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(BQ) Part 2 book Organic chemistry as a second language has contents: Ketones and aldehydes, carboxylic acid derivatives, enols and enolates, amines, nucleophilicity and basicity of amines. (BQ) Part 2 book Organic chemistry as a second language has contents: Ketones and aldehydes, carboxylic acid derivatives, enols and enolates, amines, nucleophilicity and basicity of amines.
CHAPTER KETONES AND ALDEHYDES 5.1 PREPARATION OF KETONES AND ALDEHYDES Before we can explore the reactions of ketones and aldehydes, we must first make sure that we know how to make ketones and aldehydes That information will be vital for solving synthesis problems Ketones and aldehydes can be made in many ways, as you will see in your textbook In this book, we will only see a few of these methods These few reactions should be sufficient to help you solve many synthesis problems in which a ketone or aldehyde must be prepared The most useful type of transformation is forming a C¨ O bond from an alcohol Primary alcohols can be oxidized to form aldehydes: OH O R H R And secondary alcohols can be oxidized to form ketones: OH R O R R R Tertiary alcohols cannot be oxidized, because carbon cannot form five bonds: OH O Carbon NEVER has bonds So, we need to be familiar with the reagents that will oxidize primary and secondary alcohols (to form aldehydes or ketones, respectively) Let’s start with secondary alcohols A secondary alcohol can be converted into a ketone upon treatment with sodium dichromate and sulfuric acid: OH R O Na2Cr2O7 H2SO4, H2O R R R Alternatively, the Jones reagent can be used, which is formed from CrO3 in aqueous acetone: OH R O CrO3 R aqueous acetone heat R R 129 130 CHAPTER KETONES AND ALDEHYDES Whether you use sodium dichromate or the Jones reagent, you are essentially performing an oxidation that involves a chromium oxidizing agent (the alcohol is being oxidized and the chromium reagent is being reduced) You should look through your lecture notes and textbook to see if you are responsible for the mechanisms of these oxidation reactions Whatever the case, you should definitely have these reagents at your fingertips, because you will encounter many synthesis problems that require the conversion of an alcohol into a ketone or aldehyde Chromium oxidations work well for secondary alcohols, but we run into a problem when we try to perform a chromium oxidation on a primary alcohol The initial product is indeed an aldehyde: OH O oxidation R H R But under these strong oxidizing conditions, the aldehyde does not survive The aldehyde is further oxidized to give a carboxylic acid: O O oxidation H R OH R So clearly, we need a way to oxidize a primary alcohol into an aldehyde, under conditions that will not further oxidize the aldehyde This can be accomplished with a reagent called pyridinium chlorochromate (or PCC): CrO3Cl N H pyridinium chlorochromate (PCC) This reagent provides milder oxidizing conditions, and therefore, the reaction stops at the aldehyde That is, PCC will oxidize a primary alcohol to give an aldehyde: OH O PCC R H R There is another common way to form a C¨ O bond (other than oxidation of an alcohol) You might remember the following reaction from last semester: R R R R 1) O3 2) DMS R R O O R R This reaction is called ozonolysis It essentially takes every C¨C bond in the compound, and breaks it apart into two C¨ O bonds: H O O H 1) O3 O 2) DMS O 5.1 PREPARATION OF KETONES AND ALDEHYDES 131 There are many reagents that can be used for the second step of this process (other than DMS) You should look in your lecture notes to see what reagents your instructor (or textbook) used for step of an ozonolysis So far, this section has covered only a few ways to make a C¨O bond We saw that ketones can be made by treating a secondary alcohol with sodium dichromate (or the Jones reagent), and aldehydes can be made by treating a primary alcohol with PCC We also saw that ketones and aldehydes can be made via ozonolysis Let’s get some practice with these reactions EXERCISE 5.1 Predict the major product of the following reaction: OH PCC Answer The oxidizing agent in this case is PCC, and we have seen that PCC will convert a primary alcohol into an aldehyde: O OH PROBLEMS 2) DMS OH CrO3 5.3 Aqueous acetone heat Na2Cr2O7 5.4 H2SO4, H2O OH 1) O3 5.5 2) DMS OH Na2Cr2O7 H2SO4, H2O 5.6 OH 5.7 H Predict the major product for each of the following reactions: 1) O3 5.2 PCC PCC 132 CHAPTER KETONES AND ALDEHYDES It is not enough to simply “recognize” the reagents when you see them (like we did in the previous problems) But you actually need to know the reagents well enough to write them down when they are not in front of you Let’s get some practice: EXERCISE 5.8 Identify the reagents you would use to achieve the following transformation: OH O Answer In this case, a secondary alcohol must be converted into a ketone So, we don’t need to use PCC We would only need PCC if we were trying to convert a primary alcohol into an aldehyde In this case, PCC is unnecessary Instead, we would use either sodium dichromate and sulfuric acid or the Jones reagent: Na2Cr2O7 H2SO4, H2O OH O CrO3 aqueous acetone heat PROBLEMS Identify the reagents you would use to achieve each of the following transformations Try not to look back at the previous problems while you are working on these problems O OH 5.9 H OH OH 5.10 O O 5.11 OH 5.12 O 5.2 STABILITY AND REACTIVITY OF C¨ O BONDS 133 5.2 STABILITY AND REACTIVITY OF C¨ O BONDS Ketones and aldehydes are very similar to each other in structure: O R O R R ketone H aldehyde Therefore, they are also very similar to each other in terms of reactivity Most of the reactions that we see in this chapter will work for both ketones and aldehydes So, it makes sense to learn about ketones and aldehydes in the same breath But before we can get started, we need to know some basics about C¨ O bonds Let’s start with a bit of terminology that we will use throughout the entire chapter Instead of constantly using the expression “C¨O double bond,” we will call it a carbonyl group This term is NOT used for nomenclature You will never see the term “carbonyl” appearing in the IUPAC name of a compound Rather, it is just a term that we use when we are talking about mechanisms, so that we can quickly refer to the C¨O bond without having to say “C¨ O double bond” all of the time Don’t confuse the term “carbonyl” with the term “acyl.” The term “acyl” is used to refer to a carbonyl group together with one alkyl group: carbonyl acyl O R O R R X We will use the term “acyl” in the next chapter But in this chapter, we will focus on the carbonyl group If we want to know how a carbonyl group will react, we must first consider electronic effects (the locations of ␦ϩ and ␦Ϫ) There are always two factors to explore: induction and resonance If we start with induction, we notice that oxygen is more electronegative than carbon, and therefore, the oxygen atom will withdraw electron density: O As a result, the carbon atom of the carbonyl group is ␦ϩ and the oxygen atom is ␦Ϫ Next, we look at resonance: O O And we see, once again, that the carbon atom is ␦ϩ and the oxygen atom is ␦Ϫ, this time because of resonance So, both induction and resonance paint the same picture: δ- O δ+ 134 CHAPTER KETONES AND ALDEHYDES This means that the carbon atom is very electrophilic, and the oxygen atom is very nucleophilic While there are many reactions involving the oxygen atom functioning as a nucleophile, you probably won’t see any of those reactions in your organic chemistry course Accordingly, we will focus all of our attention in this chapter on the carbon atom of a carbonyl group We will see how the carbon atom functions as an electrophile, when it functions as an electrophile, and what happens after it functions as an electrophile The geometry of a carbonyl group facilitates the carbon atom functioning as an electrophile We saw in the first semester of organic chemistry that sp2-hybridized carbon atoms have trigonal planar geometry: R O R This makes it easy for a nucleophile to attack the carbonyl group, because there is no steric hindrance that would block the incoming nucleophile: Nuc R R O In this chapter, we will see many different kinds of nucleophiles that can attack a carbonyl group In fact, this entire chapter will be organized based on the kinds of nucleophiles that can attack We will start with hydrogen nucleophiles and continue with oxygen nucleophiles, sulfur nucleophiles, nitrogen nucleophiles, and, finally, carbon nucleophiles This approach (dividing the chapter based on the kinds of nucleophiles) might be somewhat different than your textbook But hopefully, the order that we use here will help you appreciate the similarity between the reactions There is one more feature of carbonyl groups that must be mentioned before we can get started Carbonyl groups are thermodynamically very stable In other words, forming a carbonyl group is generally a process that is downhill in energy On the flipside, converting a C¨O bond into a C¶O bond is generally a process that is uphill in energy As a result, the formation of a carbonyl group is often the driving force for a reaction We will use that argument many times in this chapter, so make sure you are prepared for it The mechanisms in this chapter will be explained in terms of the stability of carbonyl groups Now let’s just quickly summarize the important characteristics that we have seen so far The carbon atom (of a carbonyl group) is electrophilic, and it is readily attacked by a nucleophile (and there are MANY different kinds of nucleophiles that can attack it) We have also seen that a carbonyl group is very stable So, the formation of a carbonyl group can serve as a driving force These principles will guide us throughout the rest of the chapter, and they can be summarized like this: • A carbonyl group can be attacked by a nucleophile, and • After a carbonyl group is attacked, it will try to re-form, if possible 5.3 H-NUCLEOPHILES 5.3 135 H-NUCLEOPHILES We will now explore the various nucleophiles that can attack ketones and aldehydes We will divide all nucleophiles into categories, and in this section, we will focus on hydrogen nucleophiles I call them “hydrogen” nucleophiles, because they are a source of a negatively charged hydrogen atom (which we call a “hydride” ion) that can attack a ketone or aldehyde The simplest way to get a hydride ion is from sodium hydride (NaH) This compound is ionic, so it is composed of Naϩ and HϪ ions (very much the way NaCl is composed of Naϩ and ClϪ ions) So, NaH is certainly a good source of hydride ions However, you will not see any reactions where we use NaH as a source of hydride nucleophiles As it turns out, NaH is a very strong base, but it is not a strong nucleophile This is an excellent example of how basicity and nucleophilicity NOT completely parallel each other The reason for this goes back to something from the first semester of organic chemistry Try to remember back to the difference between basicity and nucleophilicity Let’s review it real quickly The strength of a base is determined by the stability of the negative charge An unstable negative charge corresponds with a strong base, while a stabilized negative charge corresponds with a weak base But nucleophilicity is NOT based on stability Nucleophilicity is based on polarizability Polarizability describes the ability of an atom or molecule to distribute its electron density unevenly in response to external influences Larger atoms are more polarizable, and are therefore strong nucleophiles; while smaller atoms are less polarizable, and are therefore weak nucleophiles With that in mind, we can understand why HϪ is a strong base, but not such a strong nucleophile It is a strong base, because hydrogen does not stabilize the charge well But when we consider the nucleophilicity of HϪ, we must look at the polarizability of the hydrogen atom Hydrogen is the smallest atom, and therefore, it is the least polarizable Therefore, HϪ is generally not observed to function as a nucleophile Now we can understand why we don’t use NaH as a source for a hydrogen nucleophile It is true that it is an excellent base, and you will see NaH used several times this semester But it will always be used as a strong base; never as a nucleophile So, how we form a hydrogen nucleophile? Although HϪ itself cannot be used as a nucleophile, there are many reagents that can serve as a “delivery agent” of HϪ For example, consider the structure of sodium borohydride (NaBH4): H Na H B H H If we look at the periodic table, we see that boron is in Column 3A, and therefore, it has three valence electrons Accordingly, it can form three bonds But in sodium borohydride (above), the central boron atom has four bonds So it must be using one extra electron, and therefore, it has a negative formal charge (you can ignore the sodium ion, Naϩ, because it is just the counter ion) This reagent can serve as a delivery agent of HϪ, as seen in the following example: H O H B H H O H 136 CHAPTER KETONES AND ALDEHYDES Notice that HϪ never really exists by itself in this reaction Rather, HϪ is “delivered” from one place to another That is a good thing, because HϪ by itself would not serve as a nucleophile (as we saw earlier) But sodium borohydride can serve as a source of a hydrogen nucleophile, because the central boron atom is somewhat polarizable The polarizability of the boron atom allows the entire compound to serve as a nucleophile, and deliver a hydride ion to attack the ketone Now, it is true that boron is not so large, and therefore, it is not very polarizable As a result, NaBH4 is a somewhat tame nucleophile In fact, we will soon see that NaBH4 is selective in what it reacts with It will not react with all carbonyl groups (for example, it will not react with an ester) But it will react with ketones and with aldehydes (and that is our focus in this chapter) There is another common reagent that is very similar to sodium borohydride, but it is much more reactive This reagent is called lithium aluminum hydride (LiAlH4, or even just LAH): H Li H Al H H This reagent is very similar to NaBH4 because aluminum is also in Column 3A of the periodic table (directly beneath boron) So, it also has three valence electrons In the structure above, the aluminum atom has four bonds, which is why it has a negative charge Just as we saw with NaBH4, LAH is also a source of nucleophilic HϪ But compare these two reagents to each other—aluminum is larger than boron That means that it is more polarizable, and therefore, LAH is a much better nucleophile than NaBH4 LAH will react with almost any carbonyl group (not just ketones and aldehydes) It will soon become very important that LAH is more reactive than NaBH4 But for now, we are talking about nucleophilic attack of ketones and aldehydes; and both NaBH4 and LAH will react with ketones and aldehydes In addition to NaBH4 and LAH, there are other sources of hydrogen nucleophiles as well, but these two are the most common reagents You should look through your textbook and lecture notes to see if you are responsible for being familiar with any other hydrogen nucleophiles Now let’s take a close look at what can happen after a hydrogen nucleophile attacks a carbonyl group As we have seen, the reagent (either NaBH4 or LAH) can deliver a hydride ion to the carbonyl group, like this: H O H B H O H H In the beginning of this chapter, we covered two important rules that govern the behavior of a carbonyl group: • it is easily attacked by nucleophiles (as we just saw in the step above), and • after a carbonyl group is attacked, it will try to re-form, if possible Now we need to understand what we mean when we say: “if possible.” In trying to re-form the carbonyl group, we realize that the central carbon atom cannot form a fifth bond: O H O H NEVER draw a carbon with bonds 5.3 H-NUCLEOPHILES 137 That would be impossible, because carbon only has four orbitals to use So, in order for the carbonyl group to re-form, a leaving group must be expelled, like this: O O + LG LG So we just need to know what groups can function as leaving groups Fortunately, there is one simple rule that can guide you: NEVER expel HϪ or CϪ (there are a few exceptions to this rule, which we will see later, but unless you recognize that you are dealing with one of the rare exceptions, NOT expel HϪ or CϪ) For example, never this: O O + CH3 And never this: O O + H H We have just learned a simple general rule Now let’s try to apply this rule to determine the outcome that is expected when a ketone or aldehyde is treated with a hydrogen nucleophile Once again, the first step was for the hydrogen nucleophile to attack the carbonyl group: H O H Al H H O H Now let’s consider what can possibly happen next In order for the carbonyl group to re-form, a leaving group must be expelled But there are no leaving groups in this case The carbonyl cannot re-form by expelling CϪ: O H And it cannot re-form by expelling HϪ: O H And it cannot re-form by expelling CϪ: O H 138 CHAPTER KETONES AND ALDEHYDES So we are stuck Once a hydrogen nucleophile delivers HϪ to the carbonyl group, then it will not be possible for the carbonyl group to re-form So the reaction is complete, and it just waits for us to introduce a source of protons to quench the reaction (to protonate the alkoxide ion) To achieve this protonation, we can introduce either water or H3Oϩ as the source of protons: O H H O H HO H Regardless of the identity of the proton source that we add to the reaction flask after the reaction is complete, the product of this reaction will be an alcohol Whenever you are using this transformation in a synthesis, you must clearly show that the proton source is added AFTER the reaction has occured: O 1) LAH OH 2) H2O In other words, it is important to show that LAH and water are two separate steps Do not show it like this: O LAH OH H2O This would mean that LAH and H2O are present at the same time, and that is not possible LAH would react violently with water to form H2 gas (because Hϩ and HϪ would react with each other) As it turns out, NaBH4 is a milder source of hydride, and therefore, NaBH4 can actually be present at the same time as the proton source: O NaBH4 OH MeOH or H2O Common proton sources include MeOH and water (sometimes you might see EtOH) Notice that we didn’t show it as two separate steps When you are dealing with LAH, you must show two steps (one step for LAH and another step for the proton source); but when you are dealing with NaBH4, you should show the proton source in the same step as NaBH4 LAH and NaBH4 are very useful reagents They allow us to reduce a ketone or aldehyde, which is important when you realize that we already learned the reverse process: Oxidation OH O Reduction These two transformations will be tremendously helpful when you are trying to solve synthesis problems later on You would be surprised just how many synthesis problems involve the conversion between alcohols and ketones You need to have these two transformations at your fingertips 342 ANSWERS 8.5) O 1) KOH N H 2) H 2N Br O 3) H2N NH2 8.7) No 8.8) Yes 8.12) 8.9) Yes 1) 8.10) No NH2 O [ H+ ] , Dean-Stark N H 2) LAH 3) H2O 8.13) H 1) CH3NH2 O N CH3 [ H+ ] , Dean-Stark 2) LAH 3) H2O 8.14) H2N 1) O [ H+ ] , Dean-Stark H N H 2) LAH 3) H2O 8.15) 1) [ H+ ] , Dean-Stark O NH2 H N 2) LAH 3) H2O 8.16) O 1) NH2 H [ H+ ] , Dean-Stark N H 2) LAH 3) H2O 8.18) OH 1) Na2Cr2O7, H2SO4, H2O + 2) CH3 NH2 [ H ] , Dean-Stark 3) LAH 4) H2O H N 343 ANSWERS 8.19) 1) BH3 • THF 2) H2O2, NaOH H N 3) PCC 4) [ H+ ] , Dean-Stark NH2 5) LAH 6) H2O 8.20) O H 1) H3O+ O N 2) [H+], CH3CH2CH2NH2 Dean-Stark 3) LAH 4) H2O 8.21) 1) O3 H N 2) DMS [ H+ ] , NH2 3) Dean-Stark 4) LAH 5) H2O 8.22) H 1) Et2 CuLi O 2) Cl + [H ], NH2 Dean-Stark 3) LAH 4) H2O 8.24) O H2 N 1) H2N Cl O Cl 2) O AlCl3 3) H3O+ 8.25) O H2N 1) Cl 2) Cl2 , AlCl3 3) H3 O+ H2N Cl N 344 ANSWERS 8.27) 8.28) Cl 8.29) N O N Cl N 8.30) N N N N 8.32) NH2 Br NO2 NO2 1) NaNO2 , HCl 2) CuBr 8.33) NH2 CN 1) NaNO2 , HCl NO2 8.34) 2) CuCN NO2 NH2 Cl 1) NaNO2 , HCl NO2 8.35) 2) CuCl NH2 NO2 Br 1) NaNO2 , HCl 2) CuBr 8.36) N NH2 CN 1) NaNO2 , HCl 2) CuCN Cl INDEX A Acetals, 145–152 cyclic, 149–152 and imines/amines, 155–158 preparation of, 145–149 thioacetals vs., 153 Acetic acid (CH3COOH), 239 Acetoacetic ester, 269 Acetoacetic ester synthesis, 269–270 Acetone, 268–270 Acid anhydrides, 187, 201–203, 213, 222–223 Acid chlorides, 67, 187, 197 Acid halides, 192–201 and acylation of amines, 291–292 and C-, H-, and O-nucleophiles, 188–190 and carboxylic acids, 201 esters from, 203–204 ketones from, 225 proton transfers in reactions, 191 reactions of, 194–199 reactivity of, 187, 203, 213, 222–223 synthesis of, 192–194 Acidic conditions: Gabriel synthesis in, 285 Grignard reagents in, 165–166 hydration of nitriles in, 217 hydrolysis of amides in, 215–216 keto-enol tautomerism in, 234–236 ketones and aldehydes in, 62–63, 141–142, 144, 156–159, 234–236 N-nucleophiles in, 156–159 O-nucleophiles in, 141–142, 144 preparation of alkanes in, 154 preparation of esters in, 203–208 reverse of Fischer esterification in, 208–209, 212 SNAr reactions in, 118–120 Acidity, 62–63 Activation, 76–98 and deactivation, 76–78 and directing effects, 78–88 identifying activators and deactivators, 88–98 Activators, 78–90, 92–94 and acylation of amines, 292–294 defined, 78 directing effects, 78–88 identifying, 88–90, 92–94 moderate, 89–90, 93, 293 as ortho-para directors, 79–81, 83, 85, 94 overview, 92–94 predicting products of reaction, 95–98 strong, 85, 88–89, 92, 292–294 weak, 85–87, 90, 93 Acylation reactions: for amines, 291–295 Friedel-Crafts, 67–71 Acyl chloride, 67 Acyl group: in acylation of amines, 292–293 carbonyl vs., 133 in Friedel-Crafts acylation, 67, 69, 71 in synthesis strategies, 108–109 Acid halides, 187 Acylium ion, 67 Addition: 1,2-addition, 274–275 1,4-addition, 275–276, 278–279 Addition-elimination mechanism (SNAr mechanism), 115–121, 126–127 AlBr3 (aluminum tribromide), 57–61, 97, 100 AlCl3 (aluminum trichloride), 65–68 Alcohols: and acid anhydrides, 202 and acid halides, 189, 194–195, 200 and amides, 214, 221 345 346 INDEX Alcohols (cont.) and carboxylic acids, 227–228 IR spectra of, 11–12 and ketones, 167 See also O-nucleophiles NMR spectra of, 32, 35, 45 primary, 129, 131 secondary, 129, 131–132 tertiary, 129 Aldehydes, see Ketones and aldehydes Aldehydic protons, 35, 45 Aldol addition, 252–254 Aldol condensation, 253–260 Aldol reactions, 252–256 Alkanes, 6, 154, 160–161 Alkenes, 6, 171, 174 Alkoxides, 259–261 Alkoxide ions, 189, 191, 204, 259, 262 Alkoxy group, 261 Alkyl amines, 282 Alkylation: of ammonia, 283–284 decarboxylation vs., 268, 272 of enolates, 247–251 Friedel-Crafts, 64–68, 108 Alkyl diazonium salt, 297 Alkyl group: in amines, 281 electron donation by, 90 in Friedel-Crafts alkylation, 64, 67, 69, 71 in Grignard reaction, 168 migration of, 177–178 Alkyl halides: and alkylation of enolates, 247–251 in amine preparation, 283–286 and C-nucleophiles, 165, 170 nitrile preparation from, 217 NMR spectra of, 35 Alkynes, Alkynyl protons, 35 Allylic protons, 35 ␣, -unsaturated ketones, 253, 258–259, 274–276, 278 Alpha (␣) carbon, 231, 238 Alpha-halogenation, 239–240 Alpha (␣) protons, 32–33, 231–232, 256 ␣ spin state, 26 Aluminum tetrabromide, 60 Aluminum tribromide, see AlBr3 Amides: from amines, 282, 291–295 hydrolysis of, 215–216, 292 reactions with, 195, 213–217, 221, 224 reactivity of, 187, 203, 222–223 Amide ions, 282 Amination, reductive, 287–291 Amines, 125, 281–300 and acid anhydrides, 202 and acid halides, 195 acylation of, 291–295 and aromatic diazonium salts, 297–300 and esters, 219 IR spectra of, 15–16 as leaving group, 214 and nitrous acid, 295–298 as N-nucleophiles, 156–159 nucleophilicity and basicity of, 281–282 preparation of, 283–291 primary, see Primary amines reductive amination of, 287–291 secondary, 15–16, 157–158, 281, 287–291 SN2 reactions with, 283–286 tertiary, 281 Aminobenzene, 121–122 Amino group, 88–89, 293–294, 299 Ammonia, 195, 283–284 Ammonium ion, 156, 283 Aniline, 121–122, 125–126, 294, 299 Aqueous acid, 192, 239 Aromatic compounds, NMR spectra of, 28, 48 Aromatic diazonium salts, 298–300 Aromatic methyl protons, 35 Aromatic protons, 34 Aromatic substitution, see Electrophilic aromatic substitution; Nucleophilic aromatic substitution Arrhenium ions, 59 Aryl amines, 282 Aryl diazonium salts, 297–300 Aryl halides, 286 Aryl protons, 35 Asymmetric stretching, 16 Atomic mass, wavenumber and, Azeotropic distillation, 146 B Baeyer-Villiger reaction, 175–179, 226 Basic conditions: hydration of nitriles in, 218 hydrolysis of amides in, 216 hydrolysis of esters in, 209–211 INDEX keto-enol tautomerism in, 235–236 Basicity, 60, 135, 281–282 Bending (of bonds), Benzaldehyde, 256 Benzene: alkylation of, 65–66 acylation of, 67 halogenation of, 57–61 nitration of, 61–64 substituted, 76, 78–79 sulfonation of, 73–74 Benzyne, 122 -hydroxy ketone, 252–253, 258 -keto acids, 267 -keto esters, 259, 262, 266–268 Beta () protons, 32–33  spin state, 26 BF3, 153 Bond strength, wavenumber and, 4–8 Brϩ, 58–59 BrϪ, 60 Br2 (bromine), 56–61, 81, 97, 100, 239, 244–247 Broadband decoupling, 54 Broad signals (IR spectra), 11 Bromination reactions, 79, 84–85, 103, 299 Bromine, see Br2 Bromoform, 246 Butane, 36–37 2-Butanol, 12 tert-Butyl group: multiplicity of, 40–41 NMR splitting pattern, 41–42 steric effects for, 100, 104–105 Butyllithium (BuLi), 170 C CϪ: and acid halides, 195–196 exceptions to rule, 175, 245 rule about expelling, 137, 188–189 13C, 53–55, 121–122 Cannizzaro reaction, 175 Carbanions, 161 Carbocations: rearrangement of, 66–69 stability of, 64–65 stabilization, 115 Carbon nucleophiles, see C-nucleophiles Carbonyl group: acyl vs., 133 chemical shifts for, 32, 54 in Claisen condensations, 260–261 electrophilicity, 141–142 and Grignard reagents, 166–167 IR spectra of, 7–8 in Michael reactions, 274 re-forming of, 136–138 rules of behavior, 134, 136–137, 167, 188–192 signal intensity for (in IR spectra), 9–10 violations of rules, 175–179 Carboxylate ion, 201, 210–211, 216, 246, 261 Carboxyl group, see Decarboxylation Carboxylic acids: and acid anhydrides, 201 alcohols from, 227–228 from aldehydes, 176, 178 alpha-halogenation of, 240 347 from amides, 216 carboxylic acid derivatives vs., 187 and esters, 203–213 IR spectra of, 12–13 from methyl ketones, 246–247 NMR spectra of, 35 preparation of, 130 substituted, 272 in synthesis problems, 223–224 Carboxylic acid derivatives, 187–230 acid anhydrides, 201–203 acid halides, 189–201 amides and nitriles, 213–222 conversions of ketones/aldehydes and, 225–229 esters, 194–195, 203–213 general rules, 188–192 reactivity of, 187–188, 203, 213, 222–223 synthesis problems, 222–230 Catalysts, 60, 144 C-attack (of enolates), 242 CBr3 group, 245–246 C:C double bond, 9–10, 72 CH2 group (methylene group), 27–28 CH3COOH (acetic acid), 239 CH3 group, see Methyl group Charge: negative, 113, 116–117, 135, 276 partial, 77–78 CßH bonds, 2–3, 5–6, 10–11 Chemical equivalence, 26–30, 39 348 INDEX Chemical shift ( ␦ ), 30–35, 49, 53–54 CH group (methine group), 28 Chloride ion (ClϪ), 192–193 Chlorine, 80, 92 Chlorobenzene, 79–80, 121–122 Chloroethane, 47 Chloro group, 187, 299 Chlorohexane, 66 Chromium oxidations, 129–130 Claisen condensations, 259–266 Clemmensen reduction, 68–69, 154, 161 C:N double bond, 157, 288 13C NMR spectroscopy, 53–55 C-nucleophiles, 165–175 and carboxylic acid derivatives, 189–190 Grignard reagent, 165–169 H- vs., 167–168 phosphorus ylide, 169–174 sulfur ylide, 172–174 CßO bond, 2–3 C:O double bond, 129–131, 133–134 Complex splitting (NMR spectra), 43–44 Concentrated fuming sulfuric acid, 73–74, 100 Condensation reactions: aldol, 253–260 Claisen, 259–266 defined, 253 Dieckmann, 266 Conjugate addition, 275 Conjugated ketones, 7–8 COOH group, see Carboxylic acids Copper salts, 299 Coupling, long-range, 40 Coupling constant (J value), 41, 43–45 Crossed aldol condensations, 256 Crossed Claisen condensations, 264 Cross-over problems, 226–229, 246 Cyanide, 217 Cyano group, 91, 216, 218, 299 Cyclic acetals, 149–152 Cyclohexane, 46–47 Cyclohexanone, 247–249 D Deactivation, 76–98 and activation, 76–78 and directing effects, 78–88 identifying activators and deactivators, 88–98 Deactivators, 78–98 defined, 78 directing effects, 78–88 identifying, 90–94 as meta-directors, 79, 80, 83, 85, 94 moderate, 90–91, 93 overview, 92–94 predicting products of reaction, 95–98 strong, 85–87, 91–93 weak, 90, 93 Dean-Stark trap, 146, 149, 162 Decarboxylation, 266–273 alkylation vs., 268, 272 with -keto esters, 266–268 malonic ester synthesis, 271–273 and substituted derivatives of acetone, 268–270 Decoupling, broadband, 54 Degree of unsaturation, 47–49 ␦, see Chemical shift; Partial charge Deprotonation See also Proton transfer of amines, 281–282 of carbonyl group electrophilic, 142–144 Claisen condensation, 265 in keto-enol tautomerism, 234–237 in SNAr mechanism, 118–119 Deshielded protons, 26 Desulfonation, 74, 76, 101 Desulfurization (with Raney nickel), 154, 161 Diagnostic region (IR spectra), 5, 18–19 Diastereomeric hydrazones, 160 Diastereomeric imines, 157 Diastereomeric oximes, 159, 163 Diazonium ion, 297 Diazonium salts, 297–300 Dieckmann condensation, 266 Diels-Alder reaction, 123 Diethyl malonate, 271–272 Dilute sulfuric acid, 74, 101 2,3-Dimethyl-2-butene, 10 Dimethyl ketone, 268 Dimethyl sulfide (DMS), 173 Dipole moment, 9–10 Directing effects, 78–88 and activation/ deactivation, 78–88 and induction/ resonance, 79–80 of multiple groups on a ring, 84–87 INDEX and positions on monosubstituted benzene, 78–79 predicting products from, 80–87 Distillation, azeotropic, 146 Distribution of bond strength, 12 DMS (dimethyl sulfide), 173 Double bonds, 4, 7, 56 C:C, 9–10, 72 C:N, 157, 288 C:O, 129–131, 133–134 HDI for, 48 IR signals for, 18–19 P:O, 170–171 S:O, 72, 193 Double enolates, 243, 262 Doublet (NMR spectra), 39 Downfield (NMR spectra), 31 Dow process, 121 E Electromagnetic radiation, 1–2 Electromagnetic spectrum, Electron density, 56–57, 77 Electron-donating groups, 77, 80, 90 Electronegativity, 31–32, 77 Electron-withdrawing groups, 77, 80, 112–113 Electrophiles: bromine as, 56–57 carbonyl group as, 133–134 and nucleophiles, 56–57 Electrophilic aromatic substitution, 56–111 activation and deactivation, 76–78 defined, 59 directing effects, 78–88 electrophiles and nucleophiles in reactions, 56–57 Friedel-Crafts alkylation and acylation, 64–71 halogenation and Lewis acids, 57–61 identifying activators and deactivators, 88–98 nitration, 61–64 nucleophilic vs., 126 steric effects, 98–105 sulfonation, 72–76 synthesis strategies, 106–111 Electrophilic centers (of ␣, -unsaturated ketones), 274 Electrophilicity, 57, 141–142 Elimination-addition reactions, 121–127 Enamines, 155, 157–158, 277–280 Energy levels, vibrational, 2–3 Enols: defined, 233 keto-enol tautomerism, 233–238 from Michael reactions, 274–275 reactions with, 238–241 Enolates, 231–280 aldol reactions, 252–258 alkylation of, 247–251 and alpha protons, 231–232 Claisen condensation, 259–266 349 and decarboxylation reactions, 266–273 defined, 235 double, 243, 262 ester, 259–266 haloform reactions, 244–247 and keto-enol tautomerism, 233–238 Micheal reactions, 273–280 preparation of, 241–244 and reactions with enols, 238–241 highly stabilized, 243 Epoxides, 173–174 Esters, 203–213 acetoacetic ester synthesis, 269–270 and acids, 192 and amides, 214, 224 and amines, 219 -keto, 259, 262, 266–268 bond strength of, built-in leaving groups of, 260 in Claisen condensation, 260–261 hydrolysis reactions of, 208–213 from ketones, 176 malonic ester synthesis, 271–273 methyl, 261 NMR spectra of, 32 and O-nucleophiles, 150–151 preparation of, 190, 194–195, 203–208 reactivity of, 187, 203, 213, 222–223 Ester enolates, 259–266 Esterification reactions: Fischer, 206–208 reverse of Fischer, 208–209, 212 trans-, 262 Ethane, 47–48 350 INDEX Ethanol (EtOH), 44–45, 47, 138, 263 Ethers, 32 Ethoxide, 261–262 Ethyl acetoacetate, 269, 271 Ethyl amine, 48 Ethylbenzene, 34 Ethyl carbocation, 66 Ethyl chloride, 250 Ethylene glycol, 149, 150, 152 Ethyl group, 41–42, 65–66 EtOH, see Ethanol Excitation, vibrational, 2–3 F FeBr3, 58 Fingerprint region (IR spectra), Fischer esterification, 206–209, 212 Fluorine, 31 Friedel-Crafts acylation, 67–71, 108 Friedel-Crafts alkylation, 64–68, 108 Fuming sulfuric acid, 73–74, 100 Functional groups See also specific groups chemical shift for, 32–33 identifying, with IR spectroscopy, temporary modification of, 294 G Gabriel synthesis, 284–286 Gamma protons, 32 Grignard reagent, 165–169, 189, 196, 200, 202 H HϪ: and acid halides, 195 exceptions to rule, 175, 245 rule about expelling, 137, 188–189 Haloform reactions, 244–247 Halogens, 81 and enols, 244–247 hydrogen deficiency index for, 47 resonance vs induction for, 79–80, 92 as weak activators, 90 Halogenation reactions, 57–61 HDI (hydrogen deficiency index), 46–49 Hell-Volhard-Zelinksky reaction, 240 Hemiacetals, 145 1-Hexene, 46–47 1H NMR spectrum, see Proton NMR spectrum H-nucleophiles, 135–140, 167–168, 189–190 Hybridized atomic orbitals, 5–7 Hydration reactions, 217–218 Hydrazine (NH2NH2), 159–161, 285 Hydrazone, 160–161 Hydride ions, 135 Hydride shift, 66 Hydrogenation reactions, 288 Hydrogen bonding, 12–13 Hydrogen deficiency index (HDI), 46–49 Hydrogen nucleophiles, see H-nucleophiles Hydrolysis reactions: of amides, 214–216, 292 of esters, 208–213 in Gabriel synthesis, 285 Hydroxide: in aldol condensations, 254 in alkylation of enolates, 248 in Claisen condensation, 259–260 in electrophilic aromatic substitutions, 119, 121, 125, 127 in haloform reaction, 244–245 Hydroxide ion, 122 Hydroxylamine (NH2OH), 158–159, 163 Hydroxyl protons, 45 Hyperconjugation, 90 I Imines, 155–158, 160, 287–291 Iminium group, 278 Induction: carbonyl group, 133 nitrobenzene, 78 and resonance, 77–80 of strong deactivators, 91–92 Inductive effects (in NMR spectroscopy), 31–32 In situ preparation, 296 Integration (NMR spectra), 35–38, 49, 53 Intramolecular Claisen condensation, 266 Intramolecular Fischer esterification, 206 Intramolecular proton transfer, 176–177 Intramolecular reactions, 162, 206 Iodination, 61 Iodoform, 246 IR absorption spectra, 3–25 analyzing, 18–25 signal intensity, 9–11 signal shape, 11–18 wavenumber, 4–8 IR spectroscopy, 1–25 INDEX analyzing IR spectra, 18–25 and electromagnetic radiation, 1–2 IR spectra, 3–25 signal intensity, 9–11 signal shape, 11–18 vibrational excitation, 2–3 wavenumber, 4–8 Isopropyl benzene, 66 Isopropyl chloride, 66 Isopropyl group, 41–42 Isotopic labeling, 121–122 J Jones reagent, 129–131 J value (coupling constant), 41, 43–45 K Keto-enol tautomerism, 233–238 Ketones and aldehydes, 129–186 from acid halides, 189, 196, 225 in aldol reactions, 252–258 ␣, -unsaturated ketones, 253, 258–259, 274–276, 278 amines from, 289 -hydroxy ketone, 252–253, 258 bond strength of, 7–8 and Cannizzaro/BaeyerVilliger reactions, 175–179 Clemmensen reduction of, 62–63, 154, 161 and C-nucleophiles, 165–175 C:O bonds of, 133–134 conjugated ketones, 7–8 conversions of, 225–229 from decarboxylation reactions, 268 dimethyl ketone, 268 and enols, 238–240 and H-nucleophiles, 135–140 keto-enol tautomerism, 233–238 methyl ketones, 246–247 NMR chemical shift for, 35 and N-nucleophiles, 155–164 and O-nucleophiles, 140–152 preparation of, 129–132 “protecting” a ketone, 150–152 rules of behavior, 188–189 and S-nucleophiles, 153–155 in synthesis problems, 180–186 unsaturated ketones, 7–8 Kinetics, thermodynamics vs., 249 L Labile protons, 45 LAH (lithium aluminum hydride): and acid anhydrides, 202 and acid halides, 197 in formation of cyclic acetals, 150–151 Grignard reagent vs., 168 H-nucleophiles from, 136–140 reduction of imine with, 287 LDA (lithium diisopropylamide), 248–251, 282 Leaving groups: 351 and acid anhydride formation, 201–202 of amides, 214 for carbonyl formation, 137 of carboxylic acid derivatives, 187 for nucleophilic aromatic substitution, 112–113 Lewis acids, 58, 60, 67, 69 LiAlH4, see LAH (lithium aluminum hydride) Lithium aluminum hydride, see LAH Lithium dialkyl cuprates (R2CuLi), 196, 199, 202, 226, 277 Lithium diisopropylamide (LDA), 248–251, 282 Location (of proton NMR signal), 27 Lone pair of electrons, 88–90, 281 Long-range coupling, 40 M Magnesium, 165 Magnetic moment, 26 Major products, 98–100 Malonic ester, 271 Malonic ester synthesis, 271–273 MCPBA (meta-chloro peroxybenzoic acid), 176, 178–179 Meisenheimer complex, 115–117 MeOH, 138–139, 264 meta-Chloro peroxybenzoic acid, see MCPBA meta-directors, 79–80, 83, 85, 94 meta position, 79 meta-Xylene, 102–103 Methine group (CH group), 28 352 INDEX Methine protons, 32, 35 Methoxide, 261, 265 Methylene group (CH2 group), 27–28 Methylene protons, 32, 35 Methyl ester, 261 Methyl group (CH3 group): in bromination reactions, 79 directing effects for, 84–86 in haloform reaction, 245 installing, on aromatic ring, 64–66 IR spectra of, 16 as leaving group, 114 NMR spectra of, 28, 34 steric effects for, 104–105 Methyl ketones, 246–247 Methyl protons, 32, 35 Michael acceptors, 276–278 Michael addition, 275 Michael donors, 276–280 Michael reactions, 273–280 with enamines, 277–280 and Michael donors/acceptors, 276–280 1,4-additions, 275–276, 278–279 1,2-additions, 274–275 Migration, alkyl group, 177–178 Migratory aptitude, 178 Minor product, 98–100 Moderate activators, 89–90, 93, 293 Moderate deactivators, 90–91, 93 Molecular formula (with NMR spectra), 49 Monosubstituted benzene, 78–79 Multiplets (NMR signals), 44 Multiplicity, 39–41, 49 N NaBH4 (sodium borohydride), 135–136, 138–139, 150 NaH (sodium hydride), 135 Narrow signals (IR spectra), 11 Negative charge, 113, 116–117, 135, 276 NH2 group, see Amines NH2NH2 (hydrazine), 159–161, 285 NH2OH (hydroxylamine), 158–159, 163 Nitration, 61–64 Nitric acid, 62–64, 82, 95–96, 295 Nitriles, 216–218 Nitrobenzene, 62–64, 78–79 Nitrogen gas, 161 Nitrogen nucleophiles, see N-nucleophiles Nitro group: as deactivator, 78, 84–86, 91–92 directing effects of, 79 as electron-withdrawing group, 112 in nitration reactions, 63–64 in synthesis strategies, 107–109 1-Nitropropane, 44 Nitrosamine, 296–297 Nitrosonium ion, 296–297 Nitrous acid, 295–298 NMR spectroscopy, see Nuclear magnetic resonance spectroscopy N-nitroso amine, 296–297 N-nucleophiles, 155–164 mechanisms for reactions, 161–163 NH2NH2, 159–161 NH2OH, 158–159 primary amines, 156–159 products of reactions, 163–164 secondary amines, 157–158 NO2ϩ, 62–63, 95 nϩ1 rule, 39 Nuclear magnetic resonance, 26 Nuclear magnetic resonance (NMR) spectroscopy, 1, 26–55 13C NMR, 53–55 analyzing 1H NMR spectra, 49–53 and chemical equivalence, 26–30 chemical shift, 30–35 complex splitting, 43–44 hydrogen deficiency index, 46–49 integration, 35–38 multiplicity, 39–41 pattern recognition, 41–43 without splitting, 44–45 Nuclear spin, 26 Nucleophiles: carbon, see C-nucleophiles electron density of, 57 hydrogen, 135–140 nitrogen, see Nnucleophiles oxygen, see Onucleophiles reactions with electrophiles, 56–57 and reactivity of aromatic ring, 76–78 stabilized, 278 strength of, 135 sulfur, 153–155 Nucleophilic aromatic substitution, 112–128 INDEX criteria for, 112–114 elimination-addition, 121–126 mechanism strategies for, 126–128 SNAr mechanism, 115–121 Nucleophilicity: and activation, 77–78 of alpha (␣) carbon, 238 of amines, 281–282 basicity vs., 60, 135 and electron density, 57 O O-attack, 242 OßH bond, OH group, 77–80, 85, 88, 206 O-nucleophiles, 140–152 Acetal formation, 145–149 and carboxylic acid derivatives, 189–190 cyclic acetals, 149–152 ketones and N- vs., 155–158 overview of formation process, 140–145 Order of events (in synthesis problems), 106–109 OR (alkoxy) group, 90 ortho-para directors, 79–81, 83, 85, 94 ortho position, 79 leaving and electronwithdrawing groups in, 113, 116–117 and steric effects, 99–101 Overtone of C:O signal in IR spectra, 22 Oxidation reactions, 129–130, 229 Oxidation state (of nitriles), 216 Oximes, 159, 163 Oxophilicity, 170 Oxygen nucleophiles, see O-nucleophiles Ozonolysis, 130–131, 171 P para position, 79 leaving and electronwithdrawing groups in, 113, 116–117 and steric effects, 99–100, 104 Partial charge (␦), 77–78 Pattern recognition, NMR spectroscopy, 41–43 PCC (pyridinium chlorochromate), 130–131 Pericyclic reactions, 267 Peroxy acids, 175–176, 179 Phenol, 76–77, 122–123, 125 Phenolic proton, 117–119 Phenyl group, 178 Phosphorus ylides, 169–174 Phthalimide, 284 bonds, 7, 91 electrons, 34–35 PßO bond, 170 P:O double bond, 170–171 Polarizability, 135 Polybromination, 294 Preparation See also Synthesis of acetals, 145–149 of alkanes, 154 of amines, 283–291 of carboxylic acids, 130 of enolates, 241–244 of esters, 190, 194–195, 203–208 of ketones and aldehydes, 129–132 of nitriles, 217 in situ, 296 Primary alcohols, 129, 131 Primary alkyl amines, 297 353 Primary alkyl halides, 247 Primary amines, 156–159, 281 IR signal shape, 15–16 and nitrosonium ion, 296–297 preparation of, 283–286 Primary aryl amines, 297 Propylbenzene, 66–67, 98–99 Propyl carbocation, 66 Propyl chloride, 66 Propyl group, 66, 68–69, 99, 107–108 “Protecting” a ketone, 150–152 Protons, 35, 45 alpha, 32–33, 231–232, 256 beta, 32–33 gamma, 32 labile, 45 relative number of (in NMR spectra), 36 shielded vs deshielded, 26 Protonation See also Proton transfer of carbonyl group, 142–144 Claisen condensation, 265 in keto-enol tautomerism, 234–237 in SNAr mechanism, 118–119 Proton NMR spectrum (1H NMR spectrum), 26–53 analyzing, 49–53 chemical equivalence, 26–30 chemical shift, 30–35 complex splitting, 43–44 and hydrogen deficiency index, 46–49 integration, 35–38 multiplicity, 39–41 354 INDEX Proton NMR (cont.) pattern recognition, 41–43 without splitting, 44–45 Proton splitting, 39–41, 43–45 Proton transfer: and carboxylic acid derivatives, 191–192 drawing, 60 and Grignard reagents, 166 in hydration of nitriles, 217–218 in imine formation, 156–157 intramolecular, 176–177 in one-step synthesis of esters, 204–205 in O-nucleophile and ketone/aldehyde reactions, 144–145 in reverse Fischer esterification, 209 Pyridine, 194, 201–202 Pyridinium chloride, 194 Pyridinium chlorochromate (PCC), 130–131 Q Quartets (in NMR spectra), 39 Quaternary ammonium salt, 283 Quaternary products, 283 Quintets (in NMR spectra), 39 R R2CuLi, see Lithium dialkyl cuprates Raney nickel, 153–154, 161 Reactivity: of aromatic ring, 76–78 of carbonyl group, 133–134 of carboxylic acid derivatives, 187–188, 203, 213, 222–223 and Friedel-Crafts alkylation/acylation, 71 Reagents: for acid halide reactions, 199–201 for electrophilic vs nucleophilic substitution reactions, 126–127 Grignard, 165–169, 189, 196, 200, 202 for preparation of ketones and aldehydes, 129–132 for synthesis problems, 107 Wittig, 170, 171 Reduction-oxidation reactions, 229 Reduction reactions: amine preparation, 287–291 Clemmensen, 68–69, 154, 161 with Grignard reagent, 168 with H-nucleophiles, 138–139 with N-nucleophiles, 161 with O-nucleophiles, 151–152 with Raney nickel, 153–154, 161 of thioacetals, 153–154 Wolff-Kishner, 161 Reductive amination, 287–291 Relative number of protons (in NMR spectra), 36 Resonance: and bond strength, 7–8 carbonyl group, 133 of carboxylate ion, 210 and induction, 77–80 keto-enol tautomerism vs., 233 nuclear magnetic, 26 Resonance structures, 59, 61 of activators and deactivators, 88–89, 91 of ␣, -unsaturated ketones, 274 of aryl amines, 282 of enamines, 277–278 of enolates, 242 of Meisenheimer complex, 116 Retrosynthetic analysis, 183–184 Reverse of Fischer esterification, 208–209, 212 S Salts: copper, 299 diazonium, 297–300 quaternary ammonium, 283 Sandmeyer reactions, 299 Saponification, 210–211 Saturated compounds, 46 Secondary alcohols, 129, 131–132 Secondary alkyl group, 178 Secondary amines, 15–16, 157–158, 281, 287–291 Shielded protons, 26 Sigma bonds, 39–40 Sigma complex, 59, 63, 65, 73, 116 Signal intensity (IR spectra), 9–11 Signal shape (in IR spectra), 11–18 CßH bonds, 16 NßH bonds, 15–16 and OßH bonds, 11–15 INDEX Single bonds, CßH, 2–3, 5–6, 10–11 CßO, 2–3 IR signals for, 18–19 OßH, PßO, 170 XßH, 4, 19 Singlets (in NMR spectra), 39 SN1 reactions, 115 SN2 reactions, 115, 170, 173, 283–286 SNAr mechanism, 115–121, 126–127 S-nucleophiles, 153–155 SO2 gas, 194 SO3, 72–73 SO3H group, 73–74 Sodium amide, 282 Sodium borohydride, see NaBH4 Sodium dichromate, 129, 131 Sodium hydride (NaH), 135 Sodium nitrate, 295 S:O double bonds, 72, 193 s orbitals, Spectroscopy, see IR spectroscopy; Nuclear magnetic resonance (NMR) spectroscopy sp-hybridized carbon atoms, 54 sp2-hybridized carbon atoms, 54 sp3-hybridized carbon atoms, 54 Splitting, proton, see Proton splitting sp orbitals, Stability: of -keto ester, 262 of carbonyl group, 134 of enolates, 243, 275–276 of negative charge, 135 Stabilized nucleophiles, 278 Step-curves (in NMR spectra), 36 Steric effects, 98–105 for carbonyl group, 134 of multiple groups on rings, 102–105 and substitution with propyl benzene, 98–99 in synthesis strategies, 99–102, 107–108 Stork enamine synthesis, 279–280 Stretching (of bonds), 2, 16 Strong acids, 62–63 Strong activators, 85, 88–89, 92, 292–294 Strong bases, 135 Strong deactivators, 85–87, 91–93 Strong nucleophile, 135 Substituted carboxylic acids, 272 Substitution reactions, 59 See also Electrophilic aromatic substitution; Nucleophilic aromatic substitution Sulfonation, 72–76, 100 Sulfur, 72, 153 Sulfuric acid: concentrated fuming, 73–74, 100 dilute, 74, 101 and nitric acid, 62–64, 82, 95–96 in preparation of ketones, 129 Sulfur nucleophiles, 153–155 Sulfur ylide, 172–174 Symmetric stretching, 16 Symmetry: and integration values, 37 of ketones, 157–159 Synthesis See also Preparation 355 acetoacetic ester, 269–270 of acid halides, 192–194 of aniline, 125–126 of carboxylic acid derivatives, 222–230 with electrophilic aromatic substitution, 106–111 Gabriel, 284–286 of ketones and aldehydes, 180–186 malonic ester, 271–273 and steric effects, 99–102, 107–108 Stork enamine, 279–280 Synthesis problems: cross-over problems, 226–229 multiple answers to, 184 order of events in, 106–109 retrosynthetic analysis for, 183–184 working backwards, 183–184 T Tautomers, 233 Temporary modification of functional groups, 294 tert-Butyl group: multiplicity of, 40–41 NMR splitting pattern, 41–42 steric effects for, 100, 104–105 Tertiary alcohols, 129 Tertiary amines, 281 Tetrahedral intermediate, 142–144, 190 Tetrahydrofuran (THF), 248 Tetramethylsilane (TMS), 30 Thermodynamics, kinetics vs., 249 356 INDEX THF (tetrahydrofuran), 248 Thioacetals, 153–154 Thionyl chloride, 193 TMS (tetramethylsilane), 30 Toluene, 79 trans-esterification, 262 Trichloromethyl group, 92 Triphenylphosphine, 169–170 Triple bonds, 4, 7, 19, 48 Triplets (in NMR spectra), 39 U Unsaturated compounds, 46 Unsaturated ketones, 7–8 Unsaturation, degree of, 47–49 Upfield (in NMR spectra), 31 UV-Vis spectroscopy, 1–2 V Vibrational excitation, 2–3 Vinylic protons, 35 W Water: and acetal formation, 145–146 and acid anhydrides, 202 and acid halides, 191 in keto-enol tautomerism, 237 as proton source, 138, 140 removing Lewis acids with, 69 removing protons with, 63–64 Wavelength, Wavenumber (in IR spectra), 3–8 Weak activators, 85–87, 90, 93 Weak bases, 135 Weak deactivators, 90, 93 Wittig reaction, 170–172 Wittig reagent, 170–171 Wolff-Kishner reduction, 161 X X–H bonds, 4, 19 Y Ylides, 169–174 Z Zinc amalgam, 68–69 ... called a hemiacetal, and you can think of it as “half-way” toward making an acetal: O RO RO OH hemiacetal OR acetal We give it a special name because it is theoretically possible to isolate it and... case is PCC, and we have seen that PCC will convert a primary alcohol into an aldehyde: O OH PROBLEMS 2) DMS OH CrO3 5.3 Aqueous acetone heat Na2Cr2O7 5.4 H2SO4, H2O OH 1) O3 5.5 2) DMS OH Na2Cr2O7... O LAH OH H2O This would mean that LAH and H2O are present at the same time, and that is not possible LAH would react violently with water to form H2 gas (because Hϩ and HϪ would react with each