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An Overview of Carbonyl Compound Chemistry Dr. Yuming Zhao Department of Chemistry; email: [email protected] February 17, 2008 2 Contents 1 Carboxylic Acid Derivatives 5 1.1 Reactions involving carbon nucleophiles and hydride ions . . . . . . . . . . . . . . . 7 1.2 Understanding the roles of acid and base . . . . . . . . . . . . . . . . . . . . . . . . . 9 1.3 A bit more about amides and nitriles . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 1.4 Resonance effects in esters and amides . . . . . . . . . . . . . . . . . . . . . . . . . . 11 1.5 Retrosynthetic strategies for carboxylic acid derivatives . . . . . . . . . . . . . . . . 12 2 Regarding Ketones and Aldehydes 15 2.1 H -Nucleophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 2.2 C -Nucleophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 2.3 O-Nucleophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 2.4 S -Nucleophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 2.5 N -Nucleophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 2.6 Conjugate addition on α, β-unsaturated carbonyl compounds . . . . . . . . . . . . . 22 2.7 Retrosynthetic analyses for ketones and aldehydes . . . . . . . . . . . . . . . . . . . 23 3 Substitutions at the α-Carbons 3.1 25 Synthetic uses of malonic esters and acetoacetic esters . . . . . . . . . . . . . . . . . 27 4 Carbonyl Condensation Reactions 31 4.1 Aldol reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31 4.2 Claisen and Dieckmann condensations . . . . . . . . . . . . . . . . . . . . . . . . . . 33 4.3 Robinson annulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 3 4 CONTENTS Chapter 1 Carboxylic Acid Derivatives Carboxylic acid derivatives (categorized as Carbonyl Compounds I in the textbook) have a common structural feature, that is a heteroatom (O, N, Cl, or Br) is immediately connected to the carbon atom of a carbonyl group, except for the structure of nitriles (see below). O O R R Cl O O O R' O R R acyl halides Br O R R' O OH acid anhydride carboxylic acid carboxylic ester O R R C N NR'2 nitrile (dehydrated primary amide) amide Varieties of carboxylic acid derivatives The heteroatom substituents in above structures serve as leaving groups (good, moderate or poor sometimes) in the reactions termed Nucleophilic Acyl Substitution Reactions. The general mechanism for such reactions is illustrated below. The different natures (i.e. leaving group ability) of the substituents adjacent to the C=O group play a critical role in the reactivities of various carboxylic acid derivatives. O O O + LG R LG R LG Nu Nu 5 R Nu 6 CHAPTER 1. CARBOXYLIC ACID DERIVATIVES Notice that the above mechanism comprises two basic steps: (i) nucleophilic addition, and (ii)α- elimination. In a general sense, if the nucleophile (Nu− ) is a stronger base than the leaving anion (LG− ), the reaction can readily occur to afford the substitution product. If the nucleophile is a weaker base than the leaving anion, then the reaction simply does not occur. However, sometimes it is difficult to compare the basicities of the nucleophile and the leaving anion. A better way of making judgement is to evaluate the acidities of their conjugate acids. A weak acid (e.g. MeOH) should always correspond to a strong conjugate base (e.g. MeO− ), and vice versa. The general ranking of the reactivities for carboxylic acid derivatives is summarized below, from which you can easily observe an increasing trend of reactivity with the acidity of the conjugate acid of the leaving group anion (H-LG). O O most reactive R R Br O R O O O HO R R is a relatively strong acid (pKa ~3-5) O O R HCl and HBr are strong acids (pKa ~ -6-7) Cl OH R OR H2O and HOR are weak acids (pKa ~ 16-18) O least reactive R HNR2 is an extremely weak acid (pKa ~ 38) NR2 Ranking of reactivities for class I carbonyl compounds It is also obvious from the above ranking chart that acyl halides are suitable starting reagents for synthesizing other less reactive carboxylic acid derivatives such as acid anhydrides, esters, and amides. However, the high reactivities of acyl halides usually make them very unstable and difficult to be stored for a long period of time in the laboratory. To avert this practical difficulty, acyl halides are usually generated fresh from corresponding carboxylic acids in the presence of thinoyl chloride or PBr3 before use. This step is called ”activation” of carboxylic acid. O R O R O SOCl2 OH R O O R'COOH R' O R'OH R' Cl O R O R'NH2 R' R N H 1.1. REACTIONS INVOLVING CARBON NUCLEOPHILES AND HYDRIDE IONS 7 Although the general mechanism for reactions involving carboxylic acid derivatives (i.e. nucleophilic acyl substitution) is kind of straightforward, the detailed mechanism for a particular reaction tends to be slightly different depending on the reagents and conditions being used. For this reason, you need to be a bit careful and judicious in proposing mechanistic steps and intermediates for a particular reaction. In the following section, we will examine a few different cases. 1.1 Reactions involving carbon nucleophiles and hydride ions Carbanions and hydrides are strongly nucleophilic in nature and they are generally “very poor” leaving groups to be expelled once attached to the carbonyl carbon. Therefore, they can quickly displace the leaving group in a carboxylic acid derivative, resulting in ketone or aldehyde intermediates at the first stage (see the scheme below). O R O O Cl R H 3C H3C MgBr R Cl CH3 H3C MgBr O OH p.t. R H3 C CH3 R H 3C CH3 The ketones and aldehydes, once they are formed, are also very reactive toward the carbon nucleophiles; as a result, a second nucleophilic attack can quickly happen, eventually producing alcohols as the final products. For example, when organometallic compounds, Grignard or organolithium reagents, are used as the carbanion species, they can react with the ketone or aldehyde intermediates very rapidly to form a second tetrahedral intermediate, in which no good leaving groups are present. Overall, the reaction cannot stop at the stage of ketones and aldehydes. Rather, secondary or tertiary alcohols will be yielded as the final products. One thing you should be well aware is that carboxylic acids are not suitable for reactions with organometallic reagents, because their acidic protons will induce very fast acid-base reaction instead of nucleophilic addition. As a result, carboxylate ions will be formed. Notice that a carboxylate ion is not an electrophile any more; it is a good nucleophile. Therefore, the reaction will simply yield a magnesium carboxylate salt as shown in the following example. 8 CHAPTER 1. CARBOXYLIC ACID DERIVATIVES O R O O H R O + CH4 MgBr H3C MgBr If a strong metal hydride, such as LiAlH4 , is added to a carboxylic acid, acid-base reaction will take place at first. However, the resulting carboxylate, once associated with Al to form a Lewis complex, can be reduced readily by hydride anions and eventually lead to the formation of a primary alcohol. O R H O O H O AlH2 - H2 R AlH2 O R O H H AlH3 Li OH O LAH R R H Basically, lithium aluminium hydride (LAH) can reduce most carbonyl compounds into alcohols or amines (in the case of reduction of amides or nitriles). A weak metal hydride, such as NaBH4 , can only be useful for reducing acyl chorides, ketones and aldehydes in alcohol solvents, and it is quite inert to esters and amides. The reactivity of diisobutyl aluminium hydride (DIBAL) has a reactivity between LAH and NaBH4 . A prominent usage of DIBAL is to reduce an ester into an aldehyde at low temperature (-78 ◦ C). O R Cl R R R O 1) DIBAL, -78 oC O OR' 2) H2O, H+, then warm up NaBH4 O OH NaBH4 R OR' O H R X no rxn O R'2CuLi Cl R R' Another mild reagent worthy of remarking is lithium diorganocuprates (R2 CuLi), i.e. the Gilmann reagents. As can be seen in the last example of the above scheme, the Gilmann reagent only leads to the displacement of the halogen group with an alkyl group, but no further addition can occur on the resulting ketone. Synthetically, this provides a simple way to make ketones from carboxylic acids. 1.2. UNDERSTANDING THE ROLES OF ACID AND BASE 1.2 9 Understanding the roles of acid and base Generally speaking, if a regular acid (e.g. HCl, H2 SO4 , or HOAc) or a base (e.g. NaOH, KOH) is applied to a reaction involving a carboxylic acid derivative, it will be most likely functioning as a catalyst. In acidic conditions, the C=O group will be protonated at first to make it more electrophilic, while in basic conditions, deprotonation will occur at first to make a nucleophile more nucleophilic. For very reactive species, like acyl halides, there is no need to add an acid or a base as the catalyst. In most cases for esters or derivatives less reactive than esters, for example, hydrolysis of esters, amides, and nitriles, either acids or bases would be added to accelerate the rates of reactions. Also be aware that under these conditions proton transfer(s) can easily occur on the intermediate(s) involved in each mechanistic step. However, you should be very careful with proposing reactive intermediates under different conditions. For instance, under basic conditions any cationic intermediates exist in very low concentrations and thus should not be proposed as key intermediates in relevant mechanistic steps. On the contrary, under acidic conditions, anionic intermediates would play quite insignificant roles in mechanism and should be generally avoided. Whatever the structures of reactants are, tetrahedral intermediates should be involved in the mechanisms. There is only one exception that does not involve the tetrahedral intermediate in mechanism among the reactions we have learned so far — the hydrolysis of t-butly esters. The very stable tert-butyl carbocation (by hyperconjugative effect) makes an SN 1 pathway much more favorable than the typical addition-elimination mechanism. H+ O R O CH3 R O O O CH3 CH3 R p.t. CH3 R O H O O H H H H O O HO H H H H O R O p.t. OH R + CH3OH OH H+ H O H O H2O O + R O R O R HO O Mechanisms for acid-catalyzed ester hydrolysis reactions 10 CHAPTER 1. CARBOXYLIC ACID DERIVATIVES Recall that under acidic conditions, each mechanistic step in the hydrolysis of an ester is re- versible. Therefore, to achieve high yield, the equilibrium is usually broken by removal of the byproduct, alcohol, through distillation or by adding a large excess of water. Under basic conditions, however, the hydrolysis (or saponification) turns out to be an irreversible process, because of the formation of carboxylate ion. Check your textbook to see the detailed explanation. One thing should be noticed is that when an ester is treated with a base, say NaOH or NaOEt, under non-aqueous conditions, Claisen condesation rather than hydrolysis will happen (see below). So, you must carefully read the conditions given in the exam to decide what type of reaction is to take place. O 1) NaOH, H2O OEt 2) H2O, H + O O OH vs O 1) NaOEt OEt 2) H2O, H + O OEt To be Claisen or to be hydrolysis, this is a question! 1.3 A bit more about amides and nitriles Amides and nitriles are located at the bottom of the reactivity ranking chart for carbonyl compounds I. Therefore, to make them react, much harsher conditions need to be enlisted. Generally, an acid or a base catalyst plus heating can be used to accelerate the hydrolysis of amides or nitriles. The products are simply carboxylic acids and different types of amines (primary or secondary) depending on the starting materials. Besides hydrolysis, amides and nitriles can also be reduced by LAH to form amines. This reaction can be useful in the synthesis of amino-containing compounds using carboxylic acids as starting materials. If a primary amine is desired, you should choose to reduce a primary amide or a nitrile with LAH. In addition to this reductive amination approach, another useful method, called Gabriel synthesis, can be employed as well to make various alkylsubstituted primary amine. Again, it is time to check your textbook if you don’t know the Gabriel synthesis. 1.4. RESONANCE EFFECTS IN ESTERS AND AMIDES 11 H+ OH H O O N H CH3 CH3 N H CH3 N H O H H O H H p.t. OH H O O H N OH OH CH3 H HO + H2NCH3 O O O N H H CH3 OH N H O H CH3 OH + H2NCH3 OH- OH O O OH quenched with O H3O+ 1.4 Resonance effects in esters and amides Both amides and esters show resonance effects at the carbonyl group. However, in an amide the resonance effect is much stronger than in an ester. So the charge-separated resonance structure contributes to a significant degree to the properties of an amide. In an ester, however, the resonance effect is less significant because of the strong electronegativity of oxygen atom. In fact, the oxygen atom next the carbonyl induces a dominating inductive effect that counteracts the resonance effect. O O O N N significant O O O insignificant The interplay between resonance and inductive effects in an amide and an ester leads to different outcomes. In an amide, the resonance effect wins. As a result, an amide shows a much stronger diople moment, and the diople-diople interactions account well for the relatively high melting points for amides. The winning resonance effect also makes the stretch of C=O in an amide shifts to a lower frequency than a typical ketone C=O. In an ester, the inductive effect is the winner. Therefore, an ester usually has a fairly low melting point and, in the IR spectrum, its C=O stretching frequency is much higher than a typical C=O bond as in ketones or aldehydes. 12 CHAPTER 1. CARBOXYLIC ACID DERIVATIVES 1.5 Retrosynthetic strategies for carboxylic acid derivatives Knowing that carboxylic acid derivatives can occur a common reaction, nucleophilic acyl substitution, you may find that bond disconnection at the carbonyl carbon and heteroatom bond ((O=C)– X) is indeed a very good starting point for numerous syntheses of carboxylic acid derivatives. However, this does not mean that you should always perform this operation in the beginning of retrosynthesis. Other operations such as functional group interconversion (FGI) or functional group addition (FGA) can also be good choices depending on the exact structures of target compounds. Let’s take a look at a few examples to better understand this. The first example is to synthesize an aromatic compound containing both an amide and an ester groups. H N H3C O O O target Retrosynthesis Route 1 H3C H N O O O NH2 BD H3C + O Cl O O ??? Route 2 H N H3C O CH3OH + O O O H3C Cl FGI H N H N BD + O Cl O O NH2 H3C H N H N BD O FGI O HO Retro-oxd. O O If you start the retrosynthesis with bond disconnection at the amide group (route 1), you will get two precursors, a para-substituted aniline and an acyl chloride. It seems plausible by the first glance. But you can quickly find a problem with one of the synthons–the aniline precursor. Notice that it has both an amino group as the nucleophile and an ester group as the electrophile within the same molecule, the molecule can readily follow an intermolecular aminolysis pathway to form polyamides. So, route 1 reachs a dead end. 1.5. RETROSYNTHETIC STRATEGIES FOR CARBOXYLIC ACID DERIVATIVES 13 However, if a bond disconnection begins at the ester group, no such problems will happen because the amide group is relatively stable. Following a sequence of FGI and BD, a reasonable synthetic plan can be easily formulated as suggested by route 2. Synthesis O O O KMnO4 Cl H3 C H3 C NH2 NH HOOC NH SOCl2 O O O CH3OH NH H3CO O NH Cl It should also be noted that making an amide from aniline is a very good way to protect the amino group. Recall that aniline cannot occur Friedel-Crafts reactions directly. Over the past few years, I have seen such a mistake be made by a lot of students. So you certainly do not want to repeat this common mistake in your exams. Remember the amino group needs to be protected at first, and transforming it into an amide is a very good choice. Now, let’s try another synthesis example. O HO O O O HO OH OH Retrosynthesis O HO O FGI OH N C C O HO FGI N O FGI Br Br HO OH + CN- OH Just by looking at the starting material and the product, you may be puzzled a bit as to how to elongate the carbon chain between the two carboxyl groups by two carbon atoms. Obviously bond disconnection won’t work in the retrosynthesis. However, after performing a number of FGIs, the clue becomes clearer and clearer. The key step in this retrosynthesis is to take advantage of nitrile hydrolysis reaction. Recall that a nitrile group can be hydrolyzed into an amide, which can be further hydrolyzed into a carboxylic acid. Therefore, adding a nitrile group via an SN 2 attack will not only install a precursor to a carboxyl group, but also increase the number of carbons in the molecule by one. From the above retrosynthesis, it is very easily to propose a synthesis of glutaric acid from malonic acid. 14 CHAPTER 1. CARBOXYLIC ACID DERIVATIVES Synthesis O HO O LAH PBr3 HO OH NaCN OH Br NC Br CN H3O+ heat O O HO OH Exercise. Identify compounds A-M in the following scheme. Br H3O+ NaCN A (1) (CH3)2CuLi SOCl2 B (2) H2O heat (1) LAH (2) H2O CH3OH, H+ F C (1) DIBAL, -78 oC (2) H2O (i) CH3Li H G (2) H2O (1) LAH (2) H2O (CH3O)2O I E D J PBr3 K NaCN L (1) CH3MgBr (2) H2O M Chapter 2 Regarding Ketones and Aldehydes If you truly understand the meaning of the resonance structures of a carbonyl group shown below, you will have no problem with understanding the reactions at the carbonyl group of a ketone or an aldehyde. O O O O O O Nu H Nu: B: The resonance structure on the right hand side tells that the carbonyl carbon possesses partly carbon cation character. Like a typical carbon cation, two possible reactions can occur around the carbonyl carbon. The first is simply an addition reaction in which a nucleophile is added to the carbonyl to form a new covalent bond (termed AdN , addition nucleophilic). The second is a β-elimination in the presence of a base instead of a nucleophile. This reaction, which kind of resembles the E1 reaction, leads to the formation of an enolate, and the enolate forms the very basis for many complex condensation and annulation reactions in Chapter 18 of the textbook. For direct carbonyl addition reactions, there are two conditions can be used–acidic and basic. In acidic conditions, the C=O bond becomes more polar after protonation, which in turn makes the carbonyl carbon more electrophilic. By this means, the incoming nucleophile can be added to C=O at a much faster rate. 15 16 CHAPTER 2. REGARDING KETONES AND ALDEHYDES H+ H H O O O However, you should be well aware that acidic conditions may not favor the addition reaction of nucleophilic species that show strong basicity. For instance, the addition of an amine can be significantly slowed down if strong acidity (pH < 3) is applied. The reason is that the nucleophilicity of an amine will be considerably reduced after being protonated, even though the C=O group shows improved electrophilicity under acidic conditions. For this reason, the reaction between a ketone and an amine occur the fastest at an optimized pH value (ca. 5). A detailed explanation for this phenomenon is given in the context of Chapter 17 (p. 808). Notice that, under basic conditions, the electrophilicity of the C=O group is barely changed. It is virtually the increased nucleophilicity of the nucleophile that speeds up the addition step. Nucleophiles with acidic protons (e.g. H2 O, ROH) can occur rapid proton transfer under basic conditions to form corresponding anionic conjugate bases (e.g. − OH, − OR) which are far better nucleophiles than their neutral forms. For example, Neutral O O very slow O R R OH Basic O fast H O O R R O Basic condition is commonly used in Carbonyl I reactions. However, in AdN reactions of ketones and aldehydes, it is rarely used. Why? It is because the addition of an oxygen nucleophile is a reversible process, and the good leaving ability of the nucleophilic group, e.g. OR, makes tetrahedral product unstable in basic conditions. Therefore, it will reform the more stable ketone quickly. In a sense, both the forward and reverse reactions are accelerated by a base catalyst, but the equilibrium favors the left (backward) direction. What makes base-catalyzed carbonyl addition really meaningful and useful are actually the enolate involved reactions, e.g. aldol reaction, Claisen reaction, Robinson annulation. These reactions all contain an irreversible step in their mechanisms, so that the reactions can be carried on to the right (forward) direction. We shall go through them soon in the subsequent sections. 2.1. H-NUCLEOPHILES 17 Moreover, steric factors are also crucial to the reaction rate of carbonyl addition reaction (AdN ). Basically, aldehydes are more reactive than ketones because there is less steric hinderance at the carbonyl of an aldehyde. Recall that a nucleophile approaches towards the C=O via the so called Bürgi-Dunitz trajectory. Nu 107o O π* For various carbonyl involved AdN reactions, they are better to summarized based on the types of nucleophiles. 2.1 H -Nucleophiles Because the carbonyl carbon exhibits partial carbon cation character, it is much susceptible to nucleophilic attacks by various nucleophiles. Metal hydrides, such as NaBH4 , DIBAL, and LAH, can easily attack a C=O group to reduce it into an alcohol. Notice that the reduction is irreversible because the added H is an extremely poor leaving group. If an aldehydes is to be reduced, the product will be a primary alcohol. Ketones will only lead to secondary alcohols through metal hydride reduction, and there is no way to produce a tertiary alcohol by directly reduction on a carbonyl compound. O O H H+ OH H H H H H H B H H O O H H H Al H H H+ OH H 18 CHAPTER 2. REGARDING KETONES AND ALDEHYDES 2.2 C -Nucleophiles A tertiary alcohol however can be easily produced by adding a carbanion into a ketone. Organometallic compounds such as Grignard reagents and alkyllithium compounds can be regarded as equivalents to carbanions, with the reaction mechanism similar to hydride reduction. O O H OH H+ H CH3 H3C MgBr O O H3 C OH H+ Li Notice that the addition of organometallics to C=O is also irreversible, and normally a quenching step is required by the end of the reaction to dissociate the complexation between the alkoxide and the metal ion to release a neutral alcohol product. In addition to organometallics, enolates, Wittig reagents, and cyanides are also very good C nucleophiles for C=O addition. The enolate reactions will be elaborated shortly, while at this moment let’s focus on the cyanide addition. Recall that an cyanide ion can be reversibly added into C=O to form cyanohydrins. Because of the reversibility of the reaction, careful control over the pH value is critical. In general, acidic condition is required to ensure the formation of cyanohydrin (see the discussion on p. 805 in the textbook). In basic conditions, however, a cyanohydrin will be immediately reverted a ketone and a cyanide ion. H O CN OH O NC NC CN cyanohydrin OHO H O O + CN- NC NC A good LG in basic conditions 2.3. O-NUCLEOPHILES 2.3 19 O-Nucleophiles Oxygen-Nucleophiles (usually H2 O and alcohols) prefer to attack the C=O group in aldehydes or ketones under acidic conditions, because of the reasons mentioned previously. Water reacts with aldehydes or ketones to form hydrates, the stability of which are dependent on steric effects. Alcohols react with adehydes or ketones to form hemiacetals and acetals. Synthetically, this kind of addition reactions provide a very useful strategy for protecting the C=O group, as acetals can be readily reverted back to ketones or aldehydes under suitable conditions. H+, 2 equiv ROH Dean-Stark O RO OR H+, H2O Protection and deprotection of a C=O group Notice that the reaction between an O-nucleophile and C=O is normally reversible. In order to obtain the desired product, different conditions should be used accordingly. To get acetal, the reaction needs to be performed in acidic, non-aqueous solution and a Dean-Stark trap is commonly used to remove the byproduct–water–from the system. In hydrolysis of acetals, however, excess water should be added so that to shift the equilibrium of the reaction in favor of the formation of carbonyl products. The mechanisms of the formation or removal of acetals are rather lengthy and complex. However, you should be well aware of one key step as shown below. Never try a direct SN 2 mechanism, albeit it looks simple and tempting. H O H+ O OH CH3OH O CH3 p.t. OH2 O CH3 OCH3 O CH3 H O CH3 H CH3OH p.t. OH2 OCH3 O CH3 OCH3 CH3OH NEVER propose this SN2 mechanism An example demonstrating the synthetic use of such protection/deprotection strategy is given below. 20 CHAPTER 2. REGARDING KETONES AND ALDEHYDES O O O OH O Synthesis OH O O , H+ O O O O O O OH O H+, H2O O LAH OH OH Dean-Stark 2.4 S -Nucleophiles S -Nucleophiles behave in a similar manner to O-nucleophiles in reactions with carbonyl groups. A thioacetal is formed when two thiol molecules react with one molecule of ketone or aldehyde in the presence of a Lewis acid catalyst, e.g. BF3 , under non-aqueous conditions. In general a dithiol is used as a common protecting reagent for C=O. Again, the Dean-Stark trap is preferred to be used in the synthesis in order to remove the byproduct, H2 O. SH O O O SH , BF3 S S O O LAH O S S H+, H2O OH OH HgCl2 Dean-Stark Raney Ni OH The resulting thioacetal is capable of protecting a C=O group as is an acetal. However, sometimes thioacetals can find other synthetic usages instead of merely C=O protection. A notable transformation is the desulfurization reaction shown above. This reaction provides an alternative means to remove C=O group in addition to the well known Clemensen and Wolff-Kishner reactions. 2.5 N -Nucleophiles Ketone and aldehydes can react smoothly with primary or secondary amines under moderately acidic conditions. The mechanism involves two essential steps, addition and elimination. For primary amines, the elimination step yields imines as the products, whereas for secondary amines iminium ions are formed. 2.5. N-NUCLEOPHILES 21 H+ H OH O O OH2 p.t. p.t. N N NH2 R NH R H R R R NH2 H H+ H OH O O OH2 p.t. N N HN R R R N R R NH R R R R R Reactions between amines and ketones or aldehydes are called condensation reactions; that is, one molecule of water is lost during the reaction. For condensation reactions involving primary amines and carbonyl compounds, the two hydrogens on the amino group (NH2 ) are both eliminated during dehydration to yield an imine (C=N) product and H2 O. As for secondary amines, the dehydration reaction removes one hydrogen from the amino group and another hydrogen from the nearby α-hydrogen(s), forming an enamine (C=C-NR) rather than an imine after dehydration. Both imines and enamines can be hydrolyzed into ketones or aldehydes in the presence of excess water and acid. Enamines are analogous carbon nucleophiles to enols or enlates. Synthetically, they show several advantages over enolates. The major synthetic uses of an enamine include direct alkylation and acylation of the α-carbon of a ketone. Notice that the enamine reactions show much better regioselectivity than the enolate reactions in general; the less substituted α-carbon is preferred to be alkylated or acylated due to steric argument. O N H O N N H3O+ CH3CH2Br heat H+ O Cl N O O H3 O + heat O 22 CHAPTER 2. REGARDING KETONES AND ALDEHYDES 2.6 Conjugate addition on α, β-unsaturated carbonyl compounds α, β-Unsaturated carbonyl compounds can occur both direct addition at C=O and 1,4-addition (also called conjugate addition), in which a nucleophilic group is added to the β-carbon of C=O. Commonly used substrates for 1,4-addition are: O O H(R) O OR CN NR2 The mechanism for 1,4-addition is shown in the following scheme. Practically, 1,4-addition offers a direct route to functionalize the β-carbon of a carbonyl compound. O O O A R H R R Nu Nu Nu: In synthesis if a target compound requires functionalization at the β-carbon, 1,4-addition could be a very good choice. An example is shown below. O O COOH Retrosynthesis O α COOH β FGR FGA retro-conjugate CN addition [+ HBr] H O O O O FGI Br BD Synthesis O Br2, H Br t-BuOK O O O O + H+, H2O NaCN heat CN COOH Moreover, α, β-unsaturated ketones or aldehydes can be readily converted into diverse products such as ketones or alcohols through different reduction approaches. Pay particular attention to the following examples. 2.7. RETROSYNTHETIC ANALYSES FOR KETONES AND ALDEHYDES O OH 23 O H2 (xs) H2 (1 equv) Pd/C, heat Pd/C NaBH4 CeCl3 OH 2.7 Retrosynthetic analyses for ketones and aldehydes If the target compound or intermediate(s) in a synthesis is a ketone or aldehyde, you should consider using the reactions we have just gone through in the previous sections. The following lists some examples of how to perform reasonable retrosynthetic analysis for ketones and aldehydes. Example 1. Synthesis of a ketone from an aldehyde. O O H Retrosynthesis O OH O BD FGI + BrMg H Synthesis O O OH (1) BrMg PCC H (2) H2O Example 2. Synthesis of an alkene from a ketone. O Retrosynthesis O HO BD FGA + CH3Li [+ H2O] Synthesis O (1) CH3Li (2) H2O HO H2SO4 heat 24 CHAPTER 2. REGARDING KETONES AND ALDEHYDES Example 3. Two approaches to make C=C bonds from ketones. O Retrosynthesis 1 FGA OH BD O + BrMg [+ H2O] H Synthesis 1 O (1) BrMg H2SO4 OH heat (2) H2O Retrosynthesis 2 O PPh3 + Wittig reagent Synthesis 2 PPh3 NaH PPh3 PPh3 Br Br O In making a C=C bond from a ketone or an aldehyde, you can also use the Wittig reaction. Exercise. Propose reasonable routes for the following transformations starting from cyclohexanol. OH Br O OH OH Chapter 3 Substitutions at the α-Carbons Reactions of carbonyl compounds (ketones, aldehydes, esters and alike) at their α-carbons always involve the formation of enols or enolates in the initial step(s). To reasonably propose their mechanisms, you should keep the pKa values for a number of compounds in mind. R H H R R' O R' R H H H pKa ~ 17-18 O O O O R pKa ~ 20 pKa ~ 25 O O N H R' pKa ~ 30 R' R H pKa ~ 10-11 Enols are normally generated in equilibrium with aldehydes or ketones under aqueous acidic conditions. The mechanism is shown below. In the first step, the C=O group is protonated by an acid. The protonation makes the α-hydrogen far more acidic than its neutral form. As a result of the increased acidity at the α-hydrogen, a rapid proton transfer step can quickly follow up to form the enol product. In the second step, the solvent, e.g. H2 O, acts as a weak base to eliminate the α-hydrogen, and both steps are reversible. H H H+ O O R OH R H R O R H enol is a good nucleophile H 2O Notice that an enol is an electron-rich alkene as suggested by its resonance contributor. The α-carbon is electron-rich in nature, and it functions as the nucleophile in numerous polar reactions. One point needs to be clarified at the moment is that enoalization (also called tautomerization) is quite different in concept from resonance. Recall that resonance structures, no matter more or less, 25 26 CHAPTER 3. SUBSTITUTIONS AT THE α-CARBONS are different facets or portraits for a single compound. Resonance is not a chemical transformation! In drawing resonance structures, only the positions of valence electrons and lone pair electrons are changeable, whereas the positions of all nuclei of the molecule should remain the same. In contrast, enolization or tautomerization is a unique chemical transformation where only one acidic hydrogen atom of the molecule changes its position. H H O H O O O H Resonance Enolization or tautomerization Unlike enols, enolates are produced in basic conditions. Depending on the strength of the base, the enolate ions formed in a reaction can be either in equilibrium with its carbonyl precursor or exclusively produced. Generally speaking, − OH or − OR ions can only partially deprotonate typical carbonyl compounds, such as aldehydes, ketones, and esters, to form enolates in equilibration. Much stronger bases, e.g. LDA, NaH, and BuLi, however, can completely transform these carbonyl compounds into their enolate forms. The two different outcomes of enolate formation should be carefully considered and evaluated in various enolate involved reactions. Enolates are more electron-rich than enols because of their negatively charged characteristics. Hence, they tend to be more reactive towards electropohiles. One significant example is the haloform reaction. In basic conditions, excess iodine can completely replace the α-hydrogens of a methyl ketone. The resulting -CI3 serves a good leaving group in a subsequent nucleophilic acyl substitution reaction. Distinctive observation of iodoform (CHI3 )–a yellow precipitate–makes this reaction useful in identification of various methyl ketones. O I2 R CH3 O O O R R CI3 OH- R O CI3 H :CI3 HO HO: O R O + CHI3 yellow precipitate Besides halogenation reactions, enolates can also occur alkylations with a variety of alkyl halides. For unsymmetric ketones, regioselectivity needs to be considered. If a strong base LDA and low temperatures are applied, deprotonation usually favors the less substituted (i.e. less hindered) αcarbons. The resulting enolates are called kinetic enolates, because they are formed at much faster 3.1. SYNTHETIC USES OF MALONIC ESTERS AND ACETOACETIC ESTERS 27 reaction rates. If the reaction is carried out at room temperature in the presence of a relatively weak base, e.g. alkoxide ions, deprotonation occurs preferentially at the more substituted α-carbons. The enolates formed under these conditions are called thermodynamic enolates. O O Li O CH3CH2Br LDA -78 oC kinetic enolate O O Na NaOEt O CH3CH2Br EtOH 25 oC thermodynamic enolate To achieve better regioselectivity at the less substituted α-carbons, a method of using N,N dimethylhydrozone derivatives has been devised. The reason for the high selectivity rests on the steric effects illustrated below. Read the detailed explanations in the textbook. CH3 O H 2N N CH3 N CH3 CH3 N N CH3 CH3 N CH3 N CH3 N Li Li LDA CH3 favored disfavored You may recall that enamine reactions also serve a good approach to selectively functionalize substituted α-carbons of ketones (see previous section). The rationalization is based on sterics as well. 3.1 Synthetic uses of malonic esters and acetoacetic esters As mentioned in the beginning of this section, 1,3-dicarbonyl compounds have unusually acidic α-hydrogens (pKa = 10–11). The reason for this is because their enolates are highly delocalized (in resonance with two carbonyl groups). The relatively high acidity of 1,3-dicarbonyl compounds makes them very useful in synthesis. Malonic esters are handy precursors to various α-substituted carboxylic acids. For instance, a decarboxylation reaction occurs in the following synthesis, which produces a mono-carboxylic acid as the final product. 28 CHAPTER 3. SUBSTITUTIONS AT THE α-CARBONS O O O R EtO OH OEt R' Example O O O NaOH (1 equiv) (1) NaOH (1 equiv) EtO EtO O O OEt (2) Br (1 equiv) OEt EtO OEt Br Br Br O O OH O decarboxylation O HO O OH - CO2 O H+, H2O heat EtO OEt H O O O HO OH + CO2 O Mechanism of decarboxylation Acetoacetic esters are suitable precursors to methyl ketones. A synthetic example is given below. O O O R CH3 OEt R' Example O O O O O O NaOH (1 equiv) (1) NaOH (1 equiv) OEt OEt OEt (2) Br (1 equiv) Br Br Br O O O H+, H2O decarboxylation OH - CO2 heat O O OEt H O O O O + CO2 Mechanism of decarboxylation It is rather straightforward to comprehend the steps in a synthesis using malonic esters and acetoacetic acids as starting materials. However, in retrosynthesis the clues can be sometimes 3.1. SYNTHETIC USES OF MALONIC ESTERS AND ACETOACETIC ESTERS 29 obscure, particularly when the molecular structure becomes complex. A useful trick is to locate the α-carbon in a carboxylic acid or a methyl ketone at first, and then add a carboxyl group on it. The following two examples show how to perform reasonable retrosynthetic analysis for the cases where malonic esters or acetoacetic esters are to be used. O O COOH EtO OEt Step 2: Add a carboxyl group on this α-carbon Step 1: Find the α-carbon O O OH OH α OH O Step 3: Perform retrosynthesis O O OH O O HO OH FGA O EtO O OEt BD FGI O EtO OEt Br + Br [+ CO2] O O O CH3 OEt Step 2: Add a carboxyl group on this α-carbon Step 1: Find the α-carbon O O CH3 CH3 α OH O Step 3: Perform retrosynthesis O O CH3 HO FGA O O CH3 EtO FGI O O CH3 BD EtO Br [+ CO2] O CH3 + Br 30 CHAPTER 3. SUBSTITUTIONS AT THE α-CARBONS Exercise. Propose reasonable syntheses for the following compounds using diethyl malonate or acetoacetate as the starting material. OH COOH COOH O O OH Chapter 4 Carbonyl Condensation Reactions Three important carbonyl condensation reactions–aldol condensation, Claisen (Dieckmann) condensation, and Robinson annulation (Michael addition plus aldol condensation)–have been discussed in the lectures, which are very useful in making a variety of organic compounds. 4.1 Aldol reactions Aldol reactions include aldol addition and aldol condensation. Their mechanisms are straightforward. As illustrated in the following example, the first step is an aldol addition, where an enolate is added to an aldehyde. The common bases used for aldol addition are NaOH, NaOMe, and NaOEt. The aldol adduct is a β-hydroxyl aldehyde, which is usually unstable. Upon further treatment with concentrated base or acid together with heat, dehydration will occur immediately to yield a stable product, α, β-unsaturated aldehyde. In basic conditions, the elimination of water takes place through a conjugate base elimination mechanism, termed E1cb, while in acidic conditions the simple E2 mechanism is operating. O O O O NaOH E1cb NaOH H H H heat OH OH β-hydroxy aldehyde H+, heat H E2 O H OH2 31 H 32 CHAPTER 4. CARBONYL CONDENSATION REACTIONS Synthetically, aldol condensation provides an effective way of direct C-C bond formation. The following is an example demonstrating the power of the aldol reactions. O Retrosynthetic analysis O O BD FGA The synthesis seems requires the formation of this C-C bond An α,β-unsaturated ketone is a product of aldol condensation So, let's add two functional groups Synthesis O O O - H2, Pd/C NaOH H2NNH2, OH Wolff-Kishner heat Exercise. Propose synthesis using aldol reactions. OH H OH O O Ph Ph O H Cross-aldol reactions normally produce more than one products. Therefore, they are not very useful in synthesis. However, when a highly enolizable carbonyl compound and a carbonyl compound without α-hydrogens are mixed together in the presence of a base, only one major aldol product can be formed. An example of cross-aldol synthesis is given below. O O O O O H NaOEt EtO OEt EtOH EtO O EtO OEt O OEt OH NaOEt O O EtO E1cb OEt Also notice that intramolecular aldol condensation be used to make five- or six-membered cyclic ketones effectively. O O O HO NaOEt E1cb NaOEt EtOH O O O O O 4.2. CLAISEN AND DIECKMANN CONDENSATIONS 4.2 33 Claisen and Dieckmann condensations When an ester with α-hydrogens is added into a non-aqueous basic solution, condensation instead of base-catalyzed hydrolysis will happen. These reactions are called Claisen condensations, if the reactions occur intermolecularly. If the reactions are intramolecular, they are then called Dieckmann condensations. Such condensations are typically performed under the conditions of NaOMe-MeOH (for methyl esters) or NaOEt-EtOH (for ethyl esters) dependent on the types of esters being used. Generally, Claisen and Dieckmann reactions are carried out through two steps, (i) base treatment and (ii) acidic quenching. In basic conditions O OEt H OEt OEt OEt OEt OEt O O O O H O OEt O :OEt O O EtO: It is this irreversible deprotonation step that drives the reaction to completion. The first three steps are reversible. In acidic quenching step O O H + , H 2O OEt OEt O O Like the intramolecular aldol condensation, the Dieckmann reaction is also a very useful reaction to make five- or six-membered cyclic ketones. Forming smaller-sized rings, such as three or fourmembered, are however highly disfavored because of the significant ring strains encountered. O O O OEt EtO (1) NaOEt, EtOH O + (2) H , H2O O O O O Small rings cannot be formed in Diekmann condensation. 4.3 Robinson annulation Among all the methods you have learned to make six-membered rings in this course, Robinson annulation is probably the most versatile and efficient one, since it generates three new covalent bonds in one reaction. The starting materials for a Robinson annulation include a vinyl ketone 34 CHAPTER 4. CARBONYL CONDENSATION REACTIONS and a regular ketone with α-hydrogens. The reactions are usually carried out under the catalysis of bases like NaOH, NaOMe, or NaOEt. Mechanistically, the Robinson annulation consists of a typical Michael addition and an aldol condensation. You should know how to draw this mechanism correctly, at least for the sake of final examination! Review the mechanism very carefully from your lecture notes and textbook. Robinson annulation NaOH + O O O A six-membered ring bearing a conjugated vinyl ketone moiety can be cut into two pieces in its retrosynthesis. The trick here is to first locate the α-carbon that is on a C=C bond and the β-carbon on the other side of the cyclic ketone. Next, perform bond disconnections at the α-double bond and the β–γ single bond. Finally, make a C=C double bond at α–β position and install a =O group onto the carbon that previously belongs to the C=C bond as shown in the following scheme. By following these three steps, one can easily come up with the two starting materials for a desired Robinson annulation. Examine the following retrosynthetic analysis carefully to make sure truly understand how to perform synthesis using Robinson annulation reactions. Make this bicyclic compound through Robinson annulation Retrosynthesis β β BD FGA O O α Add a ketone and a C=C group at first. Then mark the α- and β-carbons α O Cut the molecule into two pieces at the marked two joints, and add a new C=C bond and a new C=O group at the right places. Synthesis O O H2 NaOH + Pd/C O Zn, HCl Clemensen O Exercise. Propose syntheses for the following compounds using Robinson annulation reactions. O O O