Following are two possible retrosynthetic analyses for the

Chloroformates have the functional group O R O Cl, in which R is often a tertbutyl or benzyl group. A chloroformate is used in the following synthesis of the antibacterial drug, linezolid (Zyvox). Linezolid (Zyvox) O N O O F O N H N Based on your knowledge of carboxylic acid derivatives, predict the product of the following transformation used in a synthesis of linezolid (Zyvox). The new functional group created is called a carbamate. Carbamates are often used as protecting groups for amine groups during complex syntheses. O N F NH2 O Cl O

Acid anhydrides are often used in place of acid chlorides because a less acidic carboxylic acid, not the much stronger acid HCl, is the byproduct of the reaction. In the following reaction of a carbohydrate derivative, acetic anhydride is used to obtain the product in 99% yield as a single stereoisomer. Note that the stereochemistry of the starting anomeric carbon is not indicated. Draw the product of the following transformation in a chair form and show the single stereoisomer product of this transformation, which is also the most stable possible chair species. , CH2Cl2 OH H3C O CH3 O O Si anomeric carbon O O O

The benzyl ether group (!OBn) is often used as a protecting group for OH groups during the synthesis of complex molecules. The following structure has a number of benzyl ether groups used for this purpose. Draw the product of the following transformation. What role does the diisopropylethylamine play in this reaction? Diisopropylethylamine H3C CH3 OBn OH OBn OBn OBn = H O H3C H3C O O N Cl I O OBn

Draw the product of the base-catalyzed aldol reaction of each compound. (a) Phenylacetaldehyde (b) Cyclopentanone

Draw the product of dehydration of each aldol product in Problem 19.1.

Draw the product of the base-catalyzed crossed aldol reaction between benzaldehyde and 3- pentanone and the product formed by its dehydration.

Show the product of Claisen condensation of ethyl 3-methylbutanoate in the presence of sodium ethoxide followed by acidifi cation with aqueous HCl.

Complete the equation for this crossed Claisen condensation. (excess) 1 1. EtO2Na1 2. H2O, HCl OEt O O OEt

Show how to convert benzoic acid to 3-methyl-1-phenyl-1-butanone (isobutyl phenyl ketone) by the following synthetic strategies, each of which uses a different type of reaction to form the new carbon- carbon bond to the carbonyl group of benzoic acid. COOH Benzoic acid 3-Methyl-1-phenyl-1- butanone ? O (a) A lithium diorganocopper (Gilman) reagent (b) A Claisen condensation

Following are structural formulas for two enamines. N (a) (b) N Me Me Draw structural formulas for the secondary amine and carbonyl compound from which each enamine is derived.

Write a mechanism for the hydrolysis of the following iminium chloride in aqueous HCl. N O 1 1 HCl/H2O 1 HH (racemic) (racemic) O Cl2 N 1 O Cl2

Show how to use alkylation or acylation of an enamine to convert acetophenone to the following compounds. Ph O O Ph O O (a) (b) Ph OEt O O (c

Show how the acetoacetic ester synthesis can be used to prepare these compounds. O O O O (a) (b) (c)

Show how to convert racemic ethyl 2-oxocyclopentanecarboxylate to this compound. O (racemic) COOH

Show how the malonic ester synthesis can be used to prepare the following substituted acetic acids. COOH O (a) (b) COOH (c) COOH

Show the product formed from each Michael product in the solution to Example 19.13 after (1) hydrolysis in aqueous NaOH, (2) acidifi cation, and (3) thermal decarboxylation of each b-ketoacid or b-dicarboxylic acid. These reactions illustrate the usefulness of the Michael reaction for the synthesis of 1,5-dicarbonyl compounds.

Show how the sequence of Michael reaction, hydrolysis, acidifi cation, and thermal decarboxylation can be used to prepare pentanedioic acid (glutaric acid).

Show how to bring about the following conversion. O ? CH3O O CH3O

Propose two syntheses of 4-phenyl-2-pentanone, each involving conjugate addition of a lithium diorganocopper reagent.

Show how you might prepare the following compounds using directed aldol reactions. OH O O OH (a) (b)

Draw a structural formula for the product of the aldol reaction of each compound and for the a,b- unsaturated aldehyde or ketone formed from dehydration of each aldol product. O O H O O (a) (b) (c)

Draw a structural formula for the product of each crossed aldol reaction and for the compound formed by dehydration of each aldol product. CHO O (a) CCH3 1 O CH O O (c) 1 HCH O 1 (b) (d) PhCHO 1 H O

When a 1:1 mixture of acetone and 2-butanone is treated with base, six aldol products are possible. Draw a structural formula for each product.

Show how to prepare each a,b-unsaturated ketone by an aldol reaction followed by dehydration of the aldol product. Ph O O (a) (b)

Show how to prepare each a,b-unsaturated aldehyde by an aldol reaction followed by dehydration of the aldol product. (a) CHO (b) CHO

When treated with base, the following compound undergoes an intramolecular aldol reaction to give a product containing a ring (yield 78%). base O O H C10H14O H 1 2O Propose a structural formula for this product.

Cyclohexene can be converted to 1-cyclopentenecarbaldehyde by the following series of reactions. CHO 1-Cyclopentenecarbaldehyde OsO4 HIO4 H2O2 C6H12O2 base C6H10O2

Propose a structural formula for each lettered compound. OH OH EtO2Na CrO 1 3 pyridine EtOH A (C11H18O2) B (C11H16O) (racemic)

How might you bring about the following conversion? O

Pulegone, C10H16O, a compound from oil of pennyroyal, has a pleasant odor midway between peppermint and camphor. Treatment of pulegone with steam produces acetone and 3- methylcyclohexanone. 1 H2O O Pulegone 3-Methylcyclohexanone Acetone O O 1 steam (a) Natural pulegone has the confi guration shown. Assign an R or S confi guration to its chiral center. (b) Propose a mechanism for the steam hydrolysis of pulegone to the compounds shown. (c) In what way does this steam hydrolysis affect the confi guration of the chiral center in pulegone? Assign an R or S confi guration to the 3-methylcyclohexanone formed in this reaction.

Propose a mechanism for this acid-catalyzed aldol reaction and the dehydration of the resulting aldol product. ArSO3H O O O O 1 H2O (racemic) O

Show the product of Claisen condensation of each ester. (a) Ethyl phenylacetate in the presence of sodium ethoxide (b) Methyl hexanoate in the presence of sodium methoxide

When a 1:1 mixture of ethyl propanoate and ethyl butanoate is treated with sodium ethoxide, four Claisen condensation products are possible. Draw a structural formula for each product.

Draw structural formulas for the b-ketoesters formed by Claisen condensation of ethyl propanoate with each ester. O O (a) EtOC9COEt O (b) PhCOEt O (c) HCOEt

Draw a structural formula for the product of saponifi cation, acidifi cation, and decarboxylation of each b-ketoester formed in Problem 19.31.

The Claisen condensation can be used as one step in the synthesis of ketones, as illustrated by this reaction sequence. O OEt 1. EtO2Na1 2. HCl, H2O NaOH, H2O heat A C9H18O HCl, H2O heat B Propose structural formulas for compounds A and B and the ketone formed in this sequence.

Propose a synthesis for each ketone, using as one step in the sequence a Claisen condensation and the reaction sequence illustrated in Problem 19.33. Ph Ph O Ph Ph O H O H (a) (b) (c)

Propose a mechanism for the following conversion. O OEt 1. NaH 2. 1 EtOH (racemic) O O O

Claisen condensation between diethyl phthalate and ethyl acetate followed by saponifi cation, acidifi cation, and decarboxylation forms a diketone, C9H6O2. 1. EtO2Na1 2. HCl, H2O NaOH, H2O heat 1 CH3COOEt A C9H6O2 HCl, H2O heat B COOEt COOEt Diethyl phthalate Ethyl acetate Propose structural formulas for compounds A, B, and the diketone.

In 1887, the Russian chemist Sergei Reformatsky at the University of Kiev discovered that treatment of an a-haloester with zinc metal in the presence of an aldehyde or ketone followed by hydrolysis in aqueous acid results in formation of a b-hydroxyester. This reaction is similar to a Grignard reaction in that a key intermediate is an organometallic compound, in this case a zinc salt of an ester enolate anion. Grignard reagents, however, are so reactive that they undergo selfcondensation with the ester. O Zn benzene 1. PhCHO 2. H2O, HCl Zinc salt of an enolate anion BrCH2COEt O CH2"COEt PhCHCH2COEt O2[ZnBr]1 OH A -hydroxyester (racemic) b Show how a Reformatsky reaction can be used to synthesize these compounds from an aldehyde or ketone and an a-haloester. O OMe O HO OMe OH O OEt (a) (b) (c) (four stereoisomers as two racemic mixtures) (four stereoisomers as two racemic mixtures) (racemic)

Many types of carbonyl condensation reactions have acquired specialized names, after the 19th century organic chemists who fi rst studied them. Propose mechanisms for the following named condensations. (a) Perkin condensation: Condensation of an aromatic aldehyde with an acid anhydride O O O O HPh Ph OH 1. CH3COO2Na1 2. H2O, HCl 1 Cinnamic acid O (b) Darzens condensation: Condensation of an a-haloester with a ketone or an aromatic aldehyde O 1 tert- BuO2K1 COOEt O Cl COOEt

When 2-methylcyclohexanone is treated with pyrrolidine, two isomeric enamines are formed. H1 O A (85%) 1 1 1 H2O N N H N B (15%) Why is enamine A with the less substituted double bond the thermodynamically favored product? (You will fi nd it helpful to examine the models of these two enamines.)

Enamines normally react with methyl iodide to give two products: one arising from alkylation at nitrogen and the second arising from alkylation at carbon. For example, Product of C-alkylation CH3I 25C reflux 1 N N I2 1 N I2 1 Product of N-alkylation (racemic) N I 1 2 CH3 CH3 CH3 Heating the mixture of C-alkylation and N-alkylation products gives only the product from C-alkylation. Propose a mechanism for this isomerization.

Propose a mechanism for the following conversion. N 1. Et3N, heat 1 COOMe 2. H3O1 Br Br MeOOC O

The following intermediate was needed for the synthesis of tamoxifen, a widely used antiestrogen drug for treating estrogen-dependent cancers such as breast and ovarian cancer. OH O OH O Needed for the synthesis of tamoxifen (A) Propose a synthesis for this intermediate from compound A.

Propose a mechanism for the following reaction. O acid HC CH3NH2 O CH 1 1 2H2O CH3 N

Propose syntheses of the following derivatives of diethyl malonate, each of which is a starting material for synthesis of a barbiturate. Needed for the synthesis of amobarbital (a) Needed for the synthesis of secobarbital (b) COOEt COOEt COOEt COOEt

2-Propylpentanoic acid (valproic acid) is an effective drug for treatment of several types of epilepsy, particularly absence seizures, which are generalized epileptic seizures characterized by brief and abrupt loss of consciousness. Propose a synthesis of valproic acid starting with diethyl malonate.

Show how to synthesize the following compounds using either the malonic ester synthesis or the acetoacetic ester synthesis. (a) 4-Phenyl-2-butanone (b) 2-Methylhexanoic acid (c) 3-Ethyl-2- pentanone (d) 2-Propyl-1,3-propanediol (e) 4-Oxopentanoic acid (f) 3-Benzyl-5-hexene-2-one (g) Cyclopropanecarboxylic acid (h) Cyclobutyl methyl ketone

Propose a mechanism for formation of 2-carbethoxy-4-butanolactone and then 4-butanolactone (g- butyrolactone) in the following sequence of reactions. 1. EtO2Na1 2. COEt O O O O O O 2- Carbethoxy- 4-butanolactone 3. NaOH, H2O, heat 4. HCl heat 4-Butanolactone ( -Butyrolactone) g EtO OEt O O

Show how the scheme for formation of 4-butanolactone in Problem 19.47 can be used to synthesize lactones (a) and (b), each of which has a peach odor and is used in perfumery. As sources of carbon atoms for these syntheses, use diethyl malonate, ethylene oxide, 1-bromoheptane, and 1-nonene. (racemic) (racemic) (a) (b) O O O

The following synthetic route is used to prepare an intermediate in the total synthesis of the anticholinergic drug benzilonium bromide. Br OMe O EtNH2 OCH3 O 2. MeO2Na1 3. H3O1 4. NaOH, H2O 6. NaBH4 5. H3O1, heat (D) N Et (racemic) 1 (B) (C) 1. (A) OH Propose structural formulas for intermediates A, B, C, and D.

Propose a mechanism for formation of the bracketed intermediate, and for the bicyclic ketone formed in the following reaction sequence. O O2 1. H3O1 2. KOH 1 N An intermediate (not isolated) (racemic) N 1 O

Discuss the different experimental conditions used to give the major and minor product distributions shown. O 1. LDA 3. acid O major 1 OH O minor O OH O 1. LDA 2. 2. 3. acid O minor 1 OH O major O OH

Why does the following reaction give the product shown as the major product when 0.95 equivalents of LDA relative to ketone are used in the fi rst step? 1. LDA 2. CH3I O O

Using one of the reactions in this chapter, give the correct starting material (AL) needed to produce each structure (af ). Name the type of reaction used. O (a) O O (b) O (c) O O O (d) O O O (e) O (f) O HO HO 5498X_19_ch19_p742-809.indd 796 12/13/10 4:45:39 PM Copyright 2010 Cengage Learning. All Rights Reserved. May not be copied, scanned, or duplicated, in whole or in part. Due to electronic rights, some third party content may be suppressed from the eBook and/or eChapter(s). Editorial review has deemed that any suppressed content does not materially affect the overall learning experience. Cengage Learning reserves the right to remove additional content at any time if subsequent rights restrictions require it. Problems 797 Br O O O O DE F O O AB C Br Br O O O O G H I J K L O O O O O O O O O O O O

Show experimental conditions by which to carry out the following synthesis. OMe Methyl acetoacetate Benzaldehyde Ph9CHO 1 O O COOMe O O O Ph MeOOC MeOOC Ph

Nifedipine (Procardia, Adalat) belongs to a class of drugs called calcium channel blockers and is effective in the treatment of various types of angina, including that induced by exercise. Show how nifedipine can be synthesized from 2-nitrobenzaldehyde, methyl acetoacetate, and ammonia. (Hint: Review the chemistry of your answers to Problems 19.43 and 19.54 and then combine that chemistry to solve this problem.) OMe O O 1 2 1 NH3 acid MeOOC COOMe NO2 H Nifedipine N NO2 CHO

The compound 3,5,5-trimethyl-2-cyclohexenone can be synthesized using acetone and ethyl acetoacetate as sources of carbon atoms. New carbon-carbon bonds in this synthesis are formed by a combination of aldol reactions and Michael reactions. Show reagents and conditions by which this synthesis might be accomplished. O O O O COOEt 3,5,5-Trimethyl- 2-cyclohexenone O O O COOH O O 1 2 3 4 5

The following b-diketone can be synthesized from cyclopentanone and an acid chloride using an enamine reaction. !CCl 1 O O O O (racemic) (a) Propose a synthesis of the starting acid chloride from cyclopentene. (b) Show the steps in the synthesis of the b-diketone using a morpholine enamine.

Oxanamide is a mild sedative belonging to a class of molecules called oxanamides. As seen in this retrosynthetic scheme, the source of carbon atoms for the synthesis of oxanamide is butanal. Oxanamide Butanal O CHO O NH2 O NH2 O Cl O OH O H 1 2 3 4 5 (a) Show reagents and experimental conditions by which oxanamide can be synthesized from butanal. (b) How many chiral centers are there in oxanamide? How many stereoisomers are possible for this compound?

The widely used anticoagulant warfarin (see Chemical Connections: From Moldy Clover to a Blood Thinner in Chapter 18) is synthesized from 4-hydroxycoumarin, benzaldehyde, and acetone as shown in this retrosynthesis. Show how warfarin is synthesized from these reagents. 5498X_19_ch19_p742- 809.indd 798 12/13/10 4:45:40 PM Copyright 2010 Cengage Learning. All Rights Reserved. May not be copied, scanned, or duplicated, in whole or in part. Due to electronic rights, some third party content may be suppressed from the eBook and/or eChapter(s). Editorial review has deemed that any suppressed content does not materially affect the overall learning experience. Cengage Learning reserves the right to remove additional content at any time if subsequent rights restrictions require it. Problems 799 O 1 1 O O O OH H O Warfarin (a synthetic anticoagulant; racemic) 4-Hydroxycoumarin Acetone Benzaldehyde O OH O O

Following is a retrosynthetic analysis for an intermediate in the industrial synthesis of vitamin A. O O (Needed for the synthesis of vitamin A) 2-Methyl-1,3-butadiene (Isoprene) Ethyl acetoacetate Cl 1 1 COOEt HCl 1 2 (a) Addition of one mole of HCl to isoprene gives 4-chloro-2-methyl-2-butene as the major product. Propose a mechanism for this addition and account its regioselectivity. (b) Propose a synthesis of the vitamin A precursor from this allylic chloride and ethyl acetoacetate.

Following are the steps in one of the several published synthesis of frontalin, a pheromone of the western pine beetle. Diethyl malonate Frontalin (racemic) (racemic) (racemic) O COOEt COOEt COOEt COOEt COOH OH OTs CN O O O OH OH cyclizes under conditions (8) O O 1 2 3 4 5 6 7 8 (a) Propose reagents for Steps 18. (b) Propose a mechanism for the cyclization of the ketodiol from Step 8 to frontalin

2-Ethyl-1-hexanol was needed for the synthesis of the sunscreen octyl p-methylcinnamate (See Chapter 23, Chemical Connections: Sunscreens and Sunblocks). Show how this alcohol could be synthesized (a) by an aldol condensation of butanal and (b) by a malonic ester synthesis starting with diethyl malonate.

Gabapentin, an anticonvulsant used in the treatment of epilepsy, is structurally related to the neurotransmitter 4-aminobutanoic acid (GABA). NH2 COOH Gabapentin 4-Aminobutanoic acid ( -Aminobutyric acid, GABA) NH2 COOH Gabapentin was designed specifi cally to be more lipophilic than GABA and, therefore, more likely to cross the blood-brain barrier, the lipid-like protective membrane that surrounds the capillary system in the brain and prevents hydrophilic (waterloving) compounds from entering the brain by passive diffusion. Given the following retrosynthetic analysis, propose a synthesis for gabapentin. O 1 NH2 COOH Gabapentin Cyclohexanone Diethyl malonate NH2 COOEt COOEt COOEt COOEt COOEt CN COOEt

The following three derivatives of succinimide are anticonvulsants and have found use in the treatment of epilepsy, particularly petit mal seizures. O O Methsuximide (racemic) Ethosuximide (racemic) N Ph O O N CH3 H Phensuximide (racemic) O O N CH3 Ph Following is a synthesis of phensuximide. NaOEt 1. NaOH, H2O 2. HCl, H2O 3. heat CH3NH2 Benzaldehyde Ethyl cyanoacetate (A) (B) (racemic) CN COOEt CN COOEt H (C) (racemic) HOOC COOH (D) (racemic) EtOOC COOEt KCN CN NC COOEt Phensuximide (racemic) O O N CH3 Ph9CHO 1 Ph Ph Ph Ph Ph 5498X_19_ch19_p742-809.indd 800 Problems 801 (a) Propose a mechanism for the formation of (A). (b) What (persons) name is given to this type of reaction involved in the conversion of (A) to (B)? (c) Describe the chemistry involved in the conversion of (B) to (C). You need not present detailed mechanisms. Rather, state what is accomplished by treating (B) fi rst with NaOH and then with HCl followed by heating. (d) Propose experimental conditions for the conversion of (C) to (D). (e) Propose a mechanism for the conversion of (D) to phensuximide. (f) Show how this same synthetic strategy can be used to prepare ethosuximide and methsuximide. (g) Of these three anticonvulsants, one is considerably more acidic than the other two. Which is the most acidic compound? Estimate its pKa and account for its acidity. How does its acidity compare with that of phenol? With that of acetic acid?

The analgesic meperidine (Demerol) was developed in the search for analgesics without the addictive effects of morphine. As shown in these structural formulas, it represents a simplifi cation of morphines structure. HO O OH O O O H N H3C N CH3 Morphine O N H3C Meperidine (redraw) Meperidine is prepared by treating phenylacetonitrile with one mole of bis- (N-2- chloroethyl)methylamine (a nitrogen mustard) in the presence of two moles of sodium hydride to give (A). Refl uxing (A) with concentrated sodium hydroxide followed by neutralization of the reaction mixture with dilute HCl gives (B). Treating (B) with ethanol in the presence of one equivalent of HCl gives meperidine as its hydrochloride salt. CN C13H16N2 Cl 2NaH Cl 1.NaOH 2.HCl Phenylacetonitrile Meperidine hydrochloride (A) C13H17NO2 C15H21NO2 ? HCl EtOH, HCl (B) N9CH3 (a) Propose structural formulas for (A) and (B). (b) Propose a mechanism for the formation of (A).

Verapamil (Effexor), a coronary artery vasodilator, is used in the treatment of angina caused by insuffi cient blood fl ow to cardiac muscle. Even though its effect on coronary vasculature tone was recognized over 30 years ago, it has only been more recently that its role as a calcium channel blocker has become understood. Below is a retrosynthetic analysis leading to a convergent synthesis; it is convergent because (A) and (B) are made separately and then combined (i.e., the route converges) to give the fi nal product. Convergent syntheses are generally much more effi cient than those in which the skeleton is built up stepwise. 802 Chapter 19 Enolate Anions and Enamines O OMe OMe OMe OMe OMe OMe OMe OMe MeO MeO MeO MeO MeO MeO Me CN CN H Br N Me Cl N Cl Br Verapamil (racemic) (A) (racemic) CN (B) Me HN 1 1 1 Isopropyl bromide 3,4- Dimethoxyphenylacetonitrile (C) Cl9C9OEt H2N 1 (D) Ethyl chloroformate 1-Bromo-3-chloropropane 1 2 3 4 5 (a) Given this retrosynthetic analysis, propose a synthesis for verapamil from the four named starting materials. (b) It requires two steps to convert (D) to (C). The fi rst is treatment of (D) with ethyl chloroformate. What is the product of this fi rst step? What reagent can be used to convert this product to (C)? (c) How do you account for the regios

Based on this retrosynthetic analysis, propose a synthesis of the anticoagulant (inhibits blood clotting) diphenadione. 1 Diphenadione Diethyl phthalate O O O O OEt OEt O O Because of its anticoagulant activity for blood, this compound is used as a rodenticide. For the story of the discovery of the anticoagulant dicoumarin, see Chemical Connections: From Moldy Clover to a Blood Thinner in Chapter 18.

Following are two possible retrosynthetic analyses for the anticholinergic drug cycrimine. Fill in the details of each potential synthesis. O O O OH N N O N H N H 1 1 1 Cycrimine (racemic)

Show how the tranquilizer valnoctamide can be synthesized using diethyl malonate as the source of the carboxamide group. O NH2 2-Ethyl-3-methylpentanamide (Valnoctamide; racemic)

In Problem 7.28 we saw this two-step sequence in Johnsons synthesis of the steroid hormone progesterone. Propose a structural formula for the intermediate formed in Step 3, and a mechanism for its conversion in Step 4 to progesterone. O 3. O3 4. 5% KOH/H2O Me C Progesterone Me Me H H H O Me O Me Me Me H H

Monensin, a polyether antibiotic, was isolated from a strain of Streptomyces cinamonensis in 1967, and its structure was determined shortly thereafter. O OMe Me Et H H H H COOH Me HO 7 O O O O Me HO Me HO Me Me 5 Me 3 1 Monensin This molecule exhibits a broad-spectrum anticoccidial activity and, since its introduction in 1971, has been used to treat coccidial infections in poultry and as an additive . 804 Chapter 19 Enolate Anions and Enamines in cattle feed. In the synthesis of monensin, Y. Kishi chose to create the molecule in sections and then join them to create the target molecule. Following is an outline of the steps by which he created the seven-carbon-chain building block on the left side of the molecule. O O H H O Me O CN (1) 1 2 3 O Me (2) O COOH (3) O OH Me (4) OH OMe COOMe Me Me 5 7 753 Me 3 1 CN Me O (5) O Me Me OH COOEt Me (6) (7) O Me OH Me (8) O Me OBn Me Me (9) O Me OBn OMe (10) O Me OBn Me OMe (11) (12) O Me OH Me OMe O Me H O (13) Me Me OMe O Me COOMe (14) Me Me OMe O Me Me Me Me OH MeOOC several steps turn in space and compare with monensin Me Me OMe OH OMe OH H O Me OH Propose a reagent or reagents for Steps 114. Note that this fragment contains fi ve chiral centers. You do not have to predict or to rationalize the stereochemistry of each step, but rather only to propose a reagent or type of reagent to bring about each step.

We now continue the use of organic chemistry roadmaps. Because of the new and unique nature of the carbon-carbon bond forming reactions presented, we recommend that you make a new roadmap that is only for Chapter 19. To make your own roadmap for Chapters 19, take a blank full sheet of paper and write the following functional groups in the orientations shown. Note that product structures are used here along with names because the products of these reactions generally have more complex patterns of functional groups. Highlighted bonds are used to indicate the key combinations of functional groups that are characteristic for the given reaction. Make sure to fi ll the entire sheet of paper and leave plenty of room between functional groups. Most students fi nd it helpful to use a poster-sized piece of paper fi lled out in the landscape orientation. Alkylated methyl ketone R1 O H3C H3C R1 O R2 -Unsaturated carbonyl Aldol Reaction R2 O R3 R4 R1 -Ketoester OO OR4 R1 R2 R3 -Alkylated carbonyl -Hydroxy carbonyl R2 O R3 HO R4 R1 Nu = enolate forming species or amines Cyclic -Ketoester R1 R4 R5 O O R7 R3 R6 O R2 R8 Alkylated -carbon O R4 R3 R1 R2 -Dicarbonyl O O R1 R4 R2 R3 Alkylated carboxylic acid R1 O HO R1 O HO R2 diester malonic ester acetoacetic ester ketone, aldehyde NaOR HOR 1) LDA 2) R-X 3) H3O+/H2O 1) 2-amine 2) acid chloride 3) H3O+/H2O ester O R3 R2 R5 R4 R1 O R3 R2 R1 R4 Nu As before, refer to the Key Reactions section at the end of this chapter. Write the reagents required to bring about each reaction next to the arrows shown. Next, record any regiochemistry or stereochemistry considerations relevant to the reaction. You should also record any key aspects of the mechanism such as formation of an important intermediate as a helpful reminder. It is helpful to keep track of all reactions that make carbon-carbon bonds, because these help you build large molecules from smaller fragments. This especially applies to the reactions in Chapter 19. On the above organic chemistry roadmap template, the information for the aldol reaction has been added to help you get started. Appendix 11 contains a series of roadmaps for different sections of the book, but you should use those for reference only after you have completed your own.