like water is a "Protic" solvent (that is, it can donate a hydrogen bond). "Like dissolves like", means that alcohols and water are miscible. owever, once a certain number of carbons in the alkyl chain of the alcohol is reached, the alcohol is no longer soluble. This is the Six arbon ule. 3 ( 2 ) n 2 - n = Water solubility 0 miscible 1 miscible 2 8 wt % 3 4 wt % wt % 5 insoluble Water Solubility as a Function of hain Length. c. Acidity of alcohols and thiols The - and S- bonds of alcohols and thiols are able to undergo homolytic cleavage to give a proton and the conjugate base. Thus, these functional groups are organic acids, although relatively weak organic acids. leavage of the - bond of an alcohol (-) gives an alkoxide anion (- - ), whereas cleavage of the S- bond of a thiol (-S) gives a mercaptide anion (-S - ) The thiols are somewhat stronger acids than the alcohols (by 5-6 pka units) due to the weaker strength of the S- bond.

4 4 + + alcohol pka WEAKE AID ( 3 ) F (F 3 ) STNGE AID Acidity onstants of Some Acids The acidity of alcohols and thiols can be increased by the presence of neighboring electron withdrawing groups such as halogens. The electronegative group causes a dipole which inductively withdraws electron density from the bond, thus weakening it. This "Inductive Effect" falls of with increasing separation of the and halogen. F 2 2 base F 2 2 Electronegative groups will withdraw electrons (polarize the bonds) along the sigma system. This will weaken the bond of the alcohol which increases its acidity. This effect also stabilizes the conjugate base (alkoxide anion). This effect decreases rapidly as the electronegative group is moved further away along the hydrocarbon chain. F 3 ( 2 ) n n = pka ( same for n-pentanpl) Effect of Electron-Withdrawing Groups on Alcohol Acidity Because of the relatively weak acidic nature of alcohols, very strong bases much be used to quantitatively convert (i.e.,>99%) the alcohol into the alkoxide anion. Typical bases such as Sodium hudroxide (Na) give only about 50% conversion. Strong bases such as Sodium ydride (Na) and Sodium Amide (NaN2) are most often used.

5 Na 2 5 Na + pka = 16 Keq = 1 pka = Na 2 5 Na + 2 pka = 16 Keq = pka = 42 Sodium ydride (Na) results in complete deprotonation Deprotonation of Alcohols Due to their greater acidity, thiols are converted into the mercaptide anion quantitatively through the use of Sodium ydroxide (Na). 2 5 S + Na 2 5 SNa + pka = 10 Keq = 10 6 pka = 16 Thiols are stronger acids than alcohols and are completely deprotonated by Sodium ydroxide (Na). Deprotonation of Thiols II. Synthesis of Alcohols Alcohols occupy a central position in organic chemistry, and can be synthesized from a variety of functional groups (alkenes, alkyl halides, aldehydes, ketones and esters, among others).

6 Many of the routes to primary and secondary alcohols are summarized below.. A 3 2 = 2 B 3 g(ac) TF (1) NaB 4 (2) II B 3 2 MgBr + NaB 4 ethanol MgBr + 3 I LiAl 4 ether LiAl ether 3 + NaB Let's review briefly some of the methods of alcohol preparation we have already learned in rganic I lecture\ SN2 Substitution of primary and secondary alkyl halides B E D 6 l acetone + Na + Nal l Na, 2 SN1 Substitution (Solvolysis) of tertiary alkyl halides l 2 Na 3 + Nal Synthesis of Alcohols from Alkyl alides

7 Electrophilic addition to alkenes 7 B 3 2 l 2-2 primary alcohol g(ac) 2 2 NaB 4 secondary alcohol Synthesis of Alcohols from Alkenes xidation of alkenes KMn 4-2 NaS 3 s 4 cis diol Epoxidation of alkene and ring-opening trans diol Preparation of Diols from Alkenes a. Alcohols via reduction of carbonyl compounds rganic "reduction" reactions are considered to be reactions which either increase the hydrogen content of a compound or reduce the oxygen, nitrogen or halogen content of a compound. Aldehydes and ketones are easily reduced to yield alcohols. Aldehydes produce primary alcohols and ketones give secondary alcohols. Polyhydride metal salts such as Sodium borohydride (NaB4) and Lithium aluminum hydride (LiAl4) are very effective reducing agents for this process. For aldehydes and ketones, NaB4 is usually the reagent of choice because of the ease of use (LiAl4 is much more difficult to work with). These reagents transfer a "hydride" to the carbonyl carbon, the resulting alkoxide anion is protonated with dilute aqueous acid. Since both reagents contain four hydrides, the intermediates produced from the initial reaction can undergo subsequent addition until all four hydrides have been used.

8 Metal ydride educing Agents 8 Li Al Lithium Aluminum ydride LiAl 4, LA = or Aldehydes Ketones 1) LiAl 4, ether 2) 2 NaB 4, Me Na B Sodium Borohydride NaB 4 Primary Alcohols Secondary Alcohols ydride eduction of Aldehydes and Ketones Lithium ion from LA serves as Lewis Acid to activate carbonyl toward addition 1.0 equiv. Li Al 0.25 equiv. (4 available hydrides) ether eduction Mechanism Using LA Li 2 Al eaction product is still an active reducing agent ( 3 more available hydrides). A total of 4 carbonyl compounds are reduced for each LA ydrogen bond activates the carbonyl toward hydride addition -Me B 1.0 equiv equiv. (4 available hydrides) Me NaB(Me) 4 + Sodiumborohydride eduction B eaction product is still an active reducing agent ( 3 more available hydrides). A total of 4 carbonyl compounds are reduced

9 Like aldehydes and ketones, esters can be reduced to an alcohol through the use of metal hydride reagents. owever, this process is more difficult and requires LA which is a more reactive reagent. The process converts an ester into a primary (1 ) alcohol. The mechanism has been shown to occur in two discrete hydride addition steps. The first hydride addition leads to an aldenyde intermediate, which is immediatly reduced further to the alcohol, the aldehyde never builds up in solution. 9 ' ' 1) LA, ether 2) 2 NaB 4, Me Mechanism of LA reduction of esters 2 N EATIN! eductions of esters with LA results in formation of 1 alcohols. Li ' ' ' LA, ether SLW ' Ester -Donation of the lone-pair electrons from the methoxy group decreases the positive charge on the carbonyl carbon. This makes esters less reactive toward hydride addition than are ketones and aldehydes. Intermediate is unstable with respect to loss of MeLi. Li 2 LA, ether FAST - MeLi Differential eactivity of Esters with ydride eagents b. Alcohols via Grignard Addition to arbonyl ompounds. The addition of a Grignard reagent to a carbonyl compound, followed by treatment with a dilute acid yields an alcohol. Addition of a Grignard (MgX) to formaldehyde (=) gives a primary alcohol 2, addition to an aldehyde ('=) gives a secondary alcohol ', and addition to an ester ('=") or ketone ('=') gives a tertiary alcohol ''. arboxylic acids do not give Grignard addition products. The Grignard reaction is sometimes limited by the fact that Grignard reagents can not be formed from starting materials that contain a reactive functional group such as a hydroxyl group. This problem can sometimes be corrected by protecting the functional group. Alcohols can be protected by the formation of trimethylsilyl (TMS) ethers, which are inert to Grignards and can be easily converted back to the alcohol.

10 Y Y arbonyl eactivity - Y + esonance ybrid The electrophilic carbon of the carbonyl group is susceptible to attack by nucleophiles such as hydrides and Grignards 10 Synthesis of 2 and 3 alcohols 1) 'MgX, ether 2) 3 + = or Mechanism + MgX ether ' - ' MgX ' Aldehydes Ketones MgX ' 2 alcohols 3 alcohols 3 + ' Esters and arboxylic Acids ' 1) 2 equiv.'"mgx, ether 2) 3 + '' '' Ester 3 alcohol 1) 2 equiv.'"mgx, ether 2) 3 + N EATIN: Grignard reagents react with the proton of carboxylic acids. Grignard eagent Addition to Aldehydes, Ketones and Esters

11 11 Target Molecule Proposed Synthesis + MgBr PBLEM: The Grignard will react with the weakly acidic alcohol hydrogen in the substrate. This will quench the Grignard reagent, bringing the reaction to a halt. SLUTIN: "Protect" the alcohol as the trimethylsilyl ether. The ether is unreactive towards the Grignard eagent, and the alcohol can be easily regenerated. 3 l Si N Si( 3 ) 3 "Protected" alcohol 1) 3 2 MgBr ether 2) Si( 3 ) 3 Protection of Alcohols 3. eactions of Alcohols eactions of alcohols can be divided into two groups- those that occur at the - bond and those that occur at the - bond. Below is a summary of the various reactions that alcohols undergo.

12 = 2 S 3 tosyl chloride pyridine abr 2 SN2 PBr 3 SN Br Pl 3 r 3 2 S 4 pyridine P 2 l 2 Pl 3 pyridine Sl 2 SN l 3 3 Na 3 3 r 3 2 S Na Sl 2 SN2 PBr 3 Br SN2 3 3 l 3 3 a. Dehydration of Alcohols to Alkenes ne of the most important - reactions is dehydration to the alkene. In this process, the - bond is broken and a -bond is formed. ne of the most common methods of dehydration is acid catalyzed dehydration. In this process, a strong acid such as 2 S 4 protonates the hydroxyl group, thus converting it into a good leaving group (- 2 +). Loss of water by breaking the - bond generates a carbocation, with subsequent loss of an adjacent proton and formation of the -bond. The reaction occurs by an E1 mechanism. This process works extremely well with 3 alcohols, which will readily dehydrate and room temperature or even lower. owever, 2 alcohols require more forceful condition, such as temperatures of 100. This is because the less stable 2 carbocation intermediate is slower to form. Primary alcohols are even less reactive and require very harsh conditions. As a result, this is not the preferred reaction for 1 alcohols; the best method is dehydration with Pl 3 in pyridine solvent. Acid catalyzed dehydrations follow aitsev's rule, that is they will give the most stable alkene (the most substituted alkene) as the major product. If the intermediate carbocation of a 2 alcohol can rearrange to a more stable 3 carbocation, it will do so, and the major products will derive from this intermediate.

13 β 1 β 2 Protonation of generates good leaving group ( 2 ) Loss of water generates a carbocation intermediate β 3 E1 loss of a β proton to generate the olefin... three different sites of elimination are possible - + from β from β from β 3 Note that this reaction is the reverse of alkene hydration reaction; that is, we could start with the alkene and run the reaction in the other direction to produce the alcohol. Whether we end up with the alkene or alcohol depends upon the reaction conditions. For example, we could shift the equilibrium by removing the lower boiling alkene by distillation. Dehydration of Alcohols to Alkenes via Acidatalysis cat β loss of + from β % 2 carbonium ion The methyl moves with its pair of electrons loss of + 3 from β 1 β 1 3 β loss of + β 2 3 carbonium ion more stable from β % 36 % earrangement of 2 arbocations Prior to Alkene Formation l l P l Pyridine Pl 2 N E2 Mechanism Dehydration With Pl 3

14 Ease of Dehydration 14 Temperatures necessary for reaction room temp and below > > above 150 Because the acid catalyzed dehydration of an alcohol to form an alkene occurs via a carbocation, 3 and 2 alcohols react much more readily and under milder conditions than 1 alcohols. ate of Acid atalyzed Dehydration of Alcohols b onversion into Alkyl alides A second - bond reaction that alcohols undergo is conversion into alkyl halides when treated with hydrohalic acids (l or Br). The first step in this reaction is protonation of the hydroxyl group, converting it into a good leaving group ( 2 ). Tertiary alcohols then ionize to the 3 carbocation which undergoes an SN1 reaction with X-. Primary alcohols react by an SN2 displacement of water from the substrate by l-. Secondary alcohols mya react by either an Sn1 or SN2 mechanism depending on the structure of the 2 akcohol.

15 = or ' l ' ' When both and A' are alkyl groups, the tertiary carbocation is formed - 2 ' 15 l l For 's both ; this protonated alcohol intermediate undergoes backside addition of l via the SN2 pathway For secondary alcohols (one = ) either SN1 or SN2 pathways may operate E1 Excess l l SN1 l l PIMAY SENDAY TETIAY onversion of Alcohols to alides Using X Any alkene formed by an E1 process will eventually be consumed by excess l. The equilibrium will be drained to the 3 chloride. l Tertiary alcohols are readily converted even at temperatures as low as 0. Primary and secondary alcohols react with much more difficulty, and are best converted into halides by treatment with Sl 2 and PBr 3. The reactions of 1 and 2 alcohols with SL 2 and PBr 3 occur by an SN2 process. ydroxide is too poor a leaving group to be displaced directly by a halide anion in an SN2 reaction. The above reagents convert the alcohol into a much better leaving group, that is easily expelled by a backside nucleophilic attack. l Thionyl hlorosulfite chloride ester S l S l S + l N Need one chloride anion to act as nucleophile; this species keeps being regenerated as the chlorosulfite ester decomposes to sulfur dioxide and another chloride anion. onversion of Alcohols to Alkyl hlorides with Thionyl hloride l N l + c. onversion of Alcohol functional Group into Sulfonate Esters Alcohols are not good leaving groups in organic synthesis. In order to convert the alcohol into a better leaving group we often protonate it with a strong acid. We

16 16 cannot always use strongly acidic conditions to carrry out conversions of the alcohol functional group. ften times we can employ cleavage reactions of the alcohol - to convert the hydroxyl group into a much better leaving group as was done when PL 3, SL 2 and PB 3 are employed, but these are not general reactions. ne particularly useful conversion is to transform the alcohol into a sulfonate ester by treatment of the alcohol with a sulfonyl chloride. Sulfonate derivatives have about the same leaving group ability as do halides. The p-toluenesulfonate esters derived from alcohols (tosylates) serve nicely as substrates in both elimination and substitution reactions. l S sulfonyl chloride '/base ' l S '/base p-toluenesulfonyl chloride (tosyl chloride) S sulfonate ester 3 ' S good leaving group Note: abbreviation of tosylate ester is Ts p-toluenesulfonate ester (tosylate ester) 3 Inversion of chirality at chiral alcohol ()-3-heptanol Tsl pyridine Ts tosylate ester Na acetone SN2 (S)-3-heptanol + Ts Formation and use of Tosylate Esters d. xidation of Alcohols to arbonyl ompounds Using hromium (+6) eqagents The most important reaction of alcohols is their oxidation to carbonyl compounds by r (+6) oxidizing agents such as Jones' eagent (r 3 / 2 S 4 ), Na 2 r 2 7, and pyridinium chlorochromate (P). Because all these hromium reagents proceed through a mechanism which involves loss of a proton on the oxygen-bearing carbon of the alcohol, tertiary alcohols (which do not have such a hydrogen) are incapable of being oxidized by these reagents. Secondary alcohols are oxidized to ketones easily and cleanly. Primary alcohols are very easily oxidized by r(+6), but, if any water is present in the reaction, the product observed is a arboxylic Acid rather than an aldehyde. Thus with aqueous reagents such as Jones'eagent, the 1 alcohol undergoes overoxidation (unless we happen to wnt the acid). ne solution is to use P in a nonaqueous medium.

17 r 3, 2 S 4 JNES EAGENT Secondary alcohol is oxidized to a ketone with Jone's eagent. 17 Mechanism r 3 + r r + r + r Alcohol must have hydrogen on the oxygen bearing carbon. Tertiary Alcohols will not undergo oxidation. xidation of 2 Alcohols to Ketones xidation of 1 alcohol with Jones' eagent r 3, 2 S 4 2 r 3 Aldehyde is formed but none isolated In presence of water the hydrate is formed which can undergo further oxidation arboxylic acid is end product xidation of 1 alcohol with Pyridinium hlorochromate (P) r 3, l (g) N Note that this reagent combination has no water, the aldehyde produced cannot undergo hydration. This is the preferred method for the synthesis of aldehydes, xidation of 1 Alcohols to Aldehydes with P e. Periodic Acid leavage of 1,2-Diols 1,2-Diols are oxidatively cleaved by aqueous periodic acid. This is a mild reaction and offers a useful alternative to cleavage with 3, which requires an expensive ozone generator and procedes through a dangerously explosive oxonide intermediate.

18 Mechanism 1) s 4 2)NaS 3 + 1,2-DIL I Periodic leavage of 1,2-Diols I 6 PEIDI AID I yclic intermediate The periodic acid cleavage of 1,2-diols is an alternative to the ozonolysis method for converting alkenes into carbonyl compounds. ( 2 ) + 3 I 4 The periodic acid cleavage requires the existance of a five membered intermediate. Diols that do not allow the existance of such an intermediate do not undergo reaction. 18