Thiols and Sulfides Thiols Thiols, also called mercaptans , are sulfur analogs of alcohols. They are named by the same system used for alcohols, with the suffix - thiol used in place of - ol. The –SH group itself is referred to as a mercapto group . Like alcohols, thiols are weakly acidic; the p K a of CH 3 SH, for instance, is 10.3. Unlike alcohols, however, thiols don’t typically form hydrogen bonds because the sulfur atom is not sufficiently electronegative. The most striking characteristic of thiols is their appalling odor. Skunk scent, for instance, is caused primarily by the simple thiols 3-methyl-1-butanethiol and 2-butene-1-thiol. Volatile thiols such as ethanethiol are also added to natural gas and liquefied propane to serve as an easily detectable warning in case of leaks. Thiols are usually prepared from alkyl halides by S N 2 displacement with a sulfur nucleophile such as hydrosulfide anion, – SH. The reaction often works poorly unless an excess of the nucleophile is used because the product thiol can undergo a second S N 2 reaction with alkyl halide to give a sulfide (R–S–Rʹ) as by-product. To circumvent this problem, thiourea, ( NH 2 ) 2 C ═ S , is often used as the nucleophile in the preparation of a thiol from an alkyl halide. The reaction occurs by displacement of the halide ion to yield an intermediate alkyl isothiourea salt, which is hydrolyzed by subsequent reaction with aqueous base. Thiols can be oxidized by Br 2 or I 2 to yield disulfides (R–S–S–R′) . The reaction is easily reversed, and a disulfide can be reduced back to a thiol by treatment with zinc and acid. This thiol–disulfide interconversion is a key part of numerous biological processes. We’ll see in Chapter 26, for instance, that disulfide formation is involved in defining the structure and three-dimensional conformations of proteins, where disulfide “bridges” often form cross-links between cysteine amino-acid units in the protein chains. Disulfide formation is also involved in the process by which cells protect themselves from oxidative degradation. A cellular component called glutathione removes potentially harmful oxidants and is itself oxidized to glutathione disulfide in the process. Reduction back to the thiol requires the coenzyme reduced flavin adenine dinucleotide, abbreviated FADH 2 . Sulfides Sulfides are the sulfur analogs of ethers just as thiols are the sulfur analogs of alcohols. Sulfides are named by following the same rules used for ethers, with sulfide used in place of ether for simple compounds and alkylthio used in place of alkoxy for more complex substances. Treatment of a thiol with a base, such as NaH, gives the corresponding thiolate ion (RS – ), which undergoes reaction with a primary or secondary alkyl halide to give a sulfide. The reaction occurs by an S N 2 mechanism, analogous to the Williamson synthesis of ethers ( ). Despite their close structural similarity, sulfides and ethers differ substantially in their chemistry. Because the valence electrons on sulfur are farther from the nucleus and are less tightly held than those on oxygen (3 p electrons versus 2 p electrons), sulfur compounds are more nucleophilic than their oxygen analogs. Unlike dialkyl ethers, dialkyl sulfides react rapidly with primary alkyl halides by an S N 2 mechanism to give sulfonium ions (R 3 S + ). The most common example of this process in living organisms is the reaction of the amino acid methionine with adenosine triphosphate (ATP; ) to give S -adenosylmethionine. The reaction is somewhat unusual in that the biological leaving group in this S N 2 process is the triphosphate ion rather than the more frequently seen diphosphate ion ( ). Sulfonium ions are themselves useful alkylating agents because a nucleophile can attack one of the groups bonded to the positively charged sulfur, displacing a neutral sulfide as leaving group. We saw an example of this in ( ), in which S -adenosylmethionine transferred a methyl group to norepinephrine to give adrenaline. Another difference between sulfides and ethers is that sulfides are easily oxidized. Treatment of a sulfide with hydrogen peroxide, H 2 O 2 , at room temperature yields the corresponding sulfoxide (R 2 SO) , and further oxidation of the sulfoxide with a peroxyacid yields a sulfone (R 2 SO 2 ) . Dimethyl sulfoxide (DMSO) is a particularly well-known sulfoxide that is often used as a polar aprotic solvent. It must be handled with care, however, because it has a remarkable ability to penetrate the skin, carrying along whatever is dissolved in it. Problems

Science


Spectroscopy of Ethers Infrared Spectroscopy Ethers are difficult to identify by IR spectroscopy. Although they show an absorption due to C–O single-bond stretching in the range 1050 to 1150 cm –1 , many other kinds of absorptions occur in the same range. shows the IR spectrum of diethyl ether and identifies the C–O stretch. Phenyl alkyl ethers show two strong absorbances for C–O stretching at 1050 and 1250 cm –1 . shows the IR spectrum of anisole. The infrared spectrum of diethyl ether, CH 3 CH 2 OCH 2 CH 3 . The infrared spectrum of anisole . Nuclear Magnetic Resonance Spectroscopy Hydrogens on carbon next to an ether oxygen are shifted downfield from the normal alkane resonance and show 1 H NMR absorptions in the region 3.4 to 4.5 δ . This downfield shift is clearly seen in the spectrum of dipropyl ether shown in . The 1 H NMR spectrum of dipropyl ether . Protons on carbon next to oxygen are shifted downfield to 3.4 δ. Epoxides absorb at a slightly higher field than other ethers and show characteristic resonances at 2.5 to 3.5 δ in their 1 H NMR spectra, as indicated for 1,2-epoxypropane in . The methylene protons of this epoxide are diastereotopic, and display complex splitting (see and ). The 1 H NMR spectrum of 1,2-epoxypropane . Ether carbon atoms also exhibit a downfield shift in the 13 C NMR spectrum, where they usually absorb in the 50 to 80 δ range. For example, the carbon atoms next to oxygen in methyl propyl ether absorb at 58.5 and 74.8 δ . Similarly, the methyl carbon in anisole absorbs at 54.8 δ . Problems Epoxy Resins and Adhesives Few nonchemists know exactly what an epoxide is, but practically everyone has used an “epoxy glue” for household repairs or an epoxy resin for a protective coating. Worldwide, approximately 14 billion dollars’ worth of epoxy resins and adhesives are used annually for a vast number of applications, including many in the aerospace industry. Much of the Boeing 787 Dreamliner, for instance, is held together with epoxy-based adhesives. Epoxy resins and adhesives generally consist of two components that are mixed just prior to use. One component is a liquid “prepolymer,” and the second is a “curing agent” that reacts with the prepolymer and causes it to solidify. The most widely used epoxy resins and adhesives are based on a prepolymer made from bisphenol A and epichlorohydrin. On treatment with base, bisphenol A is converted into its anion, which acts as a nucleophile in an S N 2 reaction with epichlorohydrin. Each epichlorohydrin molecule can react with two molecules of bisphenol A, once by S N 2 displacement of chloride ion and once by nucleophilic opening of the epoxide ring. At the same time, each bisphenol A molecule can react with two epichlorohydrins, leading to a long polymer chain. Each end of a prepolymer chain has an unreacted epoxy group, and each chain has numerous secondary alcohol groups spaced regularly along its midsection. Kayaks are often made of a high-strength polymer coated with epoxy resin. (credit: “Potomac River Festival Virginia 2017 Great Falls Kayak Race” by Watts/Flickr, CC BY 2.0) When an epoxide is to be used, a basic curing agent such as a tertiary amine, R 3 N, is added to cause the individual prepolymer chains to link together. This cross-linking of chains is simply a base-catalyzed, S N 2 epoxide ring-opening of an –OH group in the middle of one chain with an epoxide group on the end of another chain. The result of such cross-linking is formation of a vast, three-dimensional tangle that has enormous strength and chemical resistance. alkoxymercuration crown ether disulfide (R–S–S–R′) ether (R–O–R′) mercapto group sulfide (R–S–R′) sulfone sulfonium ion sulfoxide thiol thiolate ion (RS – ) Williamson ether synthesis Summary This chapter has finished the coverage of functional groups with C–O and C–S single bonds, focusing primarily on ethers, epoxides, thiols, and sulfides. Ethers are compounds that have two organic groups bonded to the same oxygen atom, ROR′. The organic groups can be alkyl, vinylic, or aryl, and the oxygen atom can be in a ring or in an open chain. Ethers are prepared by either Williamson ether synthesis, which involves S N 2 reaction of an alkoxide ion with a primary alkyl halide, or the alkoxymercuration reaction, which involves Markovnikov addition of an alcohol to an alkene. Ethers are inert to most reagents but react with strong acids to give cleavage products. Both HI and HBr are often used. The cleavage reaction takes place by an S N 2 mechanism at the less highly substituted site if only primary and secondary alkyl groups are bonded to the ether oxygen, but by an S N 1 or E1 mechanism if one of the alkyl groups bonded to oxygen is tertiary. Epoxides are cyclic ethers with a three-membered, oxygen-containing ring. Because of the strain in the ring, epoxides undergo a cleavage reaction with both acids and bases. Acid-catalyzed ring-opening occurs with a regiochemistry that depends on the structure of the epoxide. Cleavage of the C–O bond at the less highly substituted site occurs if both epoxide carbons are primary or secondary, but cleavage of the C–O bond to the more highly substituted site occurs if one of the epoxide carbons is tertiary. Base-catalyzed epoxide ring-opening occurs by S N 2 reaction of a nucleophile at the less hindered epoxide carbon. Thiols , the sulfur analogs of alcohols, are usually prepared by S N 2 reaction of an alkyl halide with thiourea. Mild oxidation of a thiol yields a disulfide , and mild reduction of a disulfide returns the thiol. Sulfides , the sulfur analogs of ethers, are prepared by an S N 2 reaction between a thiolate anion and a primary or secondary alkyl halide. Sulfides are more nucleophilic than ethers and can be alkylated by reaction with a primary alkyl halide to yield a sulfonium ion . Sulfides can also be oxidized to sulfoxides and to sulfones . Summary of Reactions Synthesis of ethers ( ) Williamson ether synthesis Alkoxymercuration/demercuration Reactions of ethers Cleavage by HBr or HI ( ) Acid-catalyzed epoxide opening ( ) Base-catalyzed epoxide opening ( ) Synthesis of thiols ( ) Oxidation of thiols to disulfides ( ) Synthesis of sulfides ( ) Oxidation of sulfides to sulfoxides and sulfones ( ) Additional Problems Visualizing Chemistry Mechanism Problems Naming Ethers Synthesizing Ethers Reactions of Ethers and Epoxides Spectroscopy General Problems Preview of Carbonyl Chemistry Carbonyl compounds are everywhere. Most biological molecules contain carbonyl groups, as do most pharmaceutical agents and many of the synthetic chemicals that affect our everyday lives. Citric acid, found in lemons and oranges; acetaminophen, the active ingredient in many over-the-counter headache remedies; and Dacron, the polyester material used in clothing, all contain different kinds of carbonyl groups. To a great extent, the chemistry of living organisms is the chemistry of carbonyl compounds. Thus, we’ll spend the next five chapters discussing the chemistry of the carbonyl group, C=O (pronounced car-bo- neel ). There are many different kinds of carbonyl compounds and many different reactions, but there are only a few fundamental principles that tie the entire field together. The purpose of this brief preview is not to show details of specific reactions but rather to provide a framework for learning carbonyl-group chemistry. Read through this preview now, and return to it on occasion to remind yourself of the larger picture. I Kinds of Carbonyl Compounds shows some of the many different kinds of carbonyl compounds. All contain an acyl group ( R – C=O ) bonded to another substituent. The R part of the acyl group can be practically any organic part/structure, and the other substituent to which the acyl group is bonded might be a carbon, hydrogen, oxygen, halogen, nitrogen, or sulfur. Some Types of Carbonyl Compounds Name General formula Name ending Aldehyde -al Ketone -one Carboxylic acid -oic acid Acid halide -yl or -oyl halide Acid anhydride -oic anhydride Acyl phosphate -yl phosphate Ester - oate Lactone (cyclic ester) None Thioester - thioate Amide - amide Lactam (cyclic amide) None It’s useful to classify carbonyl compounds into two categories based on the kinds of chemistry they undergo. In one category are aldehydes and ketones; in the other are carboxylic acids and their derivatives. The acyl group in an aldehyde or ketone is bonded to an atom (H or C, respectively) that can’t stabilize a negative charge and therefore can’t act as a leaving group in a nucleophilic substitution reaction. The acyl group in a carboxylic acid or its derivative, however, is bonded to an atom (oxygen, halogen, sulfur, nitrogen) that can stabilize a negative charge and therefore can act as a leaving group in a nucleophilic substitution reaction. II Nature of the Carbonyl Group The carbon–oxygen double bond of a carbonyl group is similar in many respects to the carbon–carbon double bond of an alkene. The carbonyl carbon atom is sp 2 -hybridized and forms three σ bonds. The fourth valence electron remains in a carbon p orbital and forms a π bond to oxygen by overlapping with an oxygen p orbital. The oxygen atom also has two nonbonding pairs of electrons, which occupy its remaining two orbitals. Like alkenes, carbonyl compounds are planar about the double bond and have bond angles of approximately 120°. shows the structure of acetaldehyde and indicates its bond lengths and angles. As you might expect, the carbon–oxygen double bond is both shorter (122 pm versus 143 pm) and stronger [732 kJ/mol (175 kcal/mol) versus 385 kJ/mol (92 kcal/mol)] than a C–O single bond. Structure of acetaldehyde . As indicated by the electrostatic potential map in , the carbon–oxygen double bond is strongly polarized because of the high electronegativity of oxygen relative to carbon. Thus, the carbonyl carbon atom carries a partial positive charge, is an electrophilic (Lewis acidic) site, and reacts with nucleophiles. Conversely, the carbonyl oxygen atom carries a partial negative charge, is a nucleophilic (Lewis basic) site, and reacts with electrophiles. We’ll see in the next five chapters that the majority of carbonyl-group reactions can be rationalized by simple polarity arguments. III General Reactions of Carbonyl Compounds Both in the laboratory and in living organisms, most reactions of carbonyl compounds take place by one of four general mechanisms: nucleophilic addition, nucleophilic acyl substitution, alpha substitution, and carbonyl condensation. These mechanisms have many variations, just as alkene electrophilic addition reactions and S N 2 reactions do, but the variations are much easier to learn when the fundamental features of the mechanisms are made clear. Let’s see what the four mechanisms are and what kinds of chemistry carbonyl compounds undergo. Nucleophilic Addition Reactions of Aldehydes and Ketones (Chapter 19) The most common reaction of aldehydes and ketones is the nucleophilic addition reaction , in which a nucleophile, : Nu – , adds to the electrophilic carbon of the carbonyl group. Because the nucleophile uses an electron pair to form a new bond to carbon, two electrons from the carbon–oxygen double bond must move toward the electronegative oxygen atom to give an alkoxide anion. The carbonyl carbon rehybridizes from sp 2 to sp 3 during the reaction, and the alkoxide ion product therefore has tetrahedral geometry. Once formed, and depending on the nature of the nucleophile, the tetrahedral alkoxide intermediate can undergo one of two further reactions, as shown in . Often, the tetrahedral alkoxide intermediate is simply protonated by water or acid to form an alcohol product. Alternatively, the tetrahedral intermediate can be protonated and expel the oxygen to form a new double bond between the carbonyl carbon and the nucleophile. We’ll study both processes in detail in Chapter 19. The addition reaction of an aldehyde or a ketone with a nucleophile . Depending on the nucleophile, either an alcohol or a compound with a C ═ Nu double bond is formed. FORMATION OF AN ALCOHOL The simplest reaction of a tetrahedral alkoxide intermediate is protonation to yield an alcohol. We’ve already seen two examples of this kind of process during reduction of aldehydes and ketones with hydride reagents such as NaBH 4 and LiAlH 4 ( ) and during Grignard reactions ( ). During a reduction, the nucleophile that adds to the carbonyl group is a hydride ion, H : – , while during a Grignard reaction, the nucleophile is a carbanion, R 3 C : – . FORMATION OF C=Nu The second mode of nucleophilic addition, which often occurs with amine nucleophiles, involves elimination of oxygen and formation of a C=N u double bond. For example, aldehydes and ketones react with primary amines, RNH 2 , to form imines, R 2 C=NR ′ . These reactions use the same kind of tetrahedral intermediate as that formed during hydride reduction and Grignard reaction, but the initially formed alkoxide ion is not isolated. Instead, it is protonated and then loses water to form an imine, as shown in . MECHANISM Formation of an imine, R 2 C=NR′, by reaction of an amine with an aldehyde or a ketone . Nucleophilic Acyl Substitution Reactions of Carboxylic Acid Derivatives (Chapter 21) The second fundamental reaction of carbonyl compounds, nucleophilic acyl substitution , is related to the nucleophilic addition reaction just discussed but occurs only with carboxylic acid derivatives rather than with aldehydes and ketones. When the carbonyl group of a carboxylic acid derivative reacts with a nucleophile, addition occurs in the usual way, but the initially formed tetrahedral alkoxide intermediate is not isolated. Because carboxylic acid derivatives have a leaving group bonded to the carbonyl-group carbon, the tetrahedral intermediate can react further by expelling the leaving group and forming a new carbonyl compound: The net effect of nucleophilic acyl substitution is the replacement of the leaving group by the entering nucleophile. We’ll see in Chapter 21, for instance, that acid chlorides are rapidly converted into esters by treatment with alkoxide ions ( ). MECHANISM Nucleophilic acyl substitution of an acid chloride with an alkoxide ion yields an ester . Alpha-Substitution Reactions (Chapter 22) The third major reaction of carbonyl compounds, alpha substitution , occurs at the position next to the carbonyl group—the alpha ( α ) position. This reaction results in the substitution of an α hydrogen by an electrophile through the formation of an intermediate enol or enolate ion: For reasons that we’ll explore in Chapter 22, the presence of a carbonyl group renders the hydrogens on the α carbon acidic. Carbonyl compounds therefore react with strong base to yield enolate ions. Because they’re negatively charged, enolate ions act as nucleophiles and undergo many of the reactions we’ve already studied. For example, enolates react with primary alkyl halides in the S N 2 reaction. The nucleophilic enolate ion displaces halide ion, and a new C–C bond forms: The S N 2 alkylation reaction between an enolate ion and an alkyl halide is a powerful method for making C–C bonds, thereby building up larger molecules from smaller precursors. We’ll study the alkylation of many kinds of carbonyl compounds in Chapter 22. Carbonyl Condensation Reactions (Chapter 23) The fourth and last fundamental reaction of carbonyl groups, carbonyl condensation , takes place when two carbonyl compounds react with each other. When acetaldehyde is treated with base, for instance, two molecules combine to yield the hydroxy aldehyde product known as aldol ( ald ehyde + alcoh ol ): Although carbonyl condensation appears to be different from the three processes already discussed, it’s actually quite similar. A carbonyl condensation reaction is simply a combination of a nucleophilic addition step and an α -substitution step. The initially formed enolate ion of one acetaldehyde molecule acts as a nucleophile and adds to the carbonyl group of another acetaldehyde molecule, as shown in . MECHANISM A carbonyl condensation reaction between two molecules of acetaldehyde yields a hydroxy aldehyde product . IV Summary To a great extent, the chemistry of living organisms is the chemistry of carbonyl compounds. We have not looked at the details of specific carbonyl reactions in this short preview but rather have laid the groundwork for the next five chapters. All the carbonyl-group reactions we’ll be studying in Chapters 19 through 23 fall into one of the four fundamental categories discussed in this preview. Knowing where we’ll be heading should help you keep matters straight in understanding this most important of all functional groups.

Science


Why This Chapter? Few flowers are more beautiful or more fragrant than roses. Their perfumed odor is due to several simple organic compounds, including the ketone β -damascenone. (credit: modification of work “Rosa ‘Precious Platinum’” by Bernard Spragg/Wikimedia Commons, CC BY 1.0) Much of organic chemistry is the chemistry of carbonyl compounds. Aldehydes and ketones, in particular, are intermediates in the synthesis of many pharmaceutical agents, in almost all biological pathways, and in numerous industrial processes, so an understanding of their properties and reactions is essential. In this chapter, we’ll look at some of their most important reactions. Aldehydes (RCHO) and ketones (R 2 CO) are among the most widely occurring of all compounds. In nature, many substances required by living organisms are aldehydes or ketones. The aldehyde pyridoxal phosphate, for instance, is a coenzyme involved in a large number of metabolic reactions; the ketone hydrocortisone is a steroid hormone secreted by the adrenal glands to regulate fat, protein, and carbohydrate metabolism. In the chemical industry, simple aldehydes and ketones are produced in large quantities for use as solvents and as starting materials to prepare a host of other compounds. For example, more than 50 million tons per year of formaldehyde, H 2 C═O , is produced worldwide for use in building insulation materials and in the adhesive resins that bind particle board and plywood. Acetone, (CH 3 ) 2 C═O , is widely used as an industrial solvent, with approximately 8 million tons per year produced worldwide. Formaldehyde is synthesized industrially by catalytic oxidation of methanol, and one method of acetone preparation involves oxidation of 2-propanol produced by hydration of propylene.

Science


Naming Aldehydes and Ketones Aldehydes are named by replacing the terminal - e of the corresponding alkane name with - al. The parent chain must contain the –CHO group, and the –CHO carbon is numbered as carbon 1. Note in the following examples that the longest chain in 2-ethyl-4-methylpentanal is actually a hexane, but this chain does not include the –CHO group and thus is not the parent. For cyclic aldehydes in which the –CHO group is directly attached to a ring, the ring name followed by carbaldehyde is used. A few simple and well-known aldehydes have common names that are recognized by IUPAC. Several that you might encounter are listed in . Common Names of Some Simple Aldehydes Formula Common name Systematic name HCHO Formaldehyde Methanal CH 3 CHO Acetaldehyde Ethanal H 2 C═CHCHO Acrolein Propenal CH 3 CH═CHCHO Crotonaldehyde 2-Butenal Benzaldehyde Benzenecarbaldehyde Ketones are named by replacing the terminal - e of the corresponding alkane name with - one. The parent chain is the longest one that includes the ketone group, and the numbering begins at the end nearer the carbonyl carbon. As with alkenes ( ) and alcohols ( ), the locant is placed before the parent name using older rules but before the suffix with the newer IUPAC guidelines. For example: A few ketones are allowed by IUPAC to retain their common names. When it’s necessary to refer to the R–C═O group as a substituent, the name acyl (a-sil) group is used and the name ending - yl is attached. Thus, –COCH 3 is an acetyl group, –CHO is a formyl group, –COAr is an aroyl group, and –COC 6 H 5 is a benzoyl group. If other functional groups are present and the double-bonded oxygen is considered a substituent on a parent chain, the prefix oxo - is used. For example: Problems

Science


Preparing Aldehydes and Ketones Preparing Aldehydes Perhaps the best method of aldehyde synthesis is by oxidation of a primary alcohol, as we saw in . The reaction is usually carried out using the Dess–Martin periodinane reagent in dichloromethane solvent at room temperature: Another method of aldehyde synthesis is one that we’ll mention here just briefly and then return to in Section 21.6 . Certain carboxylic acid derivatives can be partially reduced to yield aldehydes. The partial reduction of an ester by diisobutylaluminum hydride (DIBAH, or DIBAL-H), for instance, is an important laboratory-scale method of aldehyde synthesis, and mechanistically related processes also occur in biological pathways. The reaction is normally carried out at –78 °C (dry-ice temperature) in toluene solution. Problems Preparing Ketones For the most part, methods of ketone synthesis are similar to those for aldehydes. Secondary alcohols are oxidized by a variety of reagents to give ketones ( ). The choice of oxidant depends on such factors as reaction scale, cost, and acid or base sensitivity of the alcohol. The Dess–Martin periodinane is a common choice although chromic acid (H 2 CrO 4 ) was frequently used in older work. Other methods include the ozonolysis of alkenes in which one of the unsaturated carbon atoms is disubstituted ( ) and Friedel–Crafts acylation of an aromatic ring with an acid chloride in the presence of AlCl 3 catalyst ( ). In addition to those methods already discussed, ketones can also be prepared from certain carboxylic acid derivatives, just as aldehydes can. Among the most useful reactions of this sort is that between an acid chloride and a lithium diorganocopper reagent, as we saw in . We’ll discuss this reaction in more detail in Section 21.4 . Problems

Science


Oxidation of Aldehydes and Ketones Aldehydes are easily oxidized to yield carboxylic acids, but ketones are generally inert toward oxidation. The difference is a consequence of structure: aldehydes have a –C H O proton that can be abstracted during oxidation, but ketones do not. Many oxidizing agents, including alkaline KMnO 4 and hot HNO 3 , convert aldehydes into carboxylic acids. The oxidation occurs rapidly at room temperature and generally works well. Aldehyde oxidations occur through intermediate 1,1-diols, or hydrates, which are formed by a reversible nucleophilic addition of water to the carbonyl group. Even though it’s formed to only a small extent at equilibrium, the hydrate reacts like any typical primary or secondary alcohol and is oxidized to a carbonyl compound ( ). Ketones are inert to most oxidizing agents but undergo a slow cleavage reaction of the C–C bond next to the carbonyl group when treated with hot alkaline KMnO 4 . The reaction is not often used, however, and is mentioned here only for completeness.

Science


Nucleophilic Addition Reactions of Aldehydes and Ketones As we saw in the Preview of Carbonyl Chemistry, the most general reaction of aldehydes and ketones is the nucleophilic addition reaction . As shown in , a nucleophile, : Nu – , approaches the carbonyl group from an angle of about 105° opposite the carbonyl oxygen and forms a bond to the electrophilic C–O carbon atom. At the same time, rehybridization of the carbonyl carbon from sp 2 to sp 3 occurs, an electron pair from the C═O bond moves toward the electronegative oxygen atom, and a tetrahedral alkoxide ion intermediate is produced. Protonation of the alkoxide by addition of acid then gives an alcohol. MECHANISM A nucleophilic addition reaction to an aldehyde or ketone. The nucleophile approaches the carbonyl group from an angle of approximately 75° to the plane of the sp 2 orbitals, the carbonyl carbon rehybridizes from sp 2 to sp 3 , and an alkoxide ion is formed. Protonation by addition of acid then gives an alcohol. The nucleophile can be either negatively charged ( : Nu – ) or neutral ( : Nu). If it’s neutral, however, it usually carries a hydrogen atom that can subsequently be eliminated, : Nu–H. For example: Nucleophilic additions to aldehydes and ketones have two general variations, as shown in . In one variation, the tetrahedral intermediate is protonated by water or acid to give an alcohol as the final product. In the second variation, the carbonyl oxygen atom is protonated and then eliminated as HO – or H 2 O to give a product with a C═Nu double bond. Two general reaction pathways following addition of a nucleophile to an aldehyde or ketone. The top pathway leads to an alcohol product; the bottom pathway leads to a product with a C═Nu double bond. Aldehydes are generally more reactive than ketones in nucleophilic addition reactions for both steric and electronic reasons. Sterically, the presence of only one large substituent bonded to the C═O carbon in an aldehyde versus two large substituents in a ketone means that a nucleophile is able to approach an aldehyde more readily. Thus, the transition state leading to the tetrahedral intermediate is less crowded and lower in energy for an aldehyde than for a ketone ( ). Steric hindrance in nucleophilic addition reactions. (a) Nucleophilic addition to an aldehyde is sterically less hindered because only one relatively large substituent is attached to the carbonyl-group carbon. (b) A ketone, however, has two large substituents and is more hindered. The approach of the nucleophile is along the C═O bond at an angle of about 75° to the plane of the carbon sp 2 orbitals. Electronically, aldehydes are more reactive than ketones because of the greater polarization of aldehyde carbonyl groups. To see this polarity difference, recall the stability order of carbocations ( ). A primary carbocation is higher in energy and thus more reactive than a secondary carbocation since it has only one alkyl group inductively stabilizing the positive charge rather than two. In the same way, an aldehyde has only one alkyl group inductively stabilizing the partial positive charge on the carbonyl carbon rather than two, and is a bit more electrophilic, and, therefore, more reactive than a ketone. One further comparison: aromatic aldehydes, such as benzaldehyde, are less reactive in nucleophilic addition reactions than aliphatic aldehydes because the electron-donating resonance effect of the aromatic ring makes the carbonyl group less electrophilic. Comparing electrostatic potential maps of formaldehyde and benzaldehyde, for example, shows that the carbonyl carbon atom is less positive (less blue) in the aromatic aldehyde. Problems

Science


Nucleophilic Addition of H 2 O: Hydration Aldehydes and ketones react with water to yield 1,1-diols, or geminal (gem) diols. The hydration reaction is reversible, and a gem diol can eliminate water to regenerate an aldehyde or ketone. The position of the equilibrium between a gem diol and an aldehyde or ketone depends on the structure of the carbonyl compound. Equilibrium generally favors the carbonyl compound for steric reasons, but the gem diol is favored for a few simple aldehydes. For example, an aqueous solution of formaldehyde consists of 99.9% gem diol and 0.1% aldehyde at equilibrium, whereas an aqueous solution of acetone consists of only about 0.1% gem diol and 99.9% ketone. The hydrate is also favored for α-keto carboxylic acids, which have adjacent positively charged carbons that destabilize the keto form and favor the hydrate. Such compounds occur commonly in many biological pathways. Pyruvic acid, which is 60% hydrate at equilibrium, and α-ketoglutaric acid, which is 50% hydrate, are examples. The nucleophilic addition of water to an aldehyde or ketone is slow under neutral conditions but is catalyzed by both base and acid. Under basic conditions ( a), the nucleophile is negatively charged (OH – ) and uses a pair of its electrons to form a bond to the electrophilic carbon atom of the C═O group. At the same time, the C═O carbon atom rehybridizes from sp 2 to sp 3 and two electrons from the C═O π bond are pushed onto the oxygen atom, giving an alkoxide ion. Protonation of the alkoxide ion by water then yields a neutral addition product plus regenerated OH – . Under acidic conditions ( b), the carbonyl oxygen atom is first protonated by H 3 O + to make the carbonyl group more strongly electrophilic. A neutral nucleophile, H 2 O, then uses a pair of electrons to bond to the carbon atom of the C═O group, and two electrons from the C═O π bond move onto the oxygen atom. The positive charge on oxygen is thereby neutralized, while the nucleophile gains a positive charge. Finally, deprotonation by water gives the neutral addition product and regenerates the H 3 O + catalyst. Note the key difference between the base-catalyzed and acid-catalyzed reactions. The base-catalyzed reaction takes place rapidly because water is converted into hydroxide ion, a much better nucleophile. The acid-catalyzed reaction takes place rapidly because the carbonyl compound is converted by protonation into a much better electrophile. MECHANISM The mechanism for a nucleophilic addition reaction of aldehydes and ketones under both basic and acidic conditions. (a) Under basic conditions, a negatively charged nucleophile adds to the carbonyl group to give an alkoxide ion intermediate, which is subsequently protonated. (b) Under acidic conditions, protonation of the carbonyl group occurs first, followed by addition of a neutral nucleophile and subsequent deprotonation. The hydration reaction just described is typical of what happens when an aldehyde or ketone is treated with a nucleophile of the type H–Y, where the Y atom is electronegative and can stabilize a negative charge (oxygen, halogen, or sulfur, for instance). In such reactions, the nucleophilic addition is reversible, with the equilibrium generally favoring the carbonyl reactant rather than the tetrahedral addition product. In other words, treatment of an aldehyde or ketone with CH 3 OH, H 2 O, HCl, HBr, or H 2 SO 4 does not normally lead to a stable alcohol addition product. Problems

Science


Nucleophilic Addition of HCN: Cyanohydrin Formation Aldehydes and unhindered ketones undergo a nucleophilic addition reaction with HCN to yield cyanohydrins , RCH(OH)C≡N . Studies carried out in the early 1900s by Arthur Lapworth showed that cyanohydrin formation is reversible and base-catalyzed. Reaction occurs slowly when pure HCN is used but rapidly when a small amount of base is added to generate the nucleophilic cyanide ion, CN – . Addition of CN – takes place by a typical nucleophilic addition pathway, yielding a tetrahedral intermediate that is protonated by HCN to give cyanohydrin product plus regenerated CN – . Cyanohydrin formation is somewhat unusual because it is one of the few examples of the addition of a protic acid (H–Y) to a carbonyl group. As noted in the previous section, protic acids such as H 2 O, HBr, HCl, and H 2 SO 4 don’t normally yield carbonyl addition products because the equilibrium constants are unfavorable. With HCN, however, equilibrium favors the cyanohydrin adduct. Cyanohydrin formation is useful because of the further chemistry that can be carried out on the product. For example, a nitrile ( R–C≡N ) can be reduced with LiAlH 4 to yield a primary amine (RCH 2 NH 2 ) and can be hydrolyzed by hot aqueous acid to yield a carboxylic acid. Thus, cyanohydrin formation provides a method for transforming an aldehyde or ketone into a different functional group. Problems

Science


Nucleophilic Addition of Hydride and Grignard Reagents: Alcohol Formation Addition of Hydride Reagents: Reduction We saw in that the most common method for preparing alcohols, both in the laboratory and in living organisms, is by the reduction of carbonyl compounds. Aldehydes are reduced with sodium borohydride (NaBH 4 ) to give primary alcohols, and ketones are reduced similarly to give secondary alcohols. Carbonyl reduction occurs by a typical nucleophilic addition mechanism under basic conditions, as shown earlier in a. Although the details of carbonyl-group reductions are complex, LiAlH 4 and NaBH 4 act as if they were donors of hydride ion nucleophile, : H – , and the initially formed alkoxide ion intermediate is then protonated by addition of aqueous acid. The reaction is effectively irreversible because the reverse process would require expulsion of a very poor leaving group. MECHANISM Mechanism of the Grignard reaction. Complexation of the carbonyl oxygen with the Lewis acid Mg 2+ and subsequent nucleophilic addition of a carbanion to an aldehyde or ketone is followed by protonation of the alkoxide intermediate to yield an alcohol. Addition of Grignard Reagents, RMgX Just as aldehydes and ketones undergo nucleophilic addition with hydride ion to give alcohols, they undergo a similar addition with Grignard reagent nucleophiles, R: – + MgX. Aldehydes give secondary alcohols on reaction with Grignard reagents in ether solution, and ketones give tertiary alcohols. As shown in , a Grignard reaction begins with an acid–base complexation of Mg 2+ to the carbonyl oxygen atom of the aldehyde or ketone, thereby making the carbonyl group a better electrophile. Nucleophilic addition of R : – then produces a tetrahedral magnesium alkoxide intermediate, and protonation by addition of water or dilute aqueous acid in a separate step yields the neutral alcohol. Like reduction, Grignard additions are effectively irreversible because a carbanion is too poor a leaving group to be expelled in a reversal step.

Science


Nucleophilic Addition of Amines: Imine and Enamine Formation Primary amines, RNH 2 , add to aldehydes and ketones to yield imines , R 2 C═NR . Secondary amines, R 2 NH, add similarly to yield enamines , R 2 N–CR ═ CR 2 ( ene + amine = unsaturated amine). Imines are particularly common as intermediates in biological pathways, where they are often called Schiff bases . The amino acid alanine, for instance, is metabolized in the body by reaction with the aldehyde pyridoxal phosphate (PLP), a derivative of vitamin B 6 , to yield a Schiff base that is further degraded. Imine formation and enamine formation seem different because one leads to a product with a C═N bond and the other leads to a product with a C═C bond. Actually, though, the reactions are quite similar. Both are typical examples of nucleophilic addition reactions in which water is eliminated from the initially formed tetrahedral intermediate and a new C═Nu double bond is formed. Imines are formed in a reversible, acid-catalyzed process ( ) that begins with nucleophilic addition of the primary amine to the carbonyl group, followed by transfer of a proton from nitrogen to oxygen to yield a neutral amino alcohol, or carbinolamine . Protonation of the carbinolamine oxygen by an acid catalyst then converts the –OH into a better leaving group (–OH 2 + ), and E1-like loss of water produces an iminium ion. Loss of a proton from nitrogen gives the final product and regenerates the acid catalyst. MECHANISM Mechanism of imine formation by reaction of an aldehyde or ketone with a primary amine. The key step is the initial nucleophilic addition to yield a carbinolamine intermediate, which then loses water to give the imine. Imine formation with such reagents as hydroxylamine and 2,4-dinitrophenylhydrazine is sometimes useful because the products of these reactions— oximes and 2,4-dinitrophenylhydrazones (2,4-DNPs), respectively—are often crystalline and easy to handle. Such crystalline derivatives are occasionally prepared as a means of purifying and characterizing liquid ketones or aldehydes. Reaction of an aldehyde or ketone with a secondary amine, R 2 NH, rather than a primary amine yields an enamine. As shown in , the process is identical to imine formation up to the iminium ion stage, but at this point there is no proton on nitrogen that can be lost to form a neutral imine product. Instead, a proton is lost from the neighboring carbon (the α carbon), yielding an enamine. MECHANISM Mechanism for enamine formation by reaction of an aldehyde or ketone with a secondary amine, R 2 NH. The iminium ion intermediate formed in step 3 has no hydrogen attached to N and so must lose H + from the carbon two atoms away. Imine and enamine formation are slow at both high pH and low pH but reach a maximum rate at a weakly acidic pH around 4 to 5. For example, the profile of pH versus rate shown in for the reaction between acetone and hydroxylamine, NH 2 OH, indicates that the maximum reaction rate occurs at pH 4.5. We can explain the observed pH dependence of imine formation by looking at the individual steps in the mechanism. As indicated in , an acid catalyst is required in step 3 to protonate the intermediate carbinolamine, thereby converting the –OH into a better leaving group. Thus, reaction will be slow if not enough acid is present (that is, at high pH). On the other hand, if too much acid is present (low pH), the basic amine nucleophile is completely protonated, so the initial nucleophilic addition step can’t occur. Dependence on pH of the rate of reaction between acetone and hydroxylamine: ( CH 3 ) 2 C═O + NH 2 OH → ( CH 3 ) 2 C═NOH + H 2 O . Evidently, a pH of 4.5 represents a compromise between the need for some acid to catalyze the rate-limiting dehydration step but not too much acid so as to avoid complete protonation of the amine. Each nucleophilic addition reaction has its own requirements, and conditions must be optimized to obtain maximum reaction rates. Predicting the Product of Reaction between a Ketone and an Amine Show the products you would obtain by acid-catalyzed reaction of 3-pentanone with methylamine, CH 3 NH 2 , and with dimethylamine, (CH 3 ) 2 NH. Strategy An aldehyde or ketone reacts with a primary amine, RNH 2 , to yield an imine, in which the carbonyl oxygen atom has been replaced by the =N–R group of the amine. Reaction of the same aldehyde or ketone with a secondary amine, R 2 NH, yields an enamine, in which the oxygen atom has been replaced by the –NR 2 group of the amine and the double bond has moved to a position between the former carbonyl carbon and the neighboring carbon. Solution Problems

Science


Nucleophilic Addition of Hydrazine: The Wolff–Kishner Reaction A useful variant of the imine-forming reaction just discussed involves the treatment of an aldehyde or ketone with hydrazine, H 2 N–NH 2 , in the presence of KOH. Called the Wolff–Kishner reaction , the process is a useful and general method for converting an aldehyde or ketone into an alkane, R 2 C=O → R 2 CH 2 . As shown in , the Wolff–Kishner reaction involves formation of a hydrazone intermediate, R 2 C═ N–NH 2 , followed by base-catalyzed double-bond migration, loss of N 2 gas to give a carbanion, and protonation to give the alkane product. The double-bond migration takes place when a base removes one of the weakly acidic NH protons in step 2 to generate a hydrazone anion, which has an allylic resonance structure that places the double bond between nitrogens and the negative charge on carbon. Reprotonation then occurs on carbon to generate the double-bond rearrangement product. The next step—loss of nitrogen and formation of an alkyl anion—is driven by the large thermodynamic stability of the N 2 molecule. MECHANISM Mechanism for the Wolff–Kishner reduction of an aldehyde or ketone to yield an alkane. Note that the Wolff–Kishner reduction accomplishes the same overall transformation as the catalytic hydrogenation of an acylbenzene to yield an alkylbenzene ( ). The Wolff–Kishner reduction is more general and more useful than catalytic hydrogenation, however, because it works well with both alkyl and aryl ketones. Problems

Science


Nucleophilic Addition of Alcohols: Acetal Formation Aldehydes and ketones react reversibly with 2 equivalents of an alcohol in the presence of an acid catalyst to yield acetals, R 2 C(OR′) 2 , which are often called ketals if derived from a ketone. Cyclohexanone, for instance, reacts with methanol in the presence of HCl to give the corresponding dimethyl acetal. Acetal formation is similar to the hydration reaction discussed in . Like water, alcohols are weak nucleophiles that add to aldehydes and ketones slowly under neutral conditions. Under acidic conditions, however, the reactivity of the carbonyl group is increased by protonation, so addition of an alcohol occurs rapidly. As shown in , nucleophilic addition of an alcohol to the carbonyl group initially yields a hydroxy ether called a hemiacetal , analogous to the gem diol formed by addition of water. Hemiacetals are formed reversibly, with equilibrium normally favoring the carbonyl compound. In the presence of acid, however, a further reaction occurs. Protonation of the –OH group, followed by an E1-like loss of water, leads to an oxonium ion, R 2 C═ O + R , which undergoes a second nucleophilic addition of alcohol to yield the protonated acetal. Loss of a proton completes the reaction. MECHANISM Mechanism of acid-catalyzed acetal formation by reaction of an aldehyde or ketone with an alcohol. Because all the steps in acetal formation are reversible, the reaction can be driven either forward (from carbonyl compound to acetal) or backward (from acetal to carbonyl compound), depending on the conditions. The forward reaction is favored by conditions that remove water from the medium and thus drive the equilibrium to the right. In practice, this is often done by distilling off water as it forms. The reverse reaction is favored by treating the acetal with a large excess of aqueous acid to drive the equilibrium to the left. Acetals are useful because they can act as protecting groups for aldehydes and ketones in the same way that trimethylsilyl ethers act as protecting groups for alcohols ( ). As we saw previously, it sometimes happens that one functional group interferes with intended chemistry elsewhere in a complex molecule. For example, if we wanted to reduce only the ester group of ethyl 4-oxopentanoate, the ketone would interfere. Treatment of the starting keto ester with LiAlH 4 would reduce both the keto group and the ester group to give a diol product. By protecting the keto group as an acetal, however, the problem can be circumvented. Like other ethers, acetals are unreactive to bases, hydride reducing agents, Grignard reagents, and catalytic hydrogenation conditions, but they are cleaved by acid. Thus, we can accomplish the selective reduction of the ester group in ethyl 4-oxopentanoate by first converting the keto group to an acetal, then reducing the ester with LiAlH 4 , and then removing the acetal by treatment with aqueous acid. (In practice, it’s often convenient to use 1 equivalent of a diol such as ethylene glycol as the alcohol to form a cyclic acetal. The mechanism of cyclic acetal formation using 1 equivalent of ethylene glycol is exactly the same as that using 2 equivalents of methanol or other monoalcohols.) Acetal and hemiacetal groups are particularly common in carbohydrate chemistry. Glucose, for instance, is a polyhydroxy aldehyde that undergoes an internal nucleophilic addition reaction and exists primarily as a cyclic hemiacetal. Predicting the Product of Reaction between a Ketone and an Alcohol Show the structure of the acetal you would obtain by acid-catalyzed reaction of 2-pentanone with 1,3-propanediol. Strategy Acid-catalyzed reaction of an aldehyde or ketone with 2 equivalents of a monoalcohol or 1 equivalent of a diol yields an acetal, in which the carbonyl oxygen atom is replaced by two –OR groups from the alcohol. Solution Problems

Science


Nucleophilic Addition of Phosphorus Ylides: The Wittig Reaction Aldehydes and ketones are converted into alkenes by means of a nucleophilic addition called the Wittig reaction , after the German chemist Georg Wittig who won the 1979 Nobel Prize in Chemistry. The reaction has no direct biological counterpart but is important both because of its wide use in drug manufacture and because of its mechanistic similarity to reactions of the coenzyme thiamin diphosphate, which we’ll see in Section 29.6 . In the Wittig reaction, a triphenylphosphorus ylide, R 2 C − – P + Ph 3 also called a phosphorane and sometimes written in the resonance form R 2 C═ P(Ph) 3 , adds to an aldehyde or ketone to yield a four-membered cyclic intermediate called an oxaphosphetane. The oxaphosphetane is not isolated, but instead spontaneously decomposes to give an alkene plus triphenylphosphine oxide, O═ PPh 3 . In effect, the oxygen atom of the aldehyde or ketone and the R 2 C= bonded to phosphorus exchange places. (An ylide —pronounced ill -id—is a neutral, dipolar compound with adjacent positive and negative charges.) The initial addition takes place by different pathways depending on the structure of the reactants and the exact experimental conditions. One pathway involves a one-step cycloaddition process analogous to the Diels–Alder cycloaddition reaction ( ). The other pathway involves a nucleophilic addition reaction to give a dipolar intermediate called a betaine ( bay -ta-een), which undergoes ring closure. The phosphorus ylides necessary for Wittig reaction are easily prepared by S N 2 reaction of primary (and some secondary) alkyl halides with triphenylphosphine, (Ph) 3 P, followed by treatment with base. Triphenylphosphine is a good nucleophile in S N 2 reactions, and yields of the resultant alkyltriphenylphosphonium salts are high. Because of the positive charge on phosphorus, the hydrogen on the neighboring carbon is weakly acidic and can be removed by a strong base such as butyllithium (BuLi) to generate the neutral ylide. For example: The Wittig reaction is extremely general, and a great many monosubstituted, disubstituted, and trisubstituted alkenes can be prepared from the appropriate combination of phosphorane and aldehyde or ketone. Tetrasubstituted alkenes, however, can’t be prepared this way because of steric hindrance. The real value of the Wittig reaction is that it yields a pure alkene of predictable structure. The C═C bond in the product is always exactly where the C═O group was in the reactant, and no alkene isomers (except E , Z isomers) are formed. For example, Wittig reaction of cyclohexanone with methylenetriphenylphosphorane yields only the single alkene product methylenecyclohexane. By contrast, addition of methylmagnesium bromide to cyclohexanone, followed by dehydration with POCl 3 , yields a roughly 9 : 1 mixture of two alkenes. Wittig reactions are used commercially in the synthesis of numerous pharmaceutical products. For example, the German chemical company BASF prepares vitamin A by using a Wittig reaction between a 15-carbon ylide and a 5-carbon aldehyde. Synthesizing an Alkene Using a Wittig Reaction What carbonyl compound and what phosphorus ylide might you use to prepare 3-ethyl-2-pentene? Strategy An aldehyde or ketone reacts with a phosphorus ylide to yield an alkene in which the oxygen atom of the carbonyl reactant is replaced by the ═CR 2 of the ylide. Preparation of the phosphorus ylide itself usually involves S N 2 reaction of a primary alkyl halide with triphenylphosphine, so the ylide is typically primary, RCH═ P(Ph) 3 . This means that the disubstituted alkene carbon in the product comes from the carbonyl reactant, while the monosubstituted alkene carbon comes from the ylide. Solution Problems

Science


Biological Reductions As a general rule, nucleophilic addition reactions are characteristic only of aldehydes and ketones, not of carboxylic acid derivatives. The reason for the difference is structural. As discussed previously in the Preview of Carbonyl Chemistry , and shown in , the tetrahedral intermediate produced by addition of a nucleophile to a carboxylic acid derivative can eliminate a leaving group, leading to a net nucleophilic acyl substitution reaction. The tetrahedral intermediate produced by addition of a nucleophile to an aldehyde or ketone, however, has only alkyl or hydrogen substituents and thus can’t usually expel a leaving group. One exception to this rule is the Cannizzaro reaction , discovered in 1853. Carboxylic acid derivatives have an electronegative substituent Y = –Br, –Cl, –OR, –NR 2 that can be expelled as a leaving group from the tetrahedral intermediate formed by nucleophilic addition. Aldehydes and ketones have no such leaving group and thus do not usually undergo this reaction. The Cannizzaro reaction takes place by nucleophilic addition of OH – to an aldehyde to give a tetrahedral intermediate, which expels hydride ion as a leaving group and is thereby oxidized. A second aldehyde molecule accepts the hydride ion in another nucleophilic addition step and is thereby reduced. Benzaldehyde, for instance, yields benzyl alcohol plus benzoic acid when heated with aqueous NaOH. The Cannizzaro reaction is rarely used today but is interesting mechanistically because it is a simple laboratory analogy for the primary biological pathway by which carbonyl reductions occur in living organisms. In nature, as we saw in , one of the most important reducing agents is NADH, reduced nicotinamide adenine dinucleotide. NADH donates H – to aldehydes and ketones, thereby reducing them, in much the same way that the tetrahedral alkoxide intermediate in a Cannizzaro reaction does. The electron lone pair on a nitrogen atom of NADH expels H – as leaving group, which adds to a carbonyl group in another molecule ( ). As an example, pyruvate is converted during intense muscle activity to ( S )-lactate, a reaction catalyzed by lactate dehydrogenase. Mechanism of biological aldehyde and ketone reductions by the coenzyme NADH. The key step is an expulsion of hydride ion from NADH and donation to the carbonyl group. Problems

Science


Conjugate Nucleophilic Addition to α , β ‑Unsaturated Aldehydes and Ketones All the reactions we’ve been discussing to this point have involved the addition of a nucleophile directly to the carbonyl group, a so-called 1,2-addition . Closely related to this direct addition is the conjugate addition , or 1,4-addition , of a nucleophile to the C═C bond of an α , β -unsaturated aldehyde or ketone. (The carbon atom next to a carbonyl group is often called the α carbon, the next carbon is the β carbon, and so on. Thus, an α , β -unsaturated aldehyde or ketone has a double bond conjugated with the carbonyl group.) The initial product of conjugate addition is a resonance-stabilized enolate ion , which typically undergoes protonation on the α carbon to give a saturated aldehyde or ketone product ( ). A comparison of direct (1,2) and conjugate (1,4) nucleophilic addition reactions. In conjugate addition, a nucleophile adds to the β carbon of an α , β -unsaturated aldehyde or ketone and protonation occurs on the α carbon. The conjugate addition of a nucleophile to an α , β -unsaturated aldehyde or ketone is caused by the same electronic factors that are responsible for direct addition. The electronegative oxygen atom of the α , β -unsaturated carbonyl compound withdraws electrons from the β carbon, thereby making it electron-poor and more electrophilic than a typical alkene carbon. As noted, conjugate addition of a nucleophile to the β carbon of an α , β -unsaturated aldehyde or ketone leads to an enolate ion intermediate, which is protonated on the α carbon to give the saturated product ( ). The net effect is addition of the nucleophile to the C═C bond, with the carbonyl group itself unchanged. In fact, of course, the carbonyl group is crucial to the success of the reaction. Without the carbonyl group, the C═C bond would not be activated for addition, and no reaction would occur. Conjugate Addition of Amines Both primary and secondary amines add to α , β -unsaturated aldehydes and ketones to yield β -amino aldehydes and ketones rather than the alternative imines. Under typical reaction conditions, both modes of addition occur rapidly. But because the reactions are reversible, they generally proceed with thermodynamic control rather than kinetic control ( ), so the more stable conjugate addition product is often obtained with the complete exclusion of the less stable direct addition product. Conjugate Addition of Water Water can add reversibly to α , β -unsaturated aldehydes and ketones to yield β -hydroxy aldehydes and ketones, although the position of the equilibrium generally favors unsaturated reactant rather than saturated adduct. Related additions to α , β -unsaturated carboxylic acids occur in numerous biological pathways, such as the citric acid cycle of food metabolism in which cis -aconitate is converted into isocitrate by conjugate addition of water to a double bond. Problems Conjugate Addition of Alkyl Groups: Organocopper Reactions The conjugate addition of an alkyl or other organic group to an α , β -unsaturated ketone (but not aldehyde) is one of the more useful 1,4-addition reactions, just as direct addition of a Grignard reagent is one of the more useful 1,2-additions. Conjugate addition of an organic group is carried out by treating the α , β -unsaturated ketone with a lithium diorganocopper reagent, R 2 CuLi. As we saw in , lithium diorganocopper (Gilman) reagents are prepared by reaction between 1 equivalent of copper(I) iodide and 2 equivalents of an organolithium regent, RLi. The organolithium reagent, in turn, is formed by reaction of lithium metal with an organohalide in the same way that a Grignard reagent is prepared by reaction of magnesium metal with an organohalide. Primary, secondary, and even tertiary alkyl groups undergo the conjugate addition reaction, as do aryl and alkenyl groups. Alkynyl groups, however, react poorly in the conjugate addition process. Diorganocopper reagents are unique in their ability to give conjugate addition products. Other organometallic reagents, such as Grignard reagents and organolithiums, normally result in direct carbonyl addition on reaction with α , β -unsaturated ketones. The mechanism of this reaction is thought to involve conjugate nucleophilic addition of the diorganocopper anion, R 2 Cu – , to the unsaturated ketone to give a copper-containing intermediate. Transfer of an R group from copper to carbon, followed by elimination of a neutral organocopper species, RCu, gives the final product. Using a Conjugate Addition Reaction How might you use a conjugate addition reaction to prepare 2-methyl-3-propylcyclopentanone? Strategy A ketone with a substituent group in its β position might be prepared by a conjugate addition of that group to an α , β -unsaturated ketone. In the present instance, the target molecule has a propyl substituent on the β carbon and might therefore be prepared from 2-methyl-2-cyclopentenone by reaction with lithium dipropylcopper. Solution Problems

Conjugate Nucleophilic Addition toα,β‑Unsaturated Aldehydes and Ketones

Science


Spectroscopy of Aldehydes and Ketones Infrared Spectroscopy Aldehydes and ketones show a strong C═O bond absorption in the IR region from 1660 to 1770 cm –1 , as the spectra of benzaldehyde and cyclohexanone demonstrate ( ). In addition, aldehydes show two characteristic C–H absorptions between 2700–2760 and 2800–2860 cm –1 . These absorbances are important for distinguishing between aldehydes and ketones. The higher-frequency absorbance is sometimes obscured in cases where the compound has numerous saturated C–H groups, but the lower-frequency peak is almost always visible. Infrared spectra of (a) benzaldehyde and (b) cyclohexanone. The exact position of the C═O absorption is diagnostic of the nature of the carbonyl group. As the data in indicate, saturated aldehydes usually show carbonyl absorptions near 1730 cm –1 in the IR spectrum, but conjugation of the aldehyde to an aromatic ring or a double bond lowers the absorption by 25 cm –1 to near 1705 cm –1 . Saturated aliphatic ketones and cyclohexanones both absorb near 1715 cm –1 , and conjugation with a double bond or an aromatic ring again lowers the absorption by 30 cm –1 to 1685–1690 cm –1 . Angle strain in the carbonyl group, caused by reducing the ring size of cyclic ketones to four or five, raises the absorption position. Cyclohexanone has its C═O stretch absorbance at 1715 cm –1 while cyclopentanone’s carbonyl stretch is at 1750 cm –1 and cyclobutanone’s is at 1785 cm –1 . Infrared Absorptions of Some Aldehydes and Ketones Carbonyl type Example Absorption (cm –1 ) Saturated aldehyde CH 3 CHO 1730 Aromatic aldehyde PhCHO 1705 α , β -Unsaturated aldehyde H 2 C═CHCHO 1705 Saturated ketone CH 3 COCH 3 1715 Cyclohexanone 1715 Cyclopentanone 1750 Cyclobutanone 1785 Aromatic ketone PhCOCH 3 1690 α , β -Unsaturated ketone H 2 C═ CHCOCH 3 1685 The values given in are remarkably constant from one aldehyde or ketone to another. As a result, IR spectroscopy is a powerful tool for identifying the kind of a carbonyl group in a molecule of unknown structure. An unknown that shows an IR absorption at 1730 cm –1 is almost certainly an aldehyde rather than a ketone; an unknown that shows an IR absorption at 1750 cm –1 is almost certainly a cyclopentanone, and so on. Problems Nuclear Magnetic Resonance Spectroscopy Aldehyde protons (RC H O) absorb near 10 δ in the 1 H NMR spectrum and are very distinctive because no other absorptions occur in this region. The aldehyde proton shows spin–spin coupling with protons on the neighboring carbon, with coupling constant J ≈ 3 Hz. Acetaldehyde, for example, shows a quartet at 9.79 δ for the aldehyde proton, indicating that there are three protons neighboring the –CHO group ( ). 1 H NMR spectrum of acetaldehyde. The absorption of the aldehyde proton appears at 9.79 δ and is split into a quartet. Hydrogens on the carbon next to a carbonyl group are slightly deshielded and usually absorb near 2.0 to 2.3 δ . The acetaldehyde methyl group in , for instance, absorbs at 2.20 δ . Methyl ketones are particularly distinctive because they always show a sharp three-proton singlet near 2.1 δ . The carbonyl-group carbon atoms of aldehydes and ketones have characteristic 13 C NMR resonances in the range 190 to 215 δ . Since no other kinds of carbons absorb in this range, the presence of an NMR absorption near 200 δ is clear evidence for a carbonyl group. Saturated aldehyde or ketone carbons usually absorb in the region from 200 to 215 δ , while aromatic and α , β -unsaturated carbonyl carbons absorb in the 190 to 200 δ region. Mass Spectrometry As discussed in , aliphatic aldehydes and ketones that have hydrogens on their gamma ( γ ) carbon atoms undergo a characteristic mass spectral cleavage called the McLafferty rearrangement . A hydrogen atom is transferred from the γ carbon to the carbonyl oxygen, the bond between the α and β carbons is broken, and a neutral alkene fragment is produced. The charge remains with the oxygen-containing fragment. In addition to fragmentation by the McLafferty rearrangement, aldehydes and ketones also undergo cleavage of the bond between the carbonyl group and the α carbon, called an α cleavage . Alpha cleavage yields a neutral radical and a resonance-stabilized acyl cation. Fragment ions from both McLafferty rearrangement and α cleavage are visible in the mass spectrum of 5-methyl-2-hexanone shown in . McLafferty rearrangement with loss of 2-methylpropene yields a fragment with m/z = 58. Alpha cleavage occurs primarily at the more substituted side of the carbonyl group, leading to a [CH 3 CO] + fragment with m/z = 43. Mass spectrum and the related reactions of 5-methyl-2-hexanone. The peak at m / z = 58 is due to McLafferty rearrangement. The abundant peak at m / z = 43 is due to α cleavage at the more highly substituted side of the carbonyl group. Note that the peak due to the molecular ion is very small. Problems Enantioselective Synthesis Whenever a chiral product is formed by reaction between achiral reagents, the product is racemic; that is, both enantiomers of the product are formed in equal amounts. The epoxidation reaction of geraniol with m -chloroperoxybenzoic acid, for instance, gives a racemic mixture of (2 S ,3 S ) and (2 R ,3 R ) epoxides. Unfortunately, it’s usually the case that only one enantiomer of a given drug or other important substance has the desired biological properties. The other enantiomer might be inactive or even dangerous. Thus, much work is currently being done on developing enantioselective methods of synthesis, which yield only one of the two possible enantiomers. So important has enantioselective synthesis become that the 2001 Nobel Prize in Chemistry was awarded to three pioneers in the field: William S. Knowles of the Monsanto Co., K. Barry Sharpless of the Scripps Research Institute, and Ryoji Noyori of Nagoya University. Several approaches to enantioselective synthesis have been developed, but the most efficient are those that use chiral catalysts to temporarily hold a substrate molecule in an unsymmetrical environment—the same strategy that nature uses when catalyzing reactions with chiral enzymes. While in that unsymmetrical environment, the substrate may be more open to reaction on one side than on another, leading to an excess of one enantiomeric product over another. As an analogy, think about picking up a coffee mug in your right hand to take a drink. The mug by itself is achiral, but as soon as you pick it up by the handle, it becomes chiral. One side of the mug now faces toward you so you can drink from it, but the other side faces away. The two sides are different, with one side much more accessible to you than the other. A substance made from the tartaric acid found at the bottom of this wine vat catalyzes enantioselective reactions. (credit: “Pinot Noir fermentation in open vat” by Pipers Brook Vineyard Media/Flickr, CC BY 2.0) Among the thousands of enantioselective reactions now known, one of the most useful is the so-called Sharpless epoxidation, in which an allylic alcohol, such as geraniol, is treated with tert -butyl hydroperoxide, (CH 3 ) 3 C–OOH, in the presence of titanium tetraisopropoxide and diethyl tartrate (DET) as a chiral auxiliary reagent. When ( R,R ) tartrate is used, geraniol is converted into its 2 S ,3 S epoxide with 98% selectivity, whereas the use of ( S,S ) tartrate gives the 2 R ,3 R epoxide enantiomer. We say that the major product in each case is formed with an enantiomeric excess of 96%, meaning that 4% of the product is racemic (2% 2 S ,3 S plus 2% 2 R ,3 R ) and an extra 96% of a single enantiomer is formed. The mechanistic details by which the chiral catalyst works are a bit complex, although it appears that a chiral complex of two tartrate molecules with one titanium is involved. acetal, R 2 C(OR′) 2 acyl group 1,2-addition 1,4-addition aldehyde (RCHO) Cannizzaro reaction carbinolamine conjugate addition cyanohydrin enamine (R 2 N–CR═ CR 2 ) hemiacetal imine (R 2 C═NR) ketal ketone (R 2 CO) McLafferty rearrangement nucleophilic addition reaction phosphorane Schiff bases Wittig reaction Wolff–Kishner reaction ylide Summary Aldehydes and ketones are among the most important of all functional groups, both in the chemical industry and in biological pathways. In this chapter, we’ve looked at some of their typical reactions. Aldehydes are normally prepared in the laboratory by oxidation of primary alcohols or by partial reduction of esters. Ketones are similarly prepared by oxidation of secondary alcohols. The nucleophilic addition reaction is the most common general reaction type for aldehydes and ketones. Many different kinds of products can be prepared by nucleophilic additions. Aldehydes and ketones are reduced by NaBH 4 or LiAlH 4 to yield primary and secondary alcohols, respectively. Addition of Grignard reagents to aldehydes and ketones also gives alcohols (secondary and tertiary, respectively), and addition of HCN yields cyanohydrins . Primary amines add to carbonyl compounds yielding imines , or Schiff bases , and secondary amines yield enamines . Reaction of an aldehyde or ketone with hydrazine and base gives an alkane (the Wolff–Kishner reaction ). Alcohols add to carbonyl groups to yield acetals , which are valuable as protecting groups. Phosphorus ylides add to aldehydes and ketones in the Wittig reaction to give alkenes. α , β -Unsaturated aldehydes and ketones often react with nucleophiles to give the product of conjugate addition , or 1,4-addition . Particularly useful are the conjugate addition of an amine and the conjugate addition of an organic group by reaction with a diorganocopper reagent. IR spectroscopy is helpful for identifying aldehydes and ketones. Carbonyl groups absorb in the IR range 1660 to 1770 cm –1 , with the exact position highly diagnostic of the kind of carbonyl group present in the molecule. 13 C NMR spectroscopy is also useful for aldehydes and ketones because their carbonyl carbons show resonances in the 190 to 215 δ range. 1 H NMR is useful for aldehyde –CHO protons, which absorb near 10 δ . Aldehydes and ketones undergo two characteristic kinds of fragmentation in the mass spectrometer: α cleavage and McLafferty rearrangement. Summary of Reactions Preparation of aldehydes ( ) Oxidation of primary alcohols ( ) Partial reduction of esters ( ) Preparation of ketones Oxidation of secondary alcohols ( ) Diorganocopper reaction with acid chlorides ( ) Oxidation of aldehydes ( ) Nucleophilic addition reactions of aldehydes and ketones Addition of hydride to give alcohols: reduction ( ) Addition of Grignard reagents to give alcohols ( ) Addition of HCN to give cyanohydrins ( ) Addition of primary amines to give imines ( ) Addition of secondary amines to give enamines ( ) Wolff–Kishner reaction to give alkanes ( ) Addition of alcohols to give acetals ( ) Addition of phosphorus ylides to give alkenes: Wittig reaction ( ) Conjugate additions to α , β -unsaturated aldehydes and ketones ( ) Conjugate addition of amines Conjugate addition of water Conjugate addition of alkyl groups by diorganocopper reaction Additional Problems Visualizing Chemistry Mechanism Problems Naming Aldehydes and Ketones Reactions of Aldehydes and Ketones Spectroscopy General Problems

Science


Why This Chapter? The burning sensation produced by touching or eating chili peppers is due to capsaicin, a carboxylic acid derivative called an amide. (credit: modification of “Chillis” by Lucas Cobb/Flickr, CC BY 2.0) Carboxylic acids are present in many industrial processes and most biological pathways and are the starting materials from which other acyl derivatives are made. Thus, an understanding of their properties and reactions is fundamental to understanding organic chemistry. We’ll look both at acids and at their close relatives, nitriles ( RC≡N ), in this chapter and at carboxylic acid derivatives in the next chapter. Carboxylic acids, RCO 2 H , occupy a central place among carbonyl compounds. Not only are they valuable in themselves, they also serve as starting materials for preparing numerous carboxylic acid derivatives such as acid chlorides, esters, amides, and thioesters. In addition, carboxylic acids are present in the majority of biological pathways. A great many carboxylic acids are found in nature: acetic acid, CH 3 CO 2 H, is the chief organic component of vinegar; butanoic acid, CH 3 CH 2 CH 2 CO 2 H, is responsible for the rancid odor of sour butter; and hexanoic acid (caproic acid), CH 3 (CH 2 ) 4 CO 2 H, is responsible for the unmistakable aroma of goats and dirty gym socks (the name comes from the Latin caper, meaning “goat”). Other examples are cholic acid, a major component of human bile, and long-chain aliphatic acids such as palmitic acid, CH 3 (CH 2 ) 14 CO 2 H, a biological precursor of fats and vegetable oils. Approximately 20 million tons of acetic acid is produced worldwide each year for a variety of purposes, including preparation of the vinyl acetate polymer used in paints and adhesives. About 20% of the acetic acid synthesized industrially is obtained by oxidation of acetaldehyde. Much of the remaining 80% is prepared by the rhodium-catalyzed reaction of methanol with carbon monoxide.

Science


Naming Carboxylic Acids and Nitriles Carboxylic Acids, RCO 2 H Simple carboxylic acids derived from open-chain alkanes are systematically named by replacing the terminal – e of the corresponding alkane name with - oic acid. The –CO 2 H carbon atom is numbered C1. Compounds that have a –CO 2 H group bonded to a ring are named using the suffix - carboxylic acid . The CO 2 H carbon is attached to C1 in this system and is not itself numbered. As a substituent, the CO 2 H group is called a carboxyl group . Because many carboxylic acids were among the first organic compounds to be isolated and purified, quite a few common names exist ( ). Biological chemists, in particular, make frequent use of these names, so you may find yourself referring back to this list on occasion. We’ll use systematic names in this book, with a few exceptions such as formic (methanoic) acid and acetic (ethanoic) acid, whose names are accepted by IUPAC and are so well known that it makes little sense to refer to them any other way. Also listed in are the names of acyl groups derived from the parent acids. Except for the eight entries at the top of , whose names have a - yl ending, all other acyl groups are named using an - oyl ending. Common Names of Some Carboxylic Acids and Acyl Groups Structure Name Acyl group HCO 2 H Formic Formyl CH 3 CO 2 H Acetic Acetyl CH 3 CH 2 CO 2 H Propionic Propionyl CH 3 CH 2 CH 2 CO 2 H Butyric Butyryl HO 2 CCO 2 H Oxalic Oxalyl HO 2 CCH 2 CO 2 H Malonic Malonyl HO 2 CCH 2 CH 2 CO 2 H Succinic Succinyl HO 2 CCH 2 CH 2 CH 2 CO 2 H Glutaric Glutaryl HO 2 CCH 2 CH 2 CH 2 CH 2 CO 2 H Adipic Adipoyl H 2 C═CHCO 2 H Acrylic Acryloyl HO 2 CCH═CHCO 2 H Maleic (cis) Fumaric (trans) Maleoyl Fumaroyl HOCH 2 CO 2 H Glycolic Glycoloyl Lactic Lactoyl Pyruvic Pyruvoyl Glyceric Glyceroyl Malic Maloyl Oxaloacetic Oxaloacetyl Benzoic Benzoyl Phthalic Phthaloyl Nitriles, RC≡N Compounds containing the –C≡N functional group are called nitriles and can undergo some chemistry similar to that of carboxylic acids. Simple open-chain nitriles are named by adding - nitrile as a suffix to the alkane name, with the nitrile carbon numbered C1. Nitriles can also be named as derivatives of carboxylic acids by replacing the - ic acid or - oic acid ending with - onitrile, or by replacing the - carboxylic acid ending with - carbonitrile. The nitrile carbon atom is attached to C1 but is not itself numbered. If another carboxylic acid derivative is present in the same molecule, the prefix cyano - is used for the C≡N group. Problems

Science


Structure and Properties of Carboxylic Acids Carboxylic acids are similar in some respects to both ketones and alcohols. Like ketones, the carboxyl carbon is sp 2 -hybridized, and carboxylic acid groups are therefore planar with C–C═O and O═C–O bond angles of approximately 120° ( ). Physical Parameters for Acetic Acid Bond angle (degrees) Bond length (pm) C–C═O 119 C–C 152 C–C–OH 119 C═O 125 O═C–OH 122 C–OH 131 Like alcohols, carboxylic acids are strongly associated because of hydrogen-bonding. Most carboxylic acids exist as cyclic dimers held together by two hydrogen bonds. This strong hydrogen-bonding has a noticeable effect on boiling points, making carboxylic acids boil far less easily than their corresponding alcohols. Acetic acid, for instance, has a boiling point of 117.9 °C, versus 78.3 °C for ethanol, even though both compounds have two carbons. The most obvious property of carboxylic acids is implied by their name: carboxylic acids are acidic. They therefore react with bases such as NaOH and NaHCO 3 to give metal carboxylate salts, RCO 2 − M + . Carboxylic acids with more than six carbons are only slightly soluble in water, but the alkali metal salts of carboxylic acids are often highly water-soluble. In fact, it’s often possible to purify an acid by extracting its salt into aqueous base, then reacidifying and extracting the pure acid back into an organic solvent. Like other Brønsted–Lowry acids discussed in , carboxylic acids dissociate slightly in dilute aqueous solution to give H 3 O + and the corresponding carboxylate anions, RCO 2 – . The extent of dissociation is given by an acidity constant, K a . A list of K a values for various carboxylic acids is given in . For most, K a is approximately 10 –4 to 10 –5 . Acetic acid, for instance, has K a = 1.75 × 10 –5 at 25 °C, which corresponds to a p K a of 4.76. In practical terms, a K a value near 10 –5 means that only about 0.1% of the molecules in a 0.1 M solution are dissociated, as opposed to the 100% dissociation found with strong mineral acids like HCl. Acidity of Some Carboxylic Acids Structure K a p K a CF 3 CO 2 H 0.59 0.23 HCO 2 H 1.77 × 10 –4 3.75 HOCH 2 CO 2 H 1.5 × 10 –4 3.84 C 6 H 5 CO 2 H 6.46 × 10 –5 4.19 H 2 C═ CHCO 2 H 5.6 × 10 –5 4.25 CH 3 CO 2 H 1.75 × 10 –5 4.76 CH 3 CH 2 CO 2 H 1.34 × 10 –5 4.87 CH 3 CH 2 OH (ethanol) (1 × 10 –16 ) (16) Although much weaker than mineral acids, carboxylic acids are nevertheless much stronger acids than alcohols and phenols. The K a of ethanol, for example, is approximately 10 –16 , making it a weaker acid than acetic acid by a factor of 10 11 . Why are carboxylic acids so much more acidic than alcohols, even though both contain –OH groups? An alcohol dissociates to give an alkoxide ion, in which the negative charge is localized on a single electronegative atom. A carboxylic acid, however, gives a carboxylate ion, in which the negative charge is delocalized over two equivalent oxygen atoms ( ). In resonance terms ( ), a carboxylate ion is a stabilized resonance hybrid of two equivalent structures. Since a carboxylate ion is more stable than an alkoxide ion, it is lower in energy and more favored in the dissociation equilibrium. An alkoxide ion has its charge localized on one oxygen atom and is less stable, while a carboxylate ion has the charge spread equally over both oxygens and is therefore more stable. Experimental evidence for the equivalence of the two carboxylate oxygens comes from X-ray crystallographic studies on sodium formate. Both carbon–oxygen bonds are 127 pm in length, midway between the C═O double bond (120 pm) and the C–O single bond (134 pm) of formic acid. An electrostatic potential map of the formate ion also shows how the negative charge (red) is spread equally over both oxygens. Problems

Science


Biological Acids and the Henderson–Hasselbalch Equation In acidic solution, at low pH, a carboxylic acid is completely undissociated and exists entirely as RCO 2 H. In basic solution, at high pH, a carboxylic acid is completely dissociated and exists entirely as RCO 2 – . Inside living cells, however, the pH is neither acidic nor basic but is instead buffered to a nearly neutral pH of 7.35–7.45. In what form, then, do carboxylic acids exist inside cells? The question is an important one for understanding the acid catalysts so often found in biological reactions. If the p K a value of a given acid and the pH of the medium are known, the percentages of dissociated and undissociated forms can be calculated using the Henderson–Hasselbalch equation . For any acid HA, we have p K a = − log [ H 3 O + ] [ A − ] [ HA ] = − log [ H 3 O + ] − log [ A − ] [ HA ] = pH − log [ A − ] [ HA ] which can be rearranged to give pH = p K a + log [ A − ] [ HA ] Henderson-Hasselbalch equation so log [ A − ] [ HA ] = pH − p K a This equation says that the logarithm of the concentration of dissociated acid [A – ] divided by the concentration of undissociated acid [HA] is equal to the pH of the solution minus the p K a of the acid. Thus, if we know both the pH of the solution and the p K a of the acid, we can calculate the ratio of [A – ] to [HA]. Furthermore, when pH = p K a , then HA and A – are present in equal amounts because log 1 = 0. As an example of how to use the Henderson–Hasselbalch equation, let’s find out what species are present in a 0.0010 M solution of acetic acid at pH = 7.3. According to Table 20-3, the p K a of acetic acid is 4.76. From the Henderson–Hasselbalch equation, we have log [ A − ] HA = pH − p K a = 7.3 − 4.76 = 2.54 [ A − ] HA = antilog ( 2.54 ) = 3.5 × 10 2 so [A − ] = ( 3.5 × 10 2 ) [ HA ] In addition, we know that [ A − ] + [ HA ] = 0.0010 M Solving the two simultaneous equations gives [A – ] = 0.0010 M and [HA] = 3 × 10 –6 M. In other words, at a physiological pH of 7.3, essentially 100% of acetic acid molecules in a 0.0010 M solution are dissociated to the acetate ion. What is true for acetic acid is also true for other carboxylic acids: At the physiological pH that occurs inside cells, carboxylic acids are almost entirely dissociated. To reflect this fact, we always refer to cellular carboxylic acids by the name of their anion—acetate, lactate, citrate, and so forth, rather than acetic acid, lactic acid, and citric acid. Problems

Science


Substituent Effects on Acidity The listing of p K a values shown previously in indicates that there are substantial differences in acidity from one carboxylic acid to another. For example, trifluoroacetic acid ( K a = 0.59) is 33,000 times as strong as acetic acid ( K a = 1.75 × 10 –5 ). How can we account for such differences? Because the dissociation of a carboxylic acid is an equilibrium process, any factor that stabilizes the carboxylate anion relative to undissociated carboxylic acid will drive the equilibrium toward increased dissociation and result in increased acidity. For instance, three electron-withdrawing fluorine atoms delocalize the negative charge in the trifluoroacetate anion, thereby stabilizing the ion and increasing the acidity of CF 3 CO 2 H. In the same way, glycolic acid (HOCH 2 CO 2 H; p K a = 3.83) is stronger than acetic acid because of the electron-withdrawing effect of the electronegative oxygen atom. Because inductive effects operate through σ bonds and are dependent on distance, the effect of halogen substitution decreases as the substituent moves farther from the carboxyl. Thus, 2-chlorobutanoic acid has p K a = 2.86, 3-chlorobutanoic acid has p K a = 4.05, and 4-chlorobutanoic acid has p K a = 4.52, similar to that of butanoic acid itself. Substituent effects on acidity are also found in substituted benzoic acids. We said during the discussion of electrophilic aromatic substitution in that substituents on the aromatic ring strongly affect reactivity. Aromatic rings with electron-donating groups are activated toward further electrophilic substitution, and aromatic rings with electron-withdrawing groups are deactivated. Exactly the same effects can be observed on the acidity of substituted benzoic acids ( ). Substituent Effects on the Acidity of p -Substituted Benzoic Acids Y K a × 10 –5 p K a –NO 2 39 3.41 Deactivating groups –CN 28 3.55 –CHO 18 3.75 –Br 11 3.96 –Cl 10 4.0 –H 6.46 4.19 –CH 3 4.3 4.34 Activating groups –OCH 3 3.5 4.46 –OH 3.3 4.48 As shows, an electron-donating (activating) group such as methoxy decreases acidity by destabilizing the carboxylate anion, and an electron-withdrawing (deactivating) group such as nitro increases acidity by stabilizing the carboxylate anion. Because it’s much easier to measure the acidity of a substituted benzoic acid than it is to determine the relative reactivity of an aromatic ring toward electrophilic substitution, the correlation between the two effects is useful for predicting reactivity. If we want to know the effect of a certain substituent on electrophilic reactivity, we can simply find the acidity of the corresponding benzoic acid. Worked Example 20.1 gives an illustration. Predicting the Effect of a Substituent on the Reactivity of an Aromatic Ring toward Electrophilic Substitution The p K a of p -(trifluoromethyl)benzoic acid is 3.6. Is the trifluoromethyl substituent an activating or deactivating group in electrophilic aromatic substitution? Strategy Decide whether p -(trifluoromethyl)benzoic acid is stronger or weaker than benzoic acid. A substituent that strengthens the acid is a deactivating group because it withdraws electrons, and a substituent that weakens the acid is an activating group because it donates electrons. Solution A p K a of 3.6 means that p -(trifluoromethyl)benzoic acid is stronger than benzoic acid, whose p K a is 4.19. Thus, the trifluoromethyl substituent favors dissociation by helping stabilize the negative charge. Trifluoromethyl must therefore be an electron-withdrawing, deactivating group. Problems

Science


Preparing Carboxylic Acids Let’s review briefly some of the methods for preparing carboxylic acids that we’ve seen in previous chapters. Oxidation of a substituted alkylbenzene with KMnO 4 gives a substituted benzoic acid ( ). Both primary and secondary alkyl groups can be oxidized, but tertiary groups are not affected. Oxidation of a primary alcohol or an aldehyde yields a carboxylic acid ( and ). Primary alcohols are often oxidized with KMnO 4 , and aldehydes are similarly oxidized with alkaline KMnO 4 . Hydrolysis of Nitriles Carboxylic acids can be prepared from nitriles on heating with aqueous acid or base by a mechanism that we’ll discuss in Section 20.7. Since nitriles themselves are usually made by S N 2 reaction of a primary or secondary alkyl halide with CN – , the two-step sequence of cyanide displacement followed by nitrile hydrolysis is a good way to make a carboxylic acid from an alkyl halide ( RBr → RC≡N → RCO 2 H ). Note that the product acid has one more carbon than the starting alkyl halide. One example occurs in a commercial route for the synthesis of the nonsteroidal anti-inflammatory drug ibuprofen. (See Chapter 15 Chemistry Matters .) Carboxylation of Grignard Reagents Another method for preparing carboxylic acids is by reaction of a Grignard reagent with CO 2 to yield a metal carboxylate, followed by protonation to give a carboxylic acid. This carboxylation reaction is usually carried out by bubbling a stream of dry CO 2 gas through a solution of the Grignard reagent. The organomagnesium halide adds to a C═O bond of carbon dioxide in a typical nucleophilic carbonyl addition reaction, and protonation of the carboxylate by addition of aqueous HCl in a separate step then gives the free carboxylic acid. For example: As noted previously, there are no Grignard reagents inside living cells, but there are other types of stabilized carbanions that are often carboxylated. One of the initial steps in fatty-acid biosynthesis, for instance, involves the formation of a carbanion from acetyl CoA, followed by carboxylation to yield malonyl CoA. Devising a Synthesis Route for a Carboxylic Acid How would you prepare phenylacetic acid (PhCH 2 CO 2 H) from benzyl bromide (PhCH 2 Br)? Strategy We’ve seen two methods for preparing carboxylic acids from alkyl halides: (1) cyanide ion displacement followed by hydrolysis and (2) formation of a Grignard reagent followed by carboxylation. The first method involves an S N 2 reaction and is therefore limited to use with primary and some secondary alkyl halides. The second method involves formation of a Grignard reagent and is therefore limited to use with organic halides that have no acidic hydrogens or reactive functional groups elsewhere in the molecule. In the present instance, either method would work well. Solution Problems

Science


Reactions of Carboxylic Acids: An Overview We commented earlier in this chapter that carboxylic acids are similar in some respects to both alcohols and ketones. Like alcohols, carboxylic acids can be deprotonated to give anions, which are good nucleophiles in S N 2 reactions. Like ketones, carboxylic acids undergo addition of nucleophiles to the carbonyl group. However, carboxylic acids also undergo other reactions characteristic of neither alcohols nor ketones. shows some of the general reactions of carboxylic acids. Some general reactions of carboxylic acids. Reactions of carboxylic acids can be grouped into the four categories indicated in . Of the four, we’ve already discussed the acidic behavior of carboxylic acids in through , and we mentioned reduction by treatment with LiAlH 4 in . The remaining two categories are examples of fundamental carbonyl-group reaction mechanisms—nucleophilic acyl substitution and α substitution—that will be discussed in detail in Chapters 21 and 22. Problems

Science


Chemistry of Nitriles Nitriles are analogous to carboxylic acids in that both have a carbon atom with three bonds to an electronegative atom and both contain a π bond. Thus, some reactions of nitriles and carboxylic acids are similar. Both kinds of compounds are electrophiles, for instance, and both undergo nucleophilic addition reactions. Nitriles occur infrequently in living organisms, although several hundred examples are known. Cyanocycline A, for instance, has been isolated from the bacterium Streptomyces lavendulae and was found to have both antimicrobial and antitumor activity. In addition, more than 1000 compounds called cyanogenic glycosides are known. Derived primarily from plants, cyanogenic glycosides contain a sugar with an acetal carbon, one oxygen of which is bonded to a nitrile-bearing carbon (sugar–O–C–CN). On hydrolysis with aqueous acid, the acetal is cleaved ( ), generating a cyanohydrin (HO–C–CN), which releases hydrogen cyanide. It’s thought that the primary function of cyanogenic glycosides is to protect the plant by poisoning any animal foolish enough to eat it. Lotaustralin from the cassava plant is an example. Preparation of Nitriles The simplest method of nitrile preparation is the S N 2 reaction of CN – with a primary or secondary alkyl halide, as discussed in . Another method for preparing nitriles is by dehydration of a primary amide, RCONH 2 . Thionyl chloride is often used for this reaction, although other dehydrating agents such as POCl 3 also work. The dehydration occurs by initial reaction of SOCl 2 on the nucleophilic amide oxygen atom, followed by deprotonation and a subsequent E2-like elimination reaction. Both methods of nitrile synthesis—S N 2 displacement by CN – on an alkyl halide and amide dehydration—are useful, but the synthesis from amides is more general because it is not limited by steric hindrance. Reactions of Nitriles Like a carbonyl group, a nitrile group is strongly polarized and has an electrophilic carbon atom. Nitriles therefore react with nucleophiles to yield sp 2 -hybridized imine anions in a reaction analogous to the formation of a sp 3 -hybridized alkoxide ion by nucleophilic addition to a carbonyl group. Some general reactions of nitriles are shown in . Some reactions of nitriles. Hydrolysis: Conversion of Nitriles into Carboxylic Acids Among the most useful reactions of nitriles is their hydrolysis to yield first an amide and then a carboxylic acid plus ammonia or an amine. The reaction occurs in either basic or acidic aqueous solution: As shown in , base-catalyzed nitrile hydrolysis involves nucleophilic addition of hydroxide ion to the polar C≡N bond to give an imine anion in a process similar to the nucleophilic addition to a polar C═O bond to give an alkoxide anion. Protonation then gives a hydroxy imine, which tautomerizes ( ) to an amide in a step similar to the tautomerization of an enol to a ketone. Further hydrolysis gives a carboxylate ion. MECHANISM Mechanism for the basic hydrolysis of a nitrile to yield an amide, which is then hydrolyzed further to a carboxylic acid anion. The further hydrolysis of the amide intermediate takes place by a nucleophilic addition of hydroxide ion to the amide carbonyl group, which yields a tetrahedral alkoxide ion. Expulsion of amide ion, NH 2 − , as leaving group gives the carboxylate ion, thereby driving the reaction toward the products. Subsequent acidification in a separate step yields the carboxylic acid. We’ll look at this process in more detail in Section 21.7 . Reduction: Conversion of Nitriles into Amines Reduction of a nitrile with LiAlH 4 gives a primary amine, RNH 2 . The reaction occurs by nucleophilic addition of hydride ion to the polar C≡N bond, yielding an imine anion, which still contains a C═N bond and therefore undergoes a second nucleophilic addition of hydride to give a dianion . Both monoanion and dianion intermediates are undoubtedly stabilized by Lewis acid–base complexation to an aluminum species, facilitating the second addition that would otherwise be difficult. Protonation of the dianion by addition of water in a subsequent step gives the amine. Reaction of Nitriles with Grignard Reagents Grignard reagents add to a nitrile to give an intermediate imine anion that is hydrolyzed by addition of water to yield a ketone. The mechanism of the hydrolysis is the exact reverse of imine formation (see ). This reaction is similar to the reduction of a nitrile to an amine, except that only one nucleophilic addition occurs rather than two and the attacking nucleophile is a carbanion (R : – ) rather than a hydride ion. For example: Synthesizing a Ketone from a Nitrile How would you prepare 2-methyl-3-pentanone from a nitrile? Strategy A ketone results from the reaction between a Grignard reagent and a nitrile, with the C≡N carbon of the nitrile becoming the carbonyl carbon. Identify the two groups attached to the carbonyl carbon atom in the product. One will come from the Grignard reagent and the other will come from the nitrile. Solution There are two possibilities. Problems

Science