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Chapter 2

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CHEM 3750
Adrian Schwan

2 - ALDEHYDES, KETONES AND DERIVATIVES Carbonyl chemistry is one of the most important areas of organic chemistry. You have been introduced to the chemistry of carboxylic acids in CHEM*2700, and in this course we will focus on aldehydes and ketones. Hence the compounds that we will study in this chapter will possess a carbonyl group, which has either hydrogens or carbons attached to it. O O O C C C R R R H carbonyl group ketone (R▯H) aldehyde Some significant aldehydes and ketones O H O O H H O O HO cinna a d hyde h l i h ospo al cam phor ras berr keto e cand ,fo d,dru s afun a ltxin li i e t, i h l t p y ( y g ) ( g ) ( ) O O O O ( )e anti e s, p rm it m usco e bice yl ( )e an io e c, a a sye d (pe f es ) (ma g rine) (candy, tothpaste) O OH O H HO H H H H O O O testoste o e p g es t o e van illi male sexhorm o e fe a l sex hormo e food fa ourig ( ) ( ) ( ) CHEM*3750 SCHWAN C OURSE N OTES F13 Chapter 2 Page 1 The reactivity of aldehydes and ketones is based on two important reactions of them. These species are prone to nucleophilic attack at the carbonyl carbon and one can make a nucleophile on a carbon ▯ to the carbonyl group. - O Nu O O base O C + Nu C C - C R R R R RCH2 R RCH R This chapter will first demonstrate some synthetic routes to aldehydes and ketones, and then will describe some of their vast chemistry based on the two principal modes of reaction shown above. 1. Synthetic Routes to Aldehydes and Ketones (SF10 16.2, 16.4, 16.5) One of the main methods for the preparation of aldehydes and ketones is oxidation of an alcohol as shown in a general sense below. O OH O RCH 2H [O] [O] R H R CH R' R R' The following are some popular routes to aldehydes and ketones and of course include oxidation of an alcohol. Most should be familiar to you. a) Aldehydes Me PCC Me O CHCH 2H 2H 2H CHCH C2 2 C Me CH 2l2 Me H primary alcohol aldehyde, 75% PCC = N+ - H ClCrO3 pyridinium chlorochromate CHEM*3750 SCHWAN C OURSE NOTESF13 Chapter 2 Page 2 b) Aldehydes and Ketones O3, C2 C2 Zn O -78 °C HOAc H + CH O 62% 2 c) Ketones Na2Cr2O7 OH H2O, H2SO4 O menthol menthone, 84% O OH O 1. PhMgBr H [O] Ph H 2. HO+ Ph Ph Ph 3 Ph Grignard chemistryfollowed byoxidation OMe 1. O O OMe O , Al3l 93% 2. HCl,2H O O Cl -78 °C + Et2CuLi O ether O CHEM*3750 SCHWAN C OURSENOTES F13 Chapter 2 Page 3 A useful method that has selected limitations is the hydration of alkynes. This is achieved with the assistance of mercuric ion Hg . When an alkyne is treated with HgSO /4 S2 /H4O,2the elements of water will add across the triple bond. In its simplest form the reaction looks like this: HgSO /4 2SO 4 O H C C H H 2 C CH 3 H A limitation arises when one considers the asymmetrically substituted alkyne: one can expect two products! O CH3CH 2 C C CH CH2CH 2H 2 3 HgSO 4H 2O 4 CH 3H 2H C2CH CH C2 C2 2 3 H 2 + O CH3CH 2 C CH C2 CH2CH2CH2 3 +2 However, if one considers the mechanism of the reaction, which begins with Hg coordinating to the triple bond and creating some cationic character on the triple bond carbons, then water attacks one of the carbons. In the above case, the two alkyl groups can stabilize the cationic charge in a comparable manner, leading to water attack at each carbon and two major products. +2 +2 Hg▯ Hg CH3CH 2 C C CH 2CH 2CH2CH 3 CH 3CH 2 C+C +H 2CH 2H 2H 3 ▯ ▯ OH 2 2 products This mechanistic information does carry within it some synthetic value. What if the two groups on either side of the triple bond differ significantly in their ability to stabilize positive charge? Water will attack at the site bearing more positive charge and that carbon ends up being the site bearing the carbonyl oxygen. Hence terminal alkynes will always be a source of methyl ketones. CHEM*3750 SCHWAN C OURSE NOTES F13 Chapter 2 Page 4 ▯+2 +2 Hg Hg H C C CH CH CH CH H C C CH CH2CH2CH2 3 ▯+ ▯+ 2 2 2 3 which of these carbons bears bear more +ve charge? O The more substituted does, according to Markovnikov CH 3 C CH 2H 2CH2CH 3 lone product example: O HgSO 4, 2SO 4 PhCH 2 C C H PhCH 2 C CH 3 H2O Of course, when the alkyne is symmetrically substituted, then a single product results O CH 3H 2 C C CH 2CH 3 HgSO /4 2O 4 CH 3H 2 CH 2 CH 2CH 3 H2O More examples: O O + AC 3 Cl C O3 OH M g r O + ue ch H w i h 2 O CHEM*3750 SCHWAN C OURSE NOTES F13 Chapter 2 Page 5 O O H PCC O O OH O HO C O3 O + H CHEM*3750 SCHWANOURSENOTEF13 Chapter 2 Page 6 2. Acidity and Enolization of Aldehydes and Ketones (SF10 3.5-3.7, 18.1, 18.2, 18.3) As stated, one of the origins of the reactivity of aldehydes and ketones is their inherent acidity, which is based on the electronic properties of the carbonyl group. The carbonyl group is an electron-withdrawing group by both induction and resonance. So, hydrogens ▯ to the group possess increased acidity simply due to their proximity and the incipient anion can be stabilized through ▯-resonance with the carbonyl group. O O - O base - H resonance structures acidic hydrogen, pKa = ca. 19-20 There is a geometric requirement for facile proton removal in this chemistry. The C-H bond that holds the removable hydrogen must be aligned with H C O the ▯-orbitals of the C=O ▯▯bond. The required conformation is trivial to achieve in a freely rotating H system, but may not be accessible in cyclic or constrained molecules. Without the proper orbital all aligned, so H is idealforremoval overlap, then the ▯-resonance stabilization of the anion is not possible. The result is that the acidity of the ▯ hydrogen is greatly reduced. Bases suitable for deprotonation of an aldehyde or ketone must meet two principal requirements: a) The base must be strong enough to remove the hydrogen. In this regard, any base whose conjugate acid has a pKagreater than 20 will be suitable. Sometimes a weaker base will work, but the reaction must proceed under equilibrium deprotonation conditions. b) The base has to perform selective attack at hydrogen and cannot have properties that will promote nucleophilic attack at the carbonyl carbon. A sterically hindered base usually provides the desired chemoselectivity. LDA, - + lithium diisopropylamide ([2e HC2 N Li ) is often the base of choice. The resonance-stabilized anion that results from these deprotonation reactions is called an enolate, which means that it is the anion of an acid called an enol. CHEM*3750 SCHWAN C OURSE NOTES F13 Chapter 2 Page 7 - O OH enolate enol These species are of course interconvertible through the transfer of one proton. As we will see shortly, the enolate and the enol can be functionalized at the ▯-carbon. Hence one can use an enol or an enolate for derivatizing the compound next to its carbonyl group. Enols can be generated through a reversible acid catalyzed reaction. H H H O O O O + H + H H H + + H 3 base (= 2O) H is much more acidic since the protonated carbonyl is a much better electron sink The methods of forming enols and enolates are fully reversible. So the carbonyl compound can be regenerated from an enol by simply adding acid and isolating the substrate (except in specialized instances). Attempted isolation of the enol from acid solution will provide the aldehyde or ketone. Mechanistically, regeneration of the carbonyl compound can be the reverse of enolate formation, or may involve the enol. O- H O + O H H Under these conditions, the keto form of the compound is regenerated upon isolation. The equilibrium between enol and keto shown above is called tautomerism, since the compounds are tautomers of one another. The carbonyl compound is usually the thermodynamically favoured form, based on the carbonyl bond strength, but there are exceptions to this rule. A number of equilibrium CHEM*3750 SCHWAN C OURSE NOTESF13 Chapter 2 Page 8 constants have been determined for keto-enol tautomerism. They are calculated as shown, and are of course dependent on the [enol] medium in which the measurement is made. If the substrate is K eq= [keto] neat, the tautomer ratio depends on the origin of the material. The Keq (keto-enol) for acetone in water is 1.5 X 10 . It should be noted that despite the fact that the ratio can significantly favor the keto form, reactions selective for the enol form can still take place, as we shall see. The relative acidity of the hydrogens next to the carbonyl groups of aldehyde or ketones has both advantages and disadvantages. For one advantage, the acidity allows for deuterium incorporation into the molecule. The protocol involves simple addition of the carbonyl compound to D O containing a trace amount of acid or base. Any 2 hydrogens in the ▯-position that can adopt the required conformation for enol or enolate formation will become fully deuterated, given sufficient time. O O - CH 3 D 2O, OD CH 3 CH 3 CD 3 H H D D O O D 2, D 3 + (Me)2CH H (Me)2CD H Another consequence of enol formation, having negative and positive implications, is the ease with which chiral ▯-carbons can invert their stereochemistry. Hence if you have taken the time to make an important, optically pure product possessing stereochemistry at the ▯-carbon, exposure to acid or bases may racemizes the material. For example, optically active 3-phenyl-2-butanone in basic ethanol (r.t.) racemizes within minutes. O - O - Ph O - Ph EtO /EtOH EtO /EtOH Ph CH 3 CH 3 H CH 3 H 3 CH 3 H3C H (S)-3-Phenyl- Achiral, planar (R)-3-Phenyl- 2-butanone 2-butanone isolation racemic ketone There are instances of advantageous isomerism of ▯-carbon, through their planar form. CHEM*3750 SCHWAN C OURSE N OTES F13 Chapter 2 Page 9 - + O O K O 10% KOH CH 2H=CH 2 CH 2H=CH 2 CH 2CH=CH 2 EtOH CH 3 CH3 CH 3 In the anionic form, the ▯-carbon is planar and in theory can be protonated from either face. However, the configuration of the ▯-carbon, which bears the methyl group, is a constant and that substituent creates a bias in the reprotonation reaction. The allyl and methyl substituents prefer to be trans to one another for steric reasons and trans isomer is produced in >95% yield under these thermodynamic conditions. The Schwan invaluable mechanism rules. 1. Do not rush mechanistic steps together. 2. Use only reagents and data that have been provided. 3. In aq acid, for every step of the mechanism, the nucleophile is neutral and the electrophile is acidic (e.g., protonated) where possible for enhanced reactivity. It follows that there are no negatively charged entities in acidic solution. 4. In aq base, for every step of the mechanisms, the nucleophile is basic and the electrophile is neutral. It follows that there are no positively charged entities in basic solution. 5. Make sure each mechanistic step is balanced: charge, atoms, electrons 6. Electrons begin every step. 7. Water and alcohols will not do S 2-like substitutions at carbon. N 8. In alcohols or water, always use solvent for proton transfers. 9. Know as many pK ’a as possible. CHEM*3750 SCHWAN C OURSE N OTES F13 Chapter 2 Page 10 3. Halogenation of Ketones and AldehySF10(18.3) The following general reaction is the topic of this section. O O acid or H + X 2 X base As noted, halogenation of these carbonyl compounds may proceed under acidic or basic conditions. Under either of these conditions the mechanism for generation of the enol or enolate is the same as previous. The reactive compound then attacks the halogen rather than any other electrophile such as a proton. via enolate O- O X X X + -H H H via enol O +O X X X Rate studies have shown that initial rates of the halogenation are independent of halogen concentration. This is interpreted to mean that introduction of halogen into the substrate is not rate determining. Furthermore, experiments have shown that the rate is dependent on concentration of carbonyl compound and acid (or base). From this evidence, it is generally believed that enol or enolate formation is rate determining. O O + Cl2, H 70 °C Cl 85% Sometimes as shown below, the reaction is autocatalytic. That is, it is very slow until some halogenation occurs which produces acid as a byproduct. The rate of halogenation then accelerates due to the presence of acid. Hence the term autocatalytic, since the reaction provides the means to promote itself. CHEM*3750 SCHWAN C OURSENOTES F13 Chapter 2 Page 11 O O + Br2 MeOH Br + HBr 70% Under basic conditions, multiple halogenation is often a problem and therefore basic conditions are not recommended if one is striving for only the monohalogenated product. Note that this reactive character can be used to one’s advantage, as shown below. For the introduction of only one halogen, the reaction is usually performed under acidic conditions since introduction of one halogen into the molecule slows further reaction. For synthetic efficiency, monohalogenation reaction must be performed under acidic conditions. Inthe halogenated form, the electron O H + O H+ withdrawing nature of the halogen retards the initial step of enol formation H X and hence slows the introductionof more halogens. halogenpulls electron densityawayfrom the carbonyl group Multiple halogenation of methyl ketones provides chemistry that has been used as a functional group identification technique, although spectroscopic methods are now more popular. Multiple halogenation of methyl ketones leads to the haloform reaction and iodine is the more common halogen employed (iodoform reaction). The mechanism involves triple iodination of the methyl group of the ketone under basic conditions. O O O base base I I R R 2 R 2 (2X) I I Then, hydroxide attacks at the carbonyl group to make a tetrahedral intermediate which expels CI3. CHEM*3750 SCHWAN C OURSE NOTES F13 Chapter 2 Page 12 Complete mechanism: O O- O H - R OH H I I H OH H H R R H H I - O O - I I O H H -OH I I I R R R I I I I O -O OH I HO - I O I - R R + I C I I R OH I I I HO- H2O -no▯▯ H's remain; -carbonyl is most electrophilic O I - I C H R O I yellow precipitate - Interaction with the solvent provides the products: iodoform and carb3xylate. CI is a good leaving group in this case because the three electronegative halogens help to stabilize the negative charge on the carbon atom. The electronegativity also accounts for the multiple halogenations at a single site. Once one halogen is introduced, the remaining hydrogens on that same carbon atom have enhanced acidity. Acidic workup affords the carboxylic acid if desired as opposed to the carboxylate. The iodoform is a bright yellow precipitate that serves as a useful indicator. If a compound is suspected of being a methyl ketone, simply add excess hydroxide and I2and look for a yellow precipitate for confirmation of the suspected structure. The reaction can also be synthetically useful in that it can be used to achieve the overall conversion of methyl ketone to carboxylic acid. CHEM*3750 SCHWAN C OURSE NOTES F13 Chapter 2 Page 13 O 1. C2 /NaOH O 2. HCl/2 O OH + CHCl 3 5-methyl-3-hexen-2-one 5-methyl-2-pentenoic acid chloroform PRACTICE PROBLEMS 3 You can now do Questions 12.4, 16.47, 18.1-18.5 18.20a & 18.33 in SF10 1. Which of the following compounds will give a positive iodoform test. a) 2-pentanone b) 3-pentanone c) hexanal d) cyclohexanone e) 2-methylcyclohexanone f) cyclohexyl methyl ketone 2. For each of the following compounds write reaction equations showing how the compound could be prepared by oxidation of an alcohol, ozonolysis of an alkene and (if possible) hydration of an alkyne. Which of the preparations that you have written would give an unacceptable mixture of isomers? a) pentanal b) 3-hexanone c) 3-heptanone d) 2-methylbutanal 3. a) Suggest how you could prepare methyl 2-phenylethyl ketone from: i) an alkyne ii) 2-bromoethyl benzene b) Draw the products of the iodoform reaction on methyl 2-phenylethyl ketone. 4. Suggest two sets of reagents that will effect the following reaction. O Cl CH 3 CHEM*3750 SCHWAN C OURSE N OTES F13 Chapter 2 Page 14 SOLUTIONS TO PRACTICE PROBLEMS 3 Q1. a) 2-pentanone YES b) 3-pentanone NO c) hexanal NO d) cyclohexanone NO e) 2-methylcyclohexanone NO f) cyclohexyl methyl ketonYES Q2. a) pentanal O PCC C CH 2H H H H O 2 1. 3 C 2. Zn H cis or trans isomer +2 O Hg C H H H2SO4 + H2O O not likely due to exclusive product Markovnikov's rule b) 3-hexanone OH +2 CrO3 O Hg H SO H+ 2 4 H2O 1. 3 2. Zn cis or trans isomer c) 3-heptanone CHEM*3750 SCHWAN C OURSE NOTES F13 Chapter 2 Page 15 OH CrO3 O 1. 3 H+ 2. Zn cis or trans isomer +2 O Hg + H 2O 4 H 2 O 50:50 mixture, therefore unacceptable d) 2-methylbutanal H H CrO O 1. O3 HOCH 2 3 + H 2. Zn H cis or trans isomer -use of Hg2/H O/H on an alkyne is not possible for same reason as in a) above. 2 Q3 a) +2 O Hg Ph H SO Ph 2 4 H2O + CrO 3H H OH Br Mg 1. CH3CHO Ph MgBr Ph ether Ph 2. HCl/2 O b) O - O 1. xs OH + CHI 3 Ph 2 Ph OH 2. mild H/2 O I I Q4. CHEM*3750 SCHWAN C OURSE NOTES F13 Chapter 2 Page 16 Cl Mg MgCl ether 1. CO 1. CH CHO 2 3 2. HCl/2O 2. HCl/2 H O OH OH CH 3 CrO /H+ SOCl 3 2 O O Me2CuLi Cl CH 3 _______________________________________________________ 4. Alkylation Reactions and EnamineSF10 18.4; 18.9) Generating an enolate from a ketone or aldehyde and quenching it with an alkylating agent affords a method for the synthesis of compounds bearing an alkyl substituent next to the carbonyl group. Simple reactions can occur in some cases. O O 1. NaH, C6 6 2. Me2C=CHCH B2 CH 2H=CMe 2 88% O - via Br CHEM*3750 SCHWAN C OURSE N OTESF13 Chapter 2 Page 17 O O Li O LDA MeI Me cold warm to r.t. EtO EtO EtO 93% + HN(iPr2 There can be problems associated with this simple approach. One is that there are two sites for deprotonation when the compound bears ▯-hydrogens on either side of the carbonyl group. For instance, which one of the three (yes three) O different hydrogens on methyl cyclohexanone is most acidic? It can be challenging to create and maintain a single enolate. CHH3 Moreover, here can also be problems with multiple H H H H alkylations, depending on the substrate and reaction conditions, because sometimes there are unwanted proton transfers that give a different enolate, even during the course of the reaction. Although some solutions have been established and will be discussed later in the chapter, the problems led to the discovery of alternative protocols to achieve simple efficient alkylation. It is useful to present these as they are still in use today. Uncontrolled alkylations can lead up to five different products, in addition to unreacted starting material!! O O O O KOH + Me + + Me M e M I O O O + M e + Me M e Me Me Me Me M e Me One useful method for overcoming some of the difficulties involves the chemistry of enamines. As their name indicates enamines contain a double bond (ene) and an amine and the name is applied to systems where the two are in conjugation. N - N+ CHEM*3750 SCHWAN C OURSEN OTESF13 Chapter 2 Page 18 Gilbert Stork of Columbia University developed the chemistry shown here and it still bears his name. Enamines are prepared by condensing a secondary amine with a ketone or an aldehyde. If the amine is a primary amine the result is an imine, which is actually the more thermodynamically stable form of an imine/enamine tautomeric equilibrium. O R R' R H + N (R' = H) N + R -H2O NH R' enamine imine The following mechanism accounts for the enamine formation. H O + +O H + H /toluene NH HO N O + NH O O NH O O O H O H H O + N + + 2 HO N HO N + + H H O iminiumion NH note with 1mines O O N O EtNH + -H O 2 2 N via deprotonation of the N at the iminium ionstage enamine CHEM*3750 SCHWAN C OURSE NOTESF13 Chapter 2 Page 19 Water must be driven from the reaction vessel in order to force the equilibrium reaction to completion. This is usually achieved through the use of a Dean Stark apparatus: evaporated compounds condense, fall into graduated tube and separate. Water stays on lower layer and never return to the flask while the benzene (or toluene) rises to the level where it runs back into the reaction vessel. reaction mixture of benzene or toluene and maybe water, which also is created by the reaction As shown above the enamine has nucleophilicity at carbon and it is this atom that is preferentially functionalized in a simple S 2 reaction. N X X N N+ I- S N CH 3 CH I 3 + H 3 usually X =-CH 2H -2 (pyrrolidine) -CH 2H C2 - 2 (piperidine) O -CH 2CH - 2 (morpholine) CH 3 In this reaction the ▯-carbon of the enamine (▯-carbon of the ketone) bears the new substituent. To remove the nitrogen auxiliary and recover the new ketone, the iminium salt is hydrolyzed under aqueous acid conditions. The amine is lost in the acidic medium and can be recycled if desired. This method is preferred over simple deprotonation and alkylation since it minimizes double or multiple alkylation. The CHEM*3750 SCHWAN C OURSE NOTES F13 Chapter 2 Page 20 reaction occurs best with reactive halo compounds such as methyl iodide, benzyl halides, allyl halides, ▯-halocarbonyl compounds and acyl halides. Below is an example of the overall reaction sequence. O O 1. pyrrolidine, H H 2. BrCH2CH3 H 67% + CH CH 3. H , 2 O 2 3 Other examples: N 1. O O O Br O 2. H O+ O 3 O O O N 1. Cl + 2. H3O 5. The Aldol CondensationSF10 19.4-19.5) To this point we have examined the reactions of enols and enolates with a number of reactive electrophiles. One can also react them with the very substrates that provide enols and enolates: CARBONYL COMPOUNDS. Under the proper conditions the carbonyl group is sufficiently reactive to accept electron density from an enol or enolate. The archetypal example in many texts is the base catalyzed reaction of two molecules of acetaldehyde. The name aldol originates from the presence of an aldehyde and an alcohol in the product molecule. This name is used even if ketones are involved in the chemistry. CHEM*3750 SCHWAN C OURSE NOTES F13 Chapter 2 Page 21 O OH O 10% NaOH, H O 2 2 CH CH CH 3 H 5 °C 3 H 2 H portion that acted as an electrophile portion that was enolate The mechanism for the reaction is straightforward and is the basis of many other reactions yet to be introduced in this chapter. It begins with the reversible generation of an enolate. The enolate then reacts as indicated. Note that all the steps are reversible and sometimes aldol condensations are difficult to complete because of a propensity to revert to starting materials. - O- O O O CH 3 H H2C H CH 3 CH2 H H H2O OH O CH 3 CH2 H H Sometimes the aldol product will lose water spontaneously to afford a double bond. The conjugation of the double bond with the carbonyl group is the driving force in the dehydration. This can often be achieved simply by heating the reaction mixture during or after the bond forming process. Sometimes making the solution acidic will achieve the same purpose. The term condensationarises from the loss-of-water step. In synthetic chemistry, condensation means: the loss of water or its equivalent. Sometimes when the equilibrium constant for aldol formation is small, the reaction can still be driven by pushing the product through to the dehydrated product, the formation of which proceeds efficiently and is less reversible. Basic conditions: CHEM*3750 SCHWAN C OURSENOTES F13 Chapter 2 Page 22 OH O H O CH CH H - H CH CH H + OH H 3 OH + H 2 Often, if the elimination of water does not proceed efficiently under basic condition, one converts the mixture to an acidic one. Under acidic conditions, loss of water is an easier process. Acidic conditions: H OH 2 OH O CH3 CH 2 H H + OH 2 O H O CH CH3H H CH CH H + H 2 H 3 OH 2 The whole aldol condensation can also be performed under acidic conditions, where an enol rather than an enolate is the nucleophile. The acid initially induces enol formation by the means shown earlier in this chapter. This enol is a weak nucleophile and will only undergo aldol chemistry when the electron accepting carbonyl group has been protonated. Mechanism for acidic aldol reaction with loss of water: CHEM*3750 SCHWAN C OURSEN OTESF13 Chapter 2 Page 23 O H OH O + + O H H CH3 CH 3 CH3 CH3 CH2 CH3 CH 3 CH3 enol formation + H OH O OH O H2O CH CH3 CH 2 CH3 CH 3 2 CH 3 CH3 CH3 acidic dehydration as shown earlier CH 3 O CH CH CH 3 3 It is very difficult to isolate the true aldol product under acidic conditions. The reaction usually carries through to the unsaturated material. Both ketones and aldehydes can undergo the aldol condensation. Aldehydes are more reactive since nucleophilic attack at the ketone carbonyl is more sterically hindered. Also, the extra electron donating substituent makes the ketone less electrophilic. Aldol condensations as shown above with two molecules of acetaldehyde are the simplest possible examples. Complications quickly arise when two different aldehydes are used, or when ketones with two sets of ▯-hydrogens are employed. For instance with two different aldehydes, four products are available. The list includes two compounds from self-condensation and two different products from a crossed aldol reaction. OH O OH O O R + R' R H H H + R R O + + R' H OH O OH O R + R' H H R' R' CHEM*3750 SCHWAN C OURSENOTES F13 Chapter 2 Page 24 Selectivity can be achieved by choosing one reactant that does not have ▯- hydrogens or has ▯-hydrogens but they are of comparatively reduced acidity. O CHO O OH + NaOH, H 2 25 °C, 4 hr. 100 % CHO NaOH, H 2 + CH 3H C2O C O CHO O CH CH 3 72% O O + (CH ) C CHO NaOH, H2O CHC(CH 3 3 CH 3 3 3 CH 81% Referring back to page 16, it was mentioned that sometimes one can prepare and maintain a single enolate anion, even when are multiple ▯-hydrogens in the system. Specifically, it may be possible to selectively generate a particular enolate and then quench that enolate with another carbonyl compound (or other electrophile such as an alkylating agent). To begin it is important to know the different between kinetic and thermodynamic enolates. The thermodynamic enolate is the more stable by definition, and represents in this case, the more substituted enolate. This corresponds to the more substituted alkene of two isomers being the more stable and the concept applies in this case, since the enolate is mostly populated by the alkene resonance structure. It follows that the kinetic enolate is the less substituted of two options which can be accessed under mild conditions that make use of the steric differences of the two▯▯-hydrogen bearing sites. The best conditions for kinetic deprotonation are: LDA, -78 ▯C in THF. Generally one can expect preferred deprotonation from the 1▯ over 2▯ or 3▯ sites and from the 2▯ over 3▯ sites. The reaction is complete and irreversible. See the reaction below. Access to the thermodynamic enolate can be more challenging (e.g., less reliable), but suitable conditions might be3Et N in DMF. DMF = HC(O)N2e . As indicated, LDA is a reliable method for the complete and irreversible formation of a lithium enolate. With asymmetric ketones, LDA will remove a proton from the least CHEM*3750 SCHWAN C OURSE N OTESF13 Chapter 2 Page 25 sterically hindered position. This is generally believed to be the best method for carrying out crossed aldol condensations. The protocol lends a good amount of certainty to predicting the product in a crossed aldol. O O Li LDA, THF -78 °C CH 3 CH 2H 3 CH2 CH 2H 3 CH3CHO OH O O Li O H2O CH3 CH 2 CH2CH 3 CH 3 CH 2 CH 2H 3 If a given substrate possesses two carbonyl groups, it is possible for the compound to undergo an intramolecular aldol condensation. This form of the reaction is only suitable for the synthesis of 5, 6, and 7 membered rings. There are some rules that can be applied at this stage. One is a reminder that aldehydes are more electrophilic than ketones. The other is that 5 membered rings will form more readily that 7- membered rings while 6-membered rings are the best. Recall that aldol condensations are reversible and there is opportunity to form the most thermodynamically stable product. Intramolecular aldol condensations will virtually always proceed through with loss of water to form the ▯▯▯-unsaturated ketone or aldehyde. When deciding the product of this cyclization, an important step in the analysis is determining when water can be readily lost from the aldol. If not, aldol formation often reverses itself. O O O NaOH, H 2 not 100 °C O O O O NaOH, H 2 100 °C CHEM*3750 SCHWAN C OURSE NOTES F13 Chapter 2 Page 26 Before we leave the aldol condensation, the role of the carbonyl group in this chemistry should be emphasized. The polarity and resonance ability of the carbonyl group enhances the acidity of the hydrogens ▯ to it, allowing for the formation of enolates. That creates the nucleophilic component of the two reactants. For the electrophilic component the carbonyl group is polarized such that the carbon can accept attack by a nucleophile and the oxygen can hold the negative charge. 6. Other Related Condensation Reactions Whereas the Aldol condensation involves the reaction of an enolate of an aldehyde or ketone with another aldehyde or ketone, the Claisen Condensation ( SF10 19.2) involves the reaction of an enolate of an ester and a carboxylic acid derivative, usually another ester. One can view the initial steps of the Claisen condensation as analogous to ketone chemistry. Enolates of esters are less acidic than enolates of ketones or aldehydes and can therefore undergo chemistry with less reactive compounds. The archetypal example in this condensation involves the reaction of two molecules of ethyl acetate induced by ethoxide ion. The mechanism of the reaction is shown below. O - + CH CH O Na O CH 2 O 2 3 CH 2H 3 CH 2 O CH2CH3 H CH 3 O -OEt O O O Na+ O CH3CH 2 - CH 3H 2 O CH O CH 2H 3 O CH 2 CH 3 -EtO 2 CH3 ▯-ketoester tetrahedral intermediate - EtO O O O O CH 3CH2 CH 3H 2 - O CH O CH3 H H 3 H H O+ 3 O O CH 3H 2 O CH3 H H CHEM*3750 SCHWAN C OURSE N OTES F13 Chapter 2 Page 27 Although the scheme above shows the ▯-ketoester as the product, it should be realized that under the reaction conditions, the material actually rests as the deprotonated form until acted upon by the addition of acid, which returns the hydrogen. That is, the Claisen reaction mixture must be quenched with acid before isolation of the product. Acetic acid, citric acid or aq. ammonium chloride are often employed. Note that anions derived from the ▯-ketoester have two carbonyl groups available for conjugation. Hence tha pK of the ▯-ketoester is much lower than that of a simple ketone or ester, since anion stabilization is offer by both of these carbonyl groups in a single molecule. Hence, the ▯-ketoester is readily deprotonated by ethoxide. - O O CH CH 3 2 O CH CH 3 O O EtO Na+ O O CH 3H 2 CH CH O CH 2 CH 3 3 2 O CH CH 3 O O- CH3CH 2 O CH CH 3 The deprotonation step as shown above is key to the completion of the reaction. The ▯-ketoester anion is essentially inert and furthermore, in anionic form, the species is captured and frozen and cannot succumb to the reversibility of the reaction. The overall reaction only works well when there are 2 or 3 hydrogens on the starting ester. The ▯- ketoester drawn above is known by the common name of ethyl acetoacetate and hence the self-condensation of esters is sometimes known as the acetoacetate ester condensation. Example: CHEM*3750 SCHWAN C OURSEN OTESF13 Chapter 2 Page 28 O 1. MeO Na+ O O 2 Me Me + O O 2. H Crossed Claisen condensations are possible when one of the esters does not possess ▯-hydrogens, much like the ideal situation for crossed aldol reactions. O O O O + O O O O diethyl succinate diethyl oxalate - + O CH 3H 3 Na O toluene O O O O O 90% O 1. CHCH O Na+ O O O 3 3 O + ethanol O O + 2. H ethyl benzoate 71% O O - + O O + 1. C3 CH3O Na H O CH3 O ethanol H O 2. H ethyl formate 80% Note that in each of the three examples above, one of the reacting esters does not contain ▯-hydrogens. Carbonate esters, which also lack ▯-hydrogens, will successfully partake in crossed Claisen reactions. Another reaction that simplifies potentially complicated reactions is the Reformatsky reaction. It begins with an ▯-halo ester and uses metallic zinc to establish *▯-Halo esters can be prepared by the Hell-Volhard-Zellinsky reaction whereby a carboxylic acid is treated with molecular halogen and elemental phosphorus SF10t839-841 forSee details of this preparation. The acid can then simply be esterified. CHEM*3750 SCHWAN C OURSE NOTES F13 Chapter 2 Page 29 an ester enolate. In this reaction, the halo ester and zinc are mixed together to create a solution containing a zinc enolate, to which the ketone or aldehyde is added. As with aldol condensations, the product of Reformatsky reactions can be readily converted to the unsaturated material by treatment with acid. This achieves the dehydration process. O - + O O(ZnBr) Zn O - O O Br (ZnBr) CHO OH O O 60% OH O O 1. Zn, toluene Br O 2. O O 70% + 3. H If two ester groups are in the same molecule and are separated by 4 or 5 carbon atoms, then one can achieve an intramolecular Claisen condensation. This reaction is called the DieckmanSF10 873) condensation. Again there is an archetypal system that exemplifies the reaction. CHEM*3750 SCHWAN C OURSEN OTESF13 Chapter 2 Page 30 O - O H H H OMe O O O O O O- O O - O - H O MeO O O - MeO - O O -MeO O anion, quench w/ acid to obtain product As with the Claisen condensation, the equilibrium is frozen at the desired product by deprotonation of the acidic hydrogen between the carbonyl groups. The Dieckmann condensation is only useful for 5 and 6 membered rings. O H CO2Et CO Et 2 CO Et EtO- H+ 2 O O O O CHEM*3750 SCHWAN C OURSENOTESF13 Chapter 2 Page 31 A form of the Claisen Condensation is very prevalent in biological systems: it is vital to the construction of many naturally occurring and biologically important chemicals. In this case the carboxylic acid being attacked is a thiolester (textbooks will tell you thioester), and the sulfur and the remainder of coenzyme A is lost in a potentially reversible step. The nucleophile is not exactly the enolate of an ester, but one that bears an extra -CO 2 unit. The release of C2 , concurrent with nucleophilic attack, assists the Claisen Condensation over its kinetic barrier. O O O -CO + 2 O CH 2 SCoA H3C SCoA O- O O O -SCoA CH 3 CH 2 SCoA H3C CH2 SCoA CoAS O reduce, dehydrate, reduce CH 3H 2CH 2 SCoA
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