20 CARBOXYLIC ACIDS

• To determine the structures of carboxylic acid derivatives, draw and name them.

• Discuss the physical properties of acid derivatives and compare their reactivity.

• Acid derivatives from compounds with other functional groups should be proposed for single-step and multistep synthesis.

• Predict the products and propose mechanisms for the reactions of carboxylic acid derivatives.

• The antibiotics can cause thebacteria to develop a resistance.
• A b-lactam is an active functional group in many antibiotics.
• Three types of antibiotics are shown in the structures.

• The most important acid derivatives are esters, amides, and nitriles.
• We often think of acid halides and anhydrides as forms of the parent acids rather than completely different compounds.

• Making and using derivatives of carboxylic acids are some of the advances in organic chemistry.
• Synthetic amides have been created that mimic the desirable properties of proteins.

• The nylon in a climbing rope is a synthetic polyamide that mimics a spider's web.
• The antimicrobial properties of naturally occurring antibiotics are extended by Amides.

• In nature and in the chemical industry, esters are common.

• A mixture of animal fats and vegetable oils are called a mixture of esters.
• The tastes and odors of fruits and flowers are created by plants.
• In addition to making synthetic esters for flavors, odors, and lubricants, chemists have made synthetic polyesters such as Dacron for clothing and Mylar for magnetic recording tapes.

• There are examples of naturally occurring esters and Amides here.
• ripe bananas have a characteristic odor, and geranyl acetate is found in the oil of roses.
• One of the best insect repellencies is -toluamide, and penicillin G is one of the best antibiotics.

• Structural features of most acid derivatives are similar.
• The carboxylic acids have a carbonyl group bonding to a negative atom.

• Acid derivatives include nitriles because they can be hydrolyzed to give acids.

• An alcohol and carboxylic acid combination with a loss of a molecule of water is called an ester.
• It has been shown that an acid with an alcohol can be used to create esters.

• The names of esters have two words that reflect their structure.
• The common name is derived from the common names of the alkyl group and the carboxylate.

• The Greek letter designates the carbon atom that bears the hydroxy group.

• Substituents are the same as the parent acid.

• An amine reacts with an acid to form a salt.
• Water is driven off when this salt is heated to over 100 degrees.

• There is a pair of electrons on the nitrogen atom.
• Amides are only weakly basic, and we consider the amide functional group to be neutral.
• The carbonyl oxygen atom is the location of the protons rather than on nitrogen.
• The lack of basicity can be explained by the fact that the amide is a resonance hybrid of the conventional structure and a structure with a double bond between carbon and nitrogen.

• The carbonyl carbon atom can be bonding with pi.
• Formamide has a structure similar to an alkene.
• Many local anesthetics are amides.

• The prototype for this group of drugs is lidocaine.

• Substituted amide.

• Substituted amides.

• First name the corresponding acid if you want to name a primary amide.

• Acetanilide has historical names that are still used.

• Lactams are formed when the carboxyl group and the amino group join to form an amide.

• Although nitriles lack the carbonyl group of carboxylic acids, they are classified as acid derivatives because they hydrolyze to give carboxylic acids and can be synthesised by dehydration of amides.

• The bond angle is 180 degrees.
• The structure of a nitrile is similar to that of a terminal alkyne, except that the nitrogen atom of the nitrile has a single pair of electrons.

• nitrile has a single pair of electrons on nitrogen, but it is not very basic.
• The electrons are tightly bound and unreactive, and they are close to the nucleus.

• The names of nitriles are derived from carboxylic acids.

• The acid chlorides are the most common acyl halides.

• The halogen atom of an acyl halide withdraws electron density from the carbonyl carbon, enhancing its electrophilic nature and making acyl halides particularly reactive toward nucleophilic acyl substitution.
• The halide ion is a good leaving group.

• A molecule of water is lost in an acid anhydride.

• Anhydrides are activated derivatives of carboxylic acids and not as reactive as acid halides.
• The carbonyl group is activated by the chlorine atom in an acid chloride.
• The carboxylate group serves these functions.

• Half of anhydride's acid units are lost when leaving groups.
• We wouldn't use the anhydride as an activated form if the acid was expensive.
• The leaving group is used by the acid chloride.
• The necessary anhydride is cheap and readily available.
• The ones we use the most are acetic anhydride, phthalic anhydride, succinic anhydride, and maleic anhydride.
• If a five- or six-membered ring results, diacids form cyclic anhydride.

• It is not always obvious which functional group of a compound is the main one and which groups should be named as substituents.
• The priorities are summarized in the table, along with the suffixes used for main groups and the prefixes used for substituents.

• The name of the carboxylic acid derivatives is reviewed in IUPAC name where possible.

• The physical properties of acid derivatives are dependent on their polarity and hydrogen-bonding properties.
• Amides have high boiling points and melting points.

• For comparison, alkanes are included.
• There are boiling points near the unbranched alkanes with similar weights.
• The boiling points of these acid derivatives are unaffected by the carbonyl group's polarity.

• elevated boiling points are caused by strongly hydrogen bonding in the liquid phase.
• The stable hydrogen-bonded dimer has a higher boiling point.
• The boiling points of nitriles are higher than those of acid chlorides.

• The points of acid derivatives are plotted.
• For comparison, alcohols and unbranched alkanes are included.

• Amides have higher boiling points and melting points than other compounds.
• The picture shows a partial negative charge on oxygen and a partial positive charge on nitrogen.
• The hydrogen is strongly electrophilic.

• They can't participate in hydrogen bond ing because they are good hydrogen bond acceptors.
• The boiling points are close to those of carboxylic acids.

• A higher temperature is needed for boiling because of Vaporization.

• R has a strongly polar nature.

• Strong hydrogen bonding in amides intermolecular attractions is caused by R stabilizing the liquid phase.

• High melting points are caused by strong hydrogen bonding between primary and secondary amides.

• Acid derivatives can be found in common organic solvents such as alcohols, ethers, chlorinated alkanes, and aromatic hydrocarbons.
• Acid chlorides and anhydride can't be used in water and alcohols because they react with them.
• Many of the smaller esters, amides, and nitriles are able to form hydrogen bonds with water because of their high polarity.

• A boiling point of 77 degC is convenient for easy evaporation from a reaction mixture.
• Miscible with water, these three solvent are often used in solvent mixture with water.

• The features of acid derivatives help us to distinguish them.

• The variations in the carbonyl absorptions are predictable and reliable for most acid derivatives.

• Strong absorptions are given by different types of carbonyl groups.
• The best way to detect and differentiate these carboxylic acid derivatives is through the use of IR.
• The IR absorptions of carbonyl functional groups are summarized in Table 21.

• The standard for comparison is 1710 cm-1 for simple ketones and acids.
• A complete table of IR frequencies can be found in Appendix 2.

• The groups absorb about 1735 cm-1.

• Only strained cyclic ketones absorb strongly in this region.
• There are many types of bonds that absorb in this region.
• We may look for it in uncertain cases, but we don't consider this absorption to be diagnostic.

• The stretching of the carbonyl is lowered.
• Simple ketones and aldehydes absorb around 1710 to 1725 cm-1.

• The stretching frequencies of simple and conjugated esters are around 1735 cm-1.

• Strong carbonyl stretching absorptions are provided by Amides, ketones, carboxylic acids, and aldehydes.

• Simple amides have lower carbonyl stretching frequencies than other carboxylic acid derivatives and can absorb up to 1680 cm-1.
• The absorption agrees with the picture of the amide.

• The amide C " O has a lower stretching Frequency.

• H absorptions are usually sharper.

• There are H bonds and two peaks in the region.

• H stretching absorptions at 3350 and 3180 cm-1.

• Lactams and unstrained lactones absorb at typical frequencies.
• The ring strain raises the absorption frequencies.
• The increase in carbonyl stretching frequencies can be seen in cyclic ketones with five-membered or smaller rings.

• A characteristic C and N are present in nitriles.

• There is a strong triple-bond stretching absorption.
• The IR spectrum of hexanenitrile shows C, N, and stretching to 2246 cm-1.

• It is possible to confirm that an acid has been converted to a pure acid chlo with the help of the absorptions listed in the table.
• The carbonyl stretching of an acid chloride occurs at a information that can be used to determine high frequencies.

• Ring strain in a lactam increases carbonyl stretching.

• The C " O absorption stretchings at 1818 and 1751 cm-1 are shown in the spectrum.

• A carboxylic acid, an ester, an amide, a nitrile, an acid chloride, or an acid anhydride may be shown next.

• List the frequencies you used to make your decision, and determine the functional group suggested by each spectrum.

• There is a correlation between acid derivatives and IR spectroscopy.
• Information about the functional groups is given by IR, while information about the alkyl groups is given by NMR.
• The combination of IR and NMR gives enough information to determine the structure.

• The chemical shifts found in acid derivatives are close to those found in similar chemicals.
• If the carbonyl group is part of a ketone, aldehyde, acid, ester, or amide, the protons alpha to a carbonyl group absorb between d 2.0 and d 2.5.

• Depending on concentration and solvent, the H protons of an amide may be broad or split.
• The protons on the a carbon atom are 888-609- 888-609- 888-609- 888-609- 888-609- 888-609- 888-609- 888-609- 888-609- 888-609- 888-609- 888-609- 888-609- 888-609- 888-609- 888-609- 888-609- 888-609- 888-609- 888-609- 888-609- 888-609- 888-609- 888-609- 888-609- 888-609- 888-609- 888-609- 888-609- 888-609- 888-609- 888-609- 888-609- 888-609- 888-609- 888-609- 888-609- 888-609- 888-609- 888-609- 888-609- 888-609- 888-609- 888-609- 888-609- 888-609- 888-609- 888-609- 888-609- 888-609-

• The two groups appear to be two singlets, not a spin-spin splitting doublet.
• The two singlets were caused by hindered rotation.

• The carbon atoms absorb up to 40 parts per million.
• 3@ hybridized carbons in oxygen in esters and nitrogen in Amides absorb around 60 to 80 parts per million, and those in nitrogen in Amides absorb around 40 to 60 parts per million.

• The amide bond was hindered by two singlets of dimethylformamide.
• The cisoid group is farther downfield than the transoid group.

• There are two distinct cisoid and transoid carbons at 31 and 36 parts per million, respectively.

• Under both basic and acidic conditions, acid derivatives react with a wide variety of nucleophilic reagents.
• The leaving group is expelled from the carbonyl group when the nucleophilic reagent adds to it.
• The leaving group is replaced by the nucleophilic reagent through this addition-elimination process.
• In the sections that follow, we look at several examples of these reactions, first under basic conditions and then under acidic conditions.
• We will note similarities with other reactions that follow the same addition-elimination pathway.

• In chemistry and biochemistry, these reactions are common.

• Most of the cell is affected by this mechanism.

• A tetrahedral intermediate is given by the addition of the nucleophile.

• The carbonyl group is regenerated when the leaving group is eliminated.

• A tetrahedral intermediate is given by the addition of the nucleophile.

• The carbonyl group is regenerated when the leaving group is eliminated.

• We can imagine converting any acid derivative into almost any other.
• Some of these reactions are not practical.
• Favorable reactions convert a more reactive acid derivative to a less reactive one.
• Predicting these reactions requires knowing the relative reactivity of acid derivatives.

• Acid derivatives have different reactivity toward acyl substitution.
• acetyl chloride reacts with water in a violently exothermic reaction, whereas acetamide is stable in boiling water.
• boiling acetamide in acid or base for several hours is how it is hydrolyzed.

• The basicity of the leaving groups leads to the order of reactivity.
• As the leaving group becomes more basic, the reactivity of the derivatives decreases.

• The reactivity of acid derivatives is affected by resonance stabilization.
• resonance stabilization is lost when a nucleophile attacks.

• There is less stabilization in esters.

• In an anhydride, the stabilization is shared between two carbonyl groups.
• The stabilization of each carbonyl group is less than the stabilization of an ester carbonyl.

• There is little stabilization of an acid chloride.

• An acid chloride can easily be converted to an anhydride, ester, or amide.
• An anhydride can be converted to an amide.
• An amide can only be added to the acid or the carboxylate ion in basic conditions.

• Many indi carbon may be involved in the conversion of acid derivatives.
• There are variations on a single intermediate.
• The addition-elimination mechanism of nucleophilic acyl substitution is the intermediate theme.
• The regenerate the carbonyl group reactions are only found in the nature of the nucleophile.

• In the acidic pathway, the acid we study these mechanisms, watch for the differences and don't feel like you have to catalyst the carbonyl group learn each specific mechanism.

• Acid chlorides can be used to synthesise anhydride, practice using path esters, and amides.
• Acid chlorides react with carboxylic acids to form anhydride.
• The strongly elec apply can be attacked by either oxygen atom of the acid.
• The trophilic carbonyl group of the acid chloride is a better strategy.

• The leaving group was eliminated.

• The standard pattern of an addition-elimination mechanism ends with a loss of a protons to give the final product.

• The leaving group was eliminated.

• Acid chlorides react with alcohols in a strongly exothermic reaction.
• Caution is needed to keep the temperature low to avoid dehydration of the alcohol, because acid chlorides are powerful dehydrating agents.
• Pyridine is added to the solution to counteract the by-product.

• The standard addition-elimination mechanism leads to the loss of a protons to give the final product.

• Acid chlorides react quickly with ammonia and amine.
• A twofold excess of the amine is required because the reaction can cause amine starting material to be protonated.
• Adding a base such as pyridine or NaOH to the amine will allow you to use less amine.

• The steps of a standard addition-elimination mechanism are followed by this reaction.

• A primary amide is created by the reaction of an acid chloride with ammonia.
• This reaction gives a secondary amide and a tertiary amide.

• Acid anhydride are still activated toward acyl substitution even though they are not as reactive as acid chlorides.
• An anhydride reacts with alcohol.
• One of the two acid units from the anhydride is expelled as the leaving group.

• The standard addition-elimination mechanism ends with the loss of a protons to give the ester.

• A primary amide is given when an anhydride is reacted with ammonia.
• Anhydride reacts with a primary amine to give a secondary amide and with a secondary amine to give a tertiary amide.

• The standard addition-elimination mechanism ends with a loss of a protons to give the amide.

• They can be converted to amides by heating with ammonia or amine.
• Primary amides are given when ammonia is used.

• Secondary amines give tertiary amides, while primary amines give secondary amides slowly.
• The nitrogen atom of the amine is transferred from the oxygen atom of the alcohol to the acyl group.

• This is a standard addition-elimination mechanism that ends with the loss of a protons.

• There is a mechanism for the reaction of benzyl alcohol with acetyl chloride.

• A mechanism for the reaction of acetic benzoic anhydride is proposed.

• It is difficult to distinguish between the two mechanisms because of the fast transfer of protons between the oxygen atoms.

• There is a mechanism for the reaction of aniline with acetic anhydride.

• A mechanism for the reaction of aniline with ethyl acetate to give acetanilide is proposed.

• You should be surprised by the loss of an alkoxide ion as a leaving group in the second step of ammonolysis.

• In our study of alkyl substitution and elimination reactions, we found that strong bases such as hydroxide and alkoxide are not good for these reactions.
• The mechanisms explain why strong bases can leave groups in acyl substitution even though they cannot in alkyl substitution.

• The one-step mechanism of the SN2 reaction is not endothermic or exothermic.

• The bond to the leaving group is half broken in the transition state, so the reaction rate is sensitive to the nature of the leaving group.
• This reaction is slow because of a poor leaving group.

• The leaving group leaves in a separate second step.
• A strong base may serve as a second step if it leaves in a transition state that resembles the reactant.
• The bond to the leaving group has barely begun to break in this exothermic step.
• The energy of an unstable, negatively charged transition state is not very sensitive to a stable molecule.

• The first example of a reaction with strong bases as leaving groups is nucleophilic acyl substitution.
• There will be many more examples.

• A strong base may serve as a leaving group if it leaves in a highly exothermic step.

• Each synthesis should have a mechanism for it.

• There is a mechanism for the reaction of benzyl and methylamine.
• Draw the transition state in which the leaving group leaves.

• The two alcohol groups can interchange when an alcohol is treated with a different alcohol in the presence of acid or base.
• The equilibrium can be driven toward the desired ester by removing the other alcohol or using a large excess of the desired alcohol.

• The simplest and best example of the acid-catalyzed and base-catalyzed nucleophilic acyl substitution mechanisms is transesterification.

• Consider the base-catalyzed transesterification of ethyl benzoate.
• This is cooking oil.

• Fats and oils can be used to attack the ester carbonyl group.

• A high molecule weight and low volatility is what O molecule is.

• One of the products is a lactone, when ethyl 4-hydroxybutyrate is heated in the presence of a trace of a basic catalyst.
• There is a mechanism for formation of this lactone.

• The stepwise procedure is used to propose a mecha CH O O nism for the following reaction.

• An ethoxy group is replaced by a methoxy group.

• The ester carbonyl group isn't strong enough to react with methanol.

• In step 3, it is converted to a strong electrophile.

• There is a bond needed for the product.

• The task is to break bonds, not form them.

• Acyl lost.
• The most common way to lose a group under acidic conditions is to substitution, which differs from protonate, and then lose it.
• The reverse of the mechanism used to gain the methoxy group is lost when the base-catalyzed reaction is lost.

• The final product must be a protonsated version of the carbonyl.

• This summary is left to you to review.

• Draw out all the individual steps to complete the mechanism for acid-catalyzed transesterification.

• The following ring- opening transesterification could be proposed.

• There is a summary of the mechanism of transesterification.

• The leaving group was eliminated.

• Extra proton transfers are required before and after the major steps.
• The first and second stages of the reaction take place.
• The first half of the reaction involves acid-catalyzed addition of the nucleophile and the second half involves acid-catalyzed elimination of the leaving group.

• The leaving group was acid-catalyzed elimination in the second half.

• Basic nucleophilic acyl substitution reactions work better with acid catalysts.
• acetic anhydride and salicylic acid are used to make aspirin.
• The reaction goes slowly when the reagents are mixed.
• The reaction can be completed in a minute or two with the addition of a drop of sulfuric acid.

• The acid-catalyzed reaction of salicylic acid with acetic anhydride can be proposed.

• Explain how a single drop of sulfuric acid increases reaction rate.

• Acid derivatives hydrolyze to produce carboxylic acids.
• Most of the time, hydrolysis occurs under acidic or basic conditions.

• Under neutral conditions acid halides and anhydride hydrolyze.
• Exposure to moist air can cause hydrolysis of an acid halide or anhydride.
• Storage acids and anhydrides under dry nitrogen and using dry solvent and reagents can help avoid hydrolysis.

• The reverse of the esterification equilibrium is acid-catalyzed hydrolysis.
• The equilibrium is driven by the addition of excess water.

• The carbonyl group is attacked by Hydroxide ion.
• The acid and the carboxylate ion are created by thepulsion of alkoxide ion.
• The exothermic transfer drives the completion of the process.
• A full mole of base is eaten.

• This is a standard addition-elimination mechanism that ends with a protons transfer.

• When a fat is hydrolyzed, the resulting long-chain sodium carboxylate salts are what we know as soap.
• Chapter 25 talks about detergents and soaps in more detail.

• Under basic conditions, draw a mechanism for the hydrolysis of this compound.

Which products will have the 18O label?

How would you prove that the 18O label is in the products?

• Base is used by soap manufacturers to hydrolyze fats.
• There are two reasons that basic hydrolysis is preferred.

• Amides hydrolyze to carboxylic acids in both acidic and basic conditions.
• Amides are the most stable of the acid derivatives, and stronger conditions are required for their hydrolysis.
• In most hydrolysis conditions, heating is done in 6 M HCl or 40% NaOH.

• The basic hydrolysis mechanism is the same as the one for the ester.
• The carbonyl is attacked by Hydroxide to give a tetrahedral intermediate.
• A carboxylic acid is quickly deprotonated to give the salt of the acid and ammonia.

• This is a standard addition-elimination mechanism that ends with a protons transfer.
• As the very poor leaving group leaves, the final proton transfer is very fast.

• The acid catalyzed hydrolysis of an ester is similar to the mechanism of amide hydrolysis under acidic conditions.
• The carbonyl group is activated by the formation of the carbonyl group.
• The amine can leave as a group of protons.
• The acid and the amine can be transferred quickly.

• The mechanism takes place in two stages.

• The leaving group was acid-catalyzed elimination in the second half.

• The products are favored under both acidic and basic conditions.
• To show which steps are exothermic to drive the reactions to completion.

• Aqueous acid or base is used to heating nitriles to Amides and carboxylic acids.
• Mild conditions can hydrolyze a nitrile.

• It can hydrolyze all the way to the carboxylic acid.

• The elec trophilic carbon of the cyano group is attacked by hydroxide.
• The tautomer of an amide is unstable.
• The amide is given when a protons is removed from oxygen and nitrogen.
• The same basepromoted mechanism is used in the further hydrolysis of the amide to the carboxylate salt.

• The enol of an amide can be found in the form of protons.

• The amide is caused by the removal and replacement of a protons.

• There is a mechanism for the basic hydrolysis of benzonitrile to the benzoate ion and ammonia.

• The mechanism for acidic hydrolysis of a nitrile is the same as the basic hydrolysis, except that the nitrile is first protonsated and then weakened by water.

• Under acidic conditions, the tautomerism involves deprotonation on oxygen and nitrogen.
• There is a mechanism for the acid-catalyzed hydrolysis of benzonitrile to benzamide.

• Alcohols, aldehydes, and amine can be reduced to alcohols, aldehydes, and amine.
• Acid derivatives are relatively difficult to reduce and need a strong agent such as LiAlH4 to do so.

• The other acid derivatives are less reactive than acid chlorides.
• Acid chlorides can be converted to primary alcohols by either lithium aluminum hydride or sodium borohydride.

• Both acid chlorides and esters react through an addition-elimination mechanism to give aldehydes.
• Diluted acid is added to the alkoxide after the reduction is complete.

• An aldehyde is reduced further to an alcohol by nucleophilic acyl substitution.

• Add acid to the workup.

• There is a mechanism for the reduction of octanoyl chloride.

• Diisobutylaluminum hydride reduces nitriles to aldehydes at low temperatures.
• Sections 18-9 and 18-10 covered these reductions.

• Some of the best synthetic routes to amine are provided by the reduction of amides and nitriles to amines.
• Primary amine is reduced to primary amides and nitriles.
• Both secondary and tertiary amines are reduced.

• The mechanism of this reduction is similar to a typical nucleophilic acyl substitu tion, with hydride ion adding to the carbonyl group.

• The nitrogen atom is a poor leaving group and the former carbonyl oxygen atom is a fair leaving group.
• An imine or iminium salt is created when the oxygen atom leaves.

• Second hydride is added.

• Primary amines are reduced to nitriles.

• The products of the reduction of aluminum hydride will be given.

• Grignard and organolithium reagents add more acid to give alkoxides.
• The alkoxides give alcohols.

• The mechanism involves substitution at the acyl carbon atom.
• Attack by the carbanion-like organometallic reagent, followed by elimination of alkoxide, gives a ketone.
• A second equivalent of the organometallic reagent is added to the ketone.
• Unless the original ester is a formate, hydrolysis gives tertiary alcohols.
• Two of the groups on the product are derived from the same reagent.

• Add acid to the alkoxide.

• Acid chlorides only react once with dialkylcuprates to give ketones.

• A Grignard or organolithium reagent is used to form the salt of an imine.
• The imine is further hydrolyzed to a ketone by acidic hydrolysis of the salt.

• Grignards add to esters and acid acetophenone with magnesium salt.

• There is a mechanism for the reaction of propanoyl chloride with 2 moles of phenylmagnesium a hydrogen from the ester and two bromide.

• After discussing the reactions and mechanisms of all the common acid derivatives, we now look at the reactions of each type of compound.
• Any reactions that are peculiar to a specific class of acid derivatives are covered in these sections.

• Acid chlorides are made using a variety of reagents.
• The most convenient reagents are Thionyl chloride and oxalyl chloride.

• Acid chlorides are not found in nature.
• Acid chlorides are easy to convert to other acid derivatives because they are the most reactive.
• The acyl chloride may be used as an intermediate in the best synthetic route to an anhydride.

• Acid chlorides are added twice to give 3deg alcohols.
• Just once, lithium dialkylcuprates add to give ketones.
• hydride is reduced to 1deg alcohols after being added to acid chlorides.
• The hydride gives aldehydes.

• In the presence of aluminum chloride, acyls acylate benzene, halobenzenes, and activated benzene derivatives.

• Section 17-11 talks about Friedel-Crafts acylation.

• There is a mechanism for the acylation of anisole.
• Friedel- Crafts acylation involves an acylium ion.

• Anhydride are activated acid derivatives and are often used for the same types of acylations.
• Acid chlorides are more reactive than anhydrides, and they are occasionally found in nature.
• The toxic ingredient "Spanish fly" is used as a vesicant to destroy warts on the skin.

• The most important carboxylic acid anhydride is acetic anhydride.

• It is produced at a rate of 4 billion pounds per year.

• Dehydrating acetic acid to give ketene is the most common industrial synthesis.

• A large increase in entropy is caused by breaking one molecule into two.
• The equilibrium favors the products at a high temperature.

• The rate of the reaction can be improved by adding triethylphosphate.

• acetic acid is fed directly into ketene, where it reacts quickly and quantitatively to give acetic anhydride.
• acetic anhydride is an inexpensive acylating reagent.

• The beetle between the fingers is less specialized than the one in the center of the body.
• Horses can eat methods.
• The most common method for making anhydride is the reaction of acid hay containing blisters with a carboxylic acid or a carboxylate salt.

• The failure was caused by cantharidin poisoning.

• The heating of the corresponding diacid can be used to make some cyclic anhydride.
• A dehydrating agent, such as acetic anhydride, can sometimes be added to accelerate this reaction.
• The equilibrium favors the products of the five- and six-membered anhydride.

• Acid chlorides and anhydride reactions are the same.
• Anhydride can be converted to less reactive acid derivatives.

• The Friedel-Crafts acylation is similar to acid chlorides.
• The catalyst may be an acidic compound.
• Cyclic anhydride can be used on the aromatic product's side chain.

• One of the two acid molecules is lost in most anhydride reactions.
• Half of the acid groups wouldn't react if a precious acid was converted to anhydride.
• It would be more efficient to convert the acid to an acid chloride.
• There are three instances when anhydrides are preferred.

• It's easy to use acetic anhydride and it gives better yields than acetyl chloride for acetylation of alcohols.

• Formyl chloride can't be used for formylation because it quickly degrades to CO and HCl.
• The formyl group is whereacetic formic anhydride reacts.
• The formyl group is less hindered than the acetyl group because it lacks a bulky, electron-donating alkyl group.
• acetic formic anhydride forms alcohols and amines with formate and formamides.

• The use of anhydride to make difunctional compounds.
• It is often necessary to convert just one acid group of a diacid.

• There is a substituted coumarin used as an is expelled as a carboxylate ion and a monofunctionalized derivative results.

• The most common acid derivatives are es.
• They are found in plant oils where they give fruity aromas.
• The odor of ripe bananas comes mostly from isoamyl acetate.
• The oil of wintergreen has been used as a medicine.
• Coumarin is found in lavender oil and sweet clover.
• The heads of sperm whales have large chambers of spermaceti, a waxy ester that helps to regulate their buoyancy in the water and that may help the head to serve as a resonating chamber for communicating underwater.

• The industry uses es as a solvent.
• It is a good solvent for a wide variety of compounds, and its toxicity is low compared with other solvents.
• Household products that contain ethasone include cleaners, polishes, glues, and spray finishes.
• Butyrate and butyl butyrate were once used as a solvent for paints and finishes, including the "butyrate dope" that was sprayed on the fabric covering of aircraft wings to make them tight and stiff.
• The most common materials used in fabrics, films, and solid plastic bottles arePolyesters, covered later in this section and in Chapter 26.

• The synthesis of erythropoietin is usually done by the esterification of an acid with an alcohol or by the reaction of an acid chloride with an alcohol.

• The acid can be treated with diazomethane.
• The alcohol group can be changed by transesterification with either acid or base.

• Acid chlorides and anhydrides are unstable.

• Most esters don't react with water under neutral conditions.
• They hydrolyze under acidic conditions and can form an amide with an amine.
• Grignard and organolithium reagents add twice to give alcohols after the hydride reduces the esters to primary alcohols.

• Under acidic conditions, such lactones form spontaneously.

• O apples, eat them from within.

• Lactones that are not favored by the body may be synthesised to attract and trap the librium.
• The equilibrium to the right is shifted because sticky insect traps baited remove water and the reaction is driven to completion.

• The human diet needs L-ascorbic acid to avoid the disease scurvy.
• The equilibrium mixture of the two forms is called ascorbic acid.
• It stops the growth and development ofbacteria.

• As shown in the preceding figure, propose a mechanism for the formation of 9-Hydroxynonanoic acid lactone.

• Explain your choice of reagent for each synthesis.

• At the moment, you are using at least five things that are made from polyesters.
• Your clothes are almost certainly sewn with Dacron(r) thread because they have some Dacron(r) fiber in them.
• The optical film in your DVD is made of Mylar.
• Some of the electronics in your cell phone are made out of Glyptal(r) polyester.
• The soft drink in your hand was made with metallized Mylar film.

• It was launched in 1964 to reflect radio a plastic bottle that was blow-molded from poly(ethylene terephthalate) resin, better waves for intercontinental telephone.

• The phthalic acid is esterified with ethylene glycol.
• When it reentered base-catalyzed transesterification of dimethyl terephthalate with ethylene glycol at the atmosphere in 1969 it burned up.

• Methanol escapes as a gas at this temperature.
• In Chapter 26 we will look at more of the polymers.

• Amides are the least reactive acid derivatives and can be made from any of the others.
• Amides are usually synthesised in the laboratory by the reaction of an acid and amine.
• Industrial synthesis involves heating an acid with an amine to drive off water and promote condensation.
• This simple industrial technique is rarely used in the laboratory, but it may work with the use of a reagent.
• The partial hydrolysis of nitriles and amine give amides.

• Amides are not basic.
• There is a nonbonding pair of electrons in the NH2 group.
• The lone pair is involved in strong resonance with the carbonyl group, which prevents it from being basic or nucleophilic.

• Only a strong acid can cause an amide to be protonsated.
• Pro tonation usually occurs on the carbonyl group because of resonance stabilization.

• Amides are the most stable acid derivatives, so they are not easy to convert to other derivatives.
• Reduction to amines is one of the best ways to synthesise amines.
• Amides can be made by a strong acid or strong base.
• Amides can be dehydrated of nitriles.

• Dehydrating agents can remove water from a primary amide and give it a nitrile.
• Dehydration of Amides is a common method for synthesis of nitriles.
• The traditional reagent for this dehydration is P2O5.

• Five-membered lactams and six-membered lac tams are formed when heating or adding a dehydrating agent to the appro priate.
• Smaller or larger rings are hard to form under these conditions.

• The unusual reactivity of b@lactams appears to be the result of the strain in the four-membered ring.
• The ring strain is relieved when a b@lactam acylates a nucleophile.

• The b@lactam ring is found in three important classes of antibiotics.

• B@lactam antibiotics interfere with the synthesis of cell walls.
• The acylatedidase is inactive for synthesis.
• The acylation step converts an amide to an ester by hydrolyzing the amide linkage of the lactam ring.

• The Show would be able to accomplish the following synthetic transformations with this combination.
• amoxicillin can be used to avoid being deactivated.

• You can use any necessary reagents.

• nylon's discovery in 1938 made possible a wide range of high-strength fibers, fabrics, and plastics that we take for granted today.
• nylon 6,6 is the most common form of nylon because it consists of a six-carbon diacid and a six-carbon diamine in repeating blocks.

• The nylon fibers have strong amide hydrogen bonding between the chains, which gives them great strength.
• Chapter 26 contains more detail on nylon chemistry.

• nitriles are considered acid derivatives because they hydrolyze to carboxylic acids.
• The same number of carbons and carboxylic acids are used to make nitriles.
• They are also made from primary alkyl halides and tosylates.
• Aryl cyanides can be made by the Sandmeyer reaction of aryldiazonium salt.

• It is possible that nitriles are further hydrolyzed to carboxylic acids.
• Reduction of a nitrile by aluminum hydride gives a primary amine, and the reaction with a Grignard reagent gives an imine that hydrolyzes to a ketone.

• The building blocks of proteins can be found in nitriles.

• The majority of carboxylic esters are alcohols and carboxylic acids.

• Thioesters are less reactive than acid chlorides and anhydride.

• The resonance stabilization of a thioester is less than that of an ester.
• The different sizes of the orbitals are located at different distances from the nucleus.

• The alkyl sulfide anion is a better leaving group than the alkoxide because it is less basic and the larger sulfur atom carries a negative charge.
• Sulfur is more polarizable than oxygen, which allows more bonding as the alkyl sulfide anion leaves.

• The resonance overlap in an ester is more effective than that in a thioester.

• CoA is a thiol with thioesters that serve as biochemical acyl transfer reagents.
• Acetyl CoA transfers an acetyl group to a nucleophile, with coenzyme A serving as the leaving group.

• Acid halides and anhydrides are not good for acylating.
• They hydrolyze under the conditions found in living organisms.
• Thioesters are good atselective acylating reagents.
• In living systems, thioesters are common acylating agents.
• Transfer of acyl groups from thioesters of CoA is one of the many biochemical acylations.
• In living systems, acetyl CoA serves as a water-stable equivalent of acetic anhydride.

• Carbonic acid is found in all carbonated beverages.

• Carbonic acid is always in equilibrium with carbon dioxide and water, but it has several important stable derivatives.

• TMU is often used as a polar solvent with a high boiling point.
• It can be washed out of a solution.

• The urethane is stable even though it is unstable.
• This is how it is made.

• There is a mechanism for the reaction of isocyanate with 1-naphthol.

• The development of sevin and Polycarbonates are bonds between the carbonate ester linkage and the carbamate ester linkage.
• The alkaloid physostigmine is used in bulletproof windows and crash helmets.
• The studies led to the synthesis.

• A diol reacts with a diisocyanate, a compound with two isocyanate groups.

• Functional groups can be converted to carboxylic acids by acidic or basic hydrolysis.

• The hydroxy group of the acid is replaced by a halogen in an activated acid derivative.

• Reduce to primary alcohols.

• The hydroxy group of the acid is replaced by a nitrogen atom and its attached hydrogens or alkyl groups.
• A amide is a mixture of two acids.

• An amine is cleaved to give an alcohol and amide.

• A molecule of water is lost in the formation of an activated acid derivative.

• Chapter 21 has reactions shown in red.
• Reactions are shown in blue.

• Carbonic acid is in equilibrium with water and carbon dioxide.
• The amides and esters are stable.

• The hydroxy group of the acid is replaced by an alkoxy group.
• An alcohol and a carboxylic acid are components of an ester.

• There is a leaving group on a carbonyl carbon atom.

• A large molecule with many smaller units bonding together.
• The units are bonded by amide linkages.

• The units are bonded together by carbonate ester linkages.

• The units are bonded by ester linkages.

• The units of the monomer are bonded together.

• A sulfur atom and a alkyl or aryl group are attached to the hydroxy group of the acid.
• A thiol and carboxylic acid are components of a thioester.

• Under either acidic or basic conditions,esterification can take place.

• A triester of the triol glycerol.

• Each skill is followed by problem numbers.

• The structures of carboxylic acid derivatives are drawn from their names.

• Explain the high boiling points and melting points of amides by comparing the physical properties of acid derivatives.
• Compare the relative reactivity of different compounds.

• Acid derivatives from compounds with other functional groups should be proposed for single-step and multistep synthesis.
• Acid deriva Problems 21-48, 50, 53, 54, 55 are the starting materials and intermediates.

• Predict the products, propose mechanisms for the reactions of carboxylic acid derivatives with reducing agents, alcohols, amines, and organometallic reagents.

• Predict the major products formed when phenylacetyl chloride reacts with the following reagents.

• There are nearly identical mechanisms for acid-catalyzed transesterification.

• Show how you would do it.

• Phosgene is the acid in carbonic acid.
• In World War I, phosgene was used as a war gas, but it is now used as a reagent for the synthesis of many useful products.
• Phosgene can react twice.

• Predict the products formed when phosgene reacts with propan-1-ol.

• Predict the products formed when phosgene reacts with 1 equivalent of aniline.

• The IR spectrum of triolein has a very strong absorption.
• 1 equivalent of glycerol and 3 equivalents of oleic acid are given by basic hydrolysis of triolein.

• The structure of triolein was drawn.

• Predict the products formed when triolein is treated with aluminum hydride.

• Show how you would do it.
• Some of the conversions may require more than one step.

• As they add to other esters, grignard reagents add carbonate esters.

• Show how you would synthesise 3-ethylpentan-3-ol using diethyl carbonate and ethyl bromide as your only organic reagents.

• It is easy to handle Diethyl carbonate.
• Phosgene is a toxic and corrosive gas.

• Show how you can use diethyl carbonate instead of phosgene.
• Show how you can use diethyl carbonate instead of methyl isocyanate.

• A mole of acetyl chloride is added to a liter of triethylamine.
• When the reaction mixture has cooled, 1 mole of alcohol is added.
• The mixture contains triethylamine, ethyl acetate, and triethylammonium chloride.

• The indicated starting material and any necessary reagents would be used to accomplish the following multistep synthesises.

• Explain the reasons for the rate enhancement.

• In each part, rank the compounds by the rate of attack at C " O by a strong, nucleophile-like methoxide.

• Explain the result.

• CH COO CH + 1 eq.

• There is a CH COOCH + 0.5 eq.

• When a student is called away to the phone, he adds ammonia to the mixture and begins to heat it.
• He returned to find that the mixture had overheated and turned black.
• He crystallises the volatile components.
• Two of the components he isolates are compounds A and B.
• The spectrum of A shows a strong absorption.
• Determine the structure of compounds A and B.

• The reaction of 1-naphthol with methyl isocyanate was shown in Section 21-16.
• This process was once used by a Union Carbide plant in India to make a pesticide.
• Either by accident or sabotage, a valve was opened on December 3, 1984 that admitted water to a large tank.
• The pressure and temperature within the tank went up, and pressure-relief valves were opened to keep the tank from bursting.

• About 2500 people were killed and many more were injured when a large quantity of isocyanate rushed out through the pressure-relief valves.

• You wrote a reaction in part a.

• An alternative synthesis of Sevin should be proposed.
• The most common alternative synthesis uses a toxic gas called phosgene.

• Some of their best-known products are shown with the structures of four useful polymers.

• A chemist was called to an abandoned aspirin factory to determine the contents of a badly corroded vat.
• She put on her breathing apparatus as soon as she noticed the overpowering odor of the fumes, knowing that two workers had become ill from breathing the fumes.
• She took a sample of the contents of the vat after entering the building.
• There was a singlet at d 2.15 in the mass spectrum and a singlet at d 2.15 in the NMR spectrum.

• The IR spectrum left no doubt about the compound's identity.
• Suggest a method for the safe disposal of the compound.

• This is where the IR and NMR spectrum are shown.
• Show how the structure is consistent with the observed absorptions.

• The IR spectrum, 13C NMR spectrum, and 1H NMR spectrum of an unknown compound are next.

• Show how the structure is consistent with the spectrum.

• There is an unknown compound of formula C5H9NO.
• When the sample is shaken with D2O, the broad NMR peak disappears.
• Show how the structure is consistent with the absorptions.

• A chemist wanted to make a ethyl ester of 2-formylbenzoic acid, but the product did not meet her expectations.
• The data is given.
• There is a mechanism for its formation.

• A large ring lactone is found in macrolide antibiotics.

• The macrolide structure is made of the lactone.

• Stereochemistry of most, but not all, of the chiral cen ters was determined using many complex NMR experiments.

• One of the oldest spices is C.

• The main flavor ingredient in cinnamon is cinnamaldehyde, which is easily synthesised using the aldol condensation of benzaldehyde 22-1 introduction with acetaldehyde.
• The availability of cheap synthetic cinnamon flavoring promoted the production of addition and nucleophilic acyl substitution, two of the main types of carbonyl reactions.
• The substitution at the carbon atom next to cinnamon sticks or powder made from the carbonyl group is called alpha substitution.

• When the carbonyl compound is converted to its enolate ion or its enol tautomer, alpha substitution takes place.
• A product is formed when a nuclyphilic attack on an electrophile replaces one of the hydrogens on a carbon atom.

• An enolate is formed by deprotonation of a carbon.

• In drawing mechanisms, you can add a carbonyl group.
• The resonance form of an attack on the carbonyl group can be seen first.
• The alkoxide gives the enolate its attacking power.

• The carbonyl group is added by the enolate.

• The enolate ion serves as the nucleophile if the electrophile is an ester.
• The enolate adds to the ester in order to form a tetrahedral intermediate.
• The substitution product is given if the leaving group is eliminated.

• Carbon-carbon bonds can be formed using alpha substitution and condensations of carbonyl compounds.
• These types of reactions are common in the metabolism of sugars and fats.
• There are many useful products that can be made from these reactions.

• The structure and formation of enols and enolate ion are considered in the beginning of our study.

• In Chapter 9 we saw that enols are a form of carbonyl compounds.
• The two forms of equilibrate are under acid or base catalysis.
• The carbonyl tautomer is important in most cases, but the enol form and the related enolate ion are also important.

• The presence of strong bases makes ketones and aldehydes weak proton acids.

• An equilibrium between the isomeric and enol forms of a carbonyl compound can be created by base.
• An alternative isomeric form of a ketone or aldehyde is called a vinyl alcohol.
• An enol intermediate, formed by the hydrolysis of an alkyne, isomerizes quickly.

• Don't confuse tautomers with resonance forms.
• There are different compounds with different atoms.
• With no catalyst present, either individual form may be isolated.

• It is catalyzed by acid.
• In acid, a protons is moved from a carbon to oxygen and then out of a carbon.

• The carbonyl oxygen is protonsated by an acid.
• The form of the carbon is enol.

• The base-catalyzed and acid-catalyzed mechanisms are shown.
• The protons are removed from a carbon and replaced with oxygen.
• Oxygen and a carbon are deprotonated first in acid.
• The old location's protons are removed and replaced at the new location.
• In acid, deprotonation occurs at the old location.

• The stereochemistry of ketones and aldehydes is affected by keto-enol tautomerism.
• If an asymmetric carbon atom has an enolizable hydrogen atom, a trace of acid or base allows that carbon to change its configuration with the enol serving as the intermediate.
• An equilibrium mixture of diastereomers is the result.

• Two different enols can be formed by phenylacetone.

• You can show the structures of the enols.

• Predict which enol will be present in the larger concentration.

• A mixture of cis and trans isomers results when -2,4-dimethylcyclohexanone is dissolved.
• This isomerization can be done with a mechanism.

• A carbonyl group increases the acidity of the protons on a carbon atom.
• A small amount of deprotonated, enolate form can be found in the equilibrium mixture when a simple ketone or aldehyde is treated with a hydroxide ion or an alkoxide ion.

• The equilibrium concentration of the enolate ion is small, but it serves as a useful nucleophile.
• The carbonyl compound reacts with a low concentration of the enolate ion.

• Sometimes the mixture of enolate and base won't work because the base reacts faster than the enolate.
• We need a base that reacts completely to convert the carbonyl compound to its enolate.
• Powerful bases can be used to convert a carbonyl compound completely to its enolate.
• LDA is the most useful base for this purpose.

• The deprotonate diisopropylamine is used to make LDA.

• LDA is less nucleophilic than NaNH2 because it is hindered by the two bulky isopropyl groups.
• LDA can't attack a carbon atom or add a carbonyl group.
• It is a powerful base, but not a strong one.
• When LDA reacts with a ketone, it forms a salt of the enolate.
• We will see if these salts can be used in synthesis.

• It is common to add the carbonyl compound slowly to a cold solution of LDA so that the enolate can be formed quickly and completely.

• There are many reactions where nucleophiles attack alkyl halides and tosylates.
• The enolate ion can become alkylated in the process.
• The enolate can react at either of the two sites.
• This is a type of substitution, with an alkyl group substituting for a hydrogen.

• A large amount of the hydroxide or alkoxide base is still present at equilibrium, so it cannot be used to form eno lates.
• These side reactions are avoided by LDA.
• LDA converts the ketone to its enolate because it is a stronger base.
• The LDA is consumed in forming the enolate, leaving the enolate to react without interference from the LDA.
• LDA is a poor nucleophile, so it doesn't react with the alkyl halide or tosylate.

• When only one kind of hydrogen can be replaced by an alkyl group, direct alkylation of enolates gives the best yields.
• A mixture of products alkylated at the different carbons may result if there are two different kinds of protons.
• Side reactions that occur when treated with LDA are not suitable for direct alkylation.

• He adds benzyl bromide to alkylate the enolate ion and heats the solution for half an hour to drive the reaction to completion.

• Suggest a way the student could make the correct product.

• The formation and alkylation of an enamine derivative is a milder alternative to direct alkylation.
• The picture of an enamine has a carbanion character.

• A carbon atom of the double bond is shown to have a high negative electrostatic potential near a simple enamine map.
• The enamine has a nucleophilic carbon atom.

• A resonance-stabilized cationic intermediate can be given by the nucleophilic carbon atom.

• The C " C double bond of an enamine is formed when a protons is lost from a carbon.

• The acid-catalyzed reaction of cyclohexanone with pyrrolidine can be proposed.

• Less reac tive than an enolate ion, enamines are more reactivity than an enol.
• Enamine reactions occur under milder conditions than enolate reactions.
• Enamines give alkylated iminium salts.
• The iminium ion is notreactive towards further acylation.
• The following example shows a reaction between benzyl bromide and cyclohexanone.

• The alkylated salt hydrolyzes.
• The mechanism for acid-catalyzed hydrolysis of an imine is similar to this one.

• If you don't mind, propose a mechanism for the hydrolysis of this iminium salt to the alkylated ketone.
• The first step is an attack by water, followed by a loss of a protons.
• pyrrolidine can leave if nitrogen is protonated.

• A variety of reactive alkyl and acyl halides can be used in the Stork reaction.

• The sequence shows the acylation of an enamine.
• The b@diketone product is hydrolyzed by the initial acylation.
• b@dicarbonyl compounds are useful intermediates in the synthesis of more complicated molecules, and they are easily alkylated.

• The expected products of the reactions are given.

• The pyrrolidine is the secondary amine.

• 2@methyl, 1@phenylpentan, and 3@one enamine.

• The halogens react quickly with enols and enolate ion.

• These reactions can be used to place halogen atoms at the alpha positions of carbonyl compounds.

• An a@halogenation reaction occurs when a ketone is treated with a base.

• The base-promoted halogenation takes place when an enolate ion is attacked.
• There are two products, the halogenated ketone and a halide ion.

• The enolate ion is formed by deprotonation of a carbon.

• The halogen is attacked by the enolate ion.

• There is a mechanism for the reaction of pentan-3-one with sodium hydroxide and bromine.

• There is a small amount of pentan-3-one present in the presence of sodium hydroxide.

• The observed product was given to the enolate by bromine.

• A strong nucleophile is an enolate.
• It can react with pathogens.

• The chlorine and phenol in the photo are much weaker than an enolate.

• In many cases, base-promoted halogenation does not end with just one hydrogen.
• The a@haloketone is more reactive to further halogenation than the starting material is.

• Most of the 2, 2-dibromopentan-3-one comes from bromination.

• The enolate ion is stable after one hydrogen is replaced by bromine.
• The first bromination takes place faster than the second.
• The second substitution takes place at the same carbon atom as the first.

• Base-promoted halogenation is rarely used for the preparation of monohalo ketones.
• The acid-catalyzed procedure is preferred.

• There is a way to show how acetophenone undergoes base-promoted chlorination.

• When a carbon atom is completely halogenated, base-promoted halogenation continues.
• trihalomethyl ketones have three protons on the carbon, and they have to be halogenated three times.

• The trihalomethyl group can serve as a reluctant leaving group for acylphilic substitution.
• A carboxylic acid is left after the trihalomethyl ketone reacts with hydroxide ion.
• A fast exchange of protons gives a carboxylate ion and a haloform.

• The haloform reaction ends with a substitution of acyls with hydroxide and -CX3.

• The haloform reaction is summarized next.
• A carboxylate ion and a haloform can be created under strongly basic conditions.

• The haloform product (iodoform) is a solid that is yellow when the halogen is iodine.

• An alcohol can give a positive iodoform test if it oxidizes to a methyl ketone.
• The alcohol can be converted to a carboxylic acid with one less carbon atom.

• There is a mechanism for the reaction of cyclohexyl methyl ketone with excess bromine.

• Acid can be used to catalyzed the a halogenation of ketones.
• The acid catalyst and the solvent can be dissolved in acetic acid.
• In contrast to basic halogenation, acidic halogenation can replace just one hydrogen or more than one depending on the amount of halogen added.

• Acid-catalyzed halogenation involves attacking the enol form on the halogen molecule.
• The a@haloketone and the hydrogen halide are caused by the loss of a protons.

• The enol form of the carbonyl compound serves as a nucleophile to attack the halogen.
• The a@haloketone is given by detonation.

• The attack of an alkene on a halogen results in the addition of the halogen across the double bond.
• The product is converted to an a@haloketone by the loss of the enol proton.
• The unsubstituted enol intermediate is less stable than the halogen-substituted enol, so we can stop the acid-catalyzed reaction at the monohalo product.
• Each successive halogenation becomes slower under acid-catalyzed conditions.

• The acid-catalyzed conversion of cyclohexanone to 2-chlorocyclohexanone can be proposed.

• The enol form of the ketone is in equilibrium.

• The enol acts as a weak nucleophile by attacking chlorine.
• The product is given by the loss of a protons.

• There is a mechanism for acid-catalyzed bromination.

• The conversion of ketones to a,b@unsaturated ketones is useful in Michael reactions.
• A method for converting cyclohexanone to cyclohex-2-en-1-one is proposed.

• Synthetic intermediates use a-bromoacids.

• CH CH acyl bromide is a nucleophilic intermediate.

• The bromide enolizes more readily than the acid.

• The enol is attacking bromine.

• If a derivative of the a@bromoacid is desired, the a@bromo acyl bromide serves as an activated intermediate.
• A water hydrolysis completes the synthesis if the a@bromoacid is needed.

• A-bromoacids can be used to convert to a-amino acids.

• If you treat them with a large amount of ammonia, you can give them a-amino acid.

• The loss of a small molecule such as water or an alcohol can lead to condensations.
• A,b@unsaturated carbonyl compound may be dehydrate by the aldol product.

• A strong nucleophilic addition of the enolate ion to a carbonyl group is what causes the aldol condensation.
• There is a product called aldol.

• An enolate ion is added to a carbonyl group.

• An enolate ion is formed when a base removes a protons.

• The carbonyl group is added by the enolate ion.

• The alkoxide gives the aldol product.

• There is a product called aldol.

• An enolate ion is formed when a base removes a protons.

• The carbonyl group is added by the enolate ion.
• The alkoxide gives the aldol product.

• The equilibrium between reactants and products is established by the aldol condensation.
• The conversion rate for acetaldehyde is 50%.

• Aldolases are small.
• Mental methods are often used to accomplish aldol condensations.
• Even though the equilibrium concentration sugars are present, Figure 22-2 shows how a good yield of the acetone aldol is obtained.
• The chemical of the product is less than 1%.
• The basic catalyst is insoluble when acetone is boiled so it condenses into a chamber reaction.
• Only the catalyst product can be used for the reaction.
• Diacetone is sometimes used in organic alcohol when the solution returns to the boiling flask.
• acetone is volatile, but diacetone alcohol is less so.

• After several hours, acetone is converted to alcohol.

• The driver drove an aldol condensation to completion.
• A clever technique gives a good yield despite the fact that the aldol condensation of acetone only gives 1% product at equilibrium.
• A basic catalyst is Ba(OH)2.
• The equilibrium concentration of the nonvolatile diacetone alcohol increases as acetone is converted to diacetone alcohol.

• The base-catalyzed aldol condensation of acetone can be proposed.

• The formation of the enolate is the first step.

• The second step is an attack on another molecule of acetone.
• There is a product called aldol.

• There is a mechanism for the condensation of cyclohexanone.

• A student wanted to dry some alcohol and let it stand for a week.
• The sample contained nearly pure acetone at the end of the week.
• The mechanism for the reaction should be proposed.

• Under acidic conditions, aldol condensations take place.
• The enol is a weak nucleophile that can be used to attack an activated carbonyl group.
• The acid-catalyzed aldol condensation of acetaldehyde is an example.
• The acid-catalyzed keto-enol tautomerism is the first step in forming the enol.
• The carbonyl of the acetaldehyde molecule is attacked by the enol.
• The aldol product is created by the loss of the enol proton.

• An enol is added to a carbonyl group.

• The enol was formed by deprotonation on C.

• The enol is added to the carbonyl.

• The deprotonation is to give the product.

• There is a complete mechanism for the acid-catalyzed aldol condensation of acetone.

• The dehydration of the alcohol functional group can be caused by heating a basic or acidic mixture.
• The product is a conjugate a,b@unsaturated aldehyde or ketone.

• Before the Wittig reaction was discovered, dehydration was the best method for joining two molecule with a double bond.
• It's the cheapest and easiest method.

• Dehydration follows a similar mechanism to those of other acid-catalyzed alcohol dehydrations.
• We haven't seen a base-catalyzed dehydration before.
• Base-catalyzed dehydration depends on the acidity of the aldol product.
• A more stable product can be given by an enolate that expels hydroxide ion.
• It's not a good leaving group in an E2 elimination, but it can serve as a stabilizing group in a strongly exothermic step like this one.
• The dehydration of 3-hydroxybutanal is shown in the following mechanism.

• Dehydration in base is different to most alcohols.
• Aconjugated product can be given by an enolate that expels hydroxide ion.

• The dehydration product can be obtained by heating the reaction mixture, even if the aldol equilibrium is unfavorable.
• Dehydration leads to a system that is exothermic.
• The dehydration drives the aldol equilibrium to the right.

• 2-methylpent-2-enal is one of the products when propionaldehyde is warmed.
• There is a mechanism for this reaction.

• Predict the products of aldol condensation, followed by dehydration.

• A mixture of several products will be formed if the compounds used in the reaction are selected carefully.

• Consider the condensation between ethanal and propanal.
• An enolate ion can be formed by either of these reagents.
• Attack by the enolate of ethanal on propanal gives a different product than the one formed by the attack of the enolate of propanal on ethanal.
• There are self-condensations of propanal and ethanal taking place.
• Depending on the reaction conditions, different proportions of the four possible products result.

• If a crossed aldol condensation is planned, only one of the reactants can form an enolate ion, so that the other compound is more likely to react with the enolate.
• Only one enolate will be present in the solution if only one of the reactants has hydrogen.
• The other reactant is more likely to be attacked by the enolate ion if it is present in excess.

• Two reactions are successful.
• Depending on the reaction conditions and the structure of the products, the aldol products may or may not be dehydrated.

• Slowly add the compound with a protons to a basic solution of the compound without a protons.
• The desired reaction is favored if the enolate ion is formed in the presence of a large excess of the other component.

• LDA can react with other aldehydes and ketones to give products that could not be formed by standard basecatalyzed aldols.
• We can use LDA to make the desired enolate ion, then add the compound we want to react as the electrophile.
• We control which enolate adds to which group.

• Determine the type of mechanism first.
• The reaction involves strong nucleophiles as intermediates.
• We don't expect to see strong acids, strong acids, strong acids, strong acids, strong acids, strong acids, strong acids, strong acids, strong acids, strong acids, strong acids, strong acids, strong acids, strong acids, strong acids, strong acids, strong acids,

• One of the aromatic rings makes it clear which ring in the product is derived from which ring in the reactants.
• The carbon atom in the products must be derived from the carbonyl group of benzaldehyde.
• Two protons and a carbonyl oxygen are lost as water.

• Consider if any of the reactants are strong enough to react without being activated.

• The reactants are not strong enough to attack the other.
• A strongly nucleophilic enolate ion results if ethoxide removes a protons from methylcyclohexanone.

• The product of this bond formation can be drawn.

• Attack at the carbonyl group of benzaldehyde leads to a b@hydroxy ketone.

• The final product must be dehydrated.
• The alcohol dehydration mechanism can't happen under these basic conditions.
• An enolate ion can be lost in a strongly exothermic step if another proton is removed.

• Use curved arrows to draw out the steps.
• Don't show more than one step at a time.
• The complete mechanism is given by combining the equations.
• As a review of the steps involved, we suggest you write out the mechanism.

• The steps just shown will help you propose mechanisms for base-catalyzed reactions.

• When acetone is treated with excess benzaldehyde in the presence of base, the crossed condensation adds two equivalents of benzaldehyde and expels two equivalents of water.

• The structure for the condensation product of acetone should be proposed.

• Write a mechanism for the same reaction at the carbon atom and explain why it isn't observed.

• It is possible to make five- and six-membered rings.
• Larger and smaller rings are less favored by their energy and are less likely to be analized.
• The reactions show how a 1,4-diketone can be used to give a cyclopentenone and how a 1,5-diketone can be used to give a cyclohexenone.

• The carbonyl group of the product may be outside the ring in some cases.

• The UV spectrum of cyclodecane-1,6-dione is similar to that of 1-acetyl-2-methylcyclopentene.

• As long as we remember the limitations of aldol condensations, they can be useful synthetic reactions for making a variety of organic compounds.
• New carbon-carbon double bonds are formed by dehydration.
• Some general principles can be used to determine if a compound is an aldol product and which reagents to use as starting materials.

• b@unsaturated aldehydes and ketones are produced by aldol condensations.
• An aldol should be considered if a target molecule has one of the function alities.
• The structure at the a,b bond is the starting materials.
• The double bond is used for the dehydrated product.
• The following analyses show the division of some products.

• The product would be given if the diketone was cyclized.

• There is a mechanism for the cyclization.

• The hydrogens of esters are weakly acidic and can be deprotonated.
• The ester carbonyl group is stable because of the other oxygen atom.
• The carbonyl group is less capable of stabilizing the negative charge of an enolate ion.

• Strong bases do deprotonate esters.

• The Claisen condensation is the most important of all the reactions.

• The carbonyl group is attacked by the enolate.
• A group that leaves a b@keto ester.
• A b@keto ester is given by the overall reaction.

• The attacking nucleophile is an enolate ion in the Claisen condensation.

• Adding the enolate will give a tetrahedral intermediate.
• The alkoxide leaving group was eliminated.

• The acylating reagent in this nucleophilic acyl substitution is served by one molecule of the ester, which is deprotonated.

• The b@keto ester products of Claisen condensations are more acidic than simple ketones, aldehydes, and esters because deprotonation gives an enolate whose negative charge is delocalized over both carbonyl groups.
• The b@keto ester is deprotonated in strong bases.

• The deprotonation makes the overall reaction exothermic and drives the reaction to completion.
• The enolate is converted back to the b@keto ester after the reaction is complete.

• The following example shows the self-condensation of ethyl acetoacetate.
• The enolate of ethyl acetoacetate is the initial product.

• There is a mechanism for the self-condensation of ethyl acetate.

• The ester enolate is formed first.
• The equilibrium for this step is far to the left.

• The expulsion of ethoxide ion gives ethyl acetoacetate.

• In the presence of ethoxide ion, ethyl acetoacetate is deprotonated.
• The reaction is driven by this exothermic deprotonation.

• ethyl acetoacetate is given when the reaction is complete.

• A poor yield is obtained by using thioesters.

• Break the structure apart at the a,b bond.
• The bond was formed in the Claisen condensation.

• Next, replace the group that was lost from the carbonyl and the one that was lost from the protons.

• Draw out the reaction.
• The base is used because of the reactants.

• There is a mechanism for the self-condensation of methyl 3-phenylpropionate promoted by a nucleophilic acyl substitution.

• Claisen condensation would give the following b@keto esters.

• A ring is formed by an internal Claisen condensation of a diester.

• Five- and six-membered rings are easy to form.

• Rings smaller than five carbons or larger than six carbons are rarely formed by this method.

• The Dieckmann condensation shows that a 1,6-diester gives a five-membered ring, and a 1,7-diester gives a six-membered ring.

• There are two Dieckmann condensations shown.

• Some of the following can be formed by Dieckmann condensations.
• Draw the starting diesters, and determine which ones are possible.

• When only one of the esters has the hydrogens needed to form an enolate, Claisen condensations can take place.
• There are some useful esters without hydrogens.

• A cross Claisen condensation can be carried out by adding a solution of the alkoxide base with no hydrogens.
• The hydrogens are slowly added to this solution, where they form an enolate and condenses.
• A crossed Claisen condensation can be seen in the condensation of ethyl acetate with ethyl benzoate.

• There is a mechanism for the crossed Claisen condensation.

• Predict the products from Claisen condensation.

• Indicate which combinations are poor choices for crossed Claisen condensations.

• Break the a,b bond of this b@keto ester, since that is the bond formed in the Claisen condensation.

• The alkoxy group should be added to the carbonyl.

• Make sure that one of the components has hydrogens and the other does not by writing out the reaction.

• Crossed Claisen condensations are1-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-6556 The ketone component is more likely to deprotonate and serve as the enolate component in the condensation.
• The ketone enolate attacks the ester, which undergoes nucleophilic acyl substitution.

• The best way to make this condensation work is if the ester has no hydrogens.
• Even when both have hydrogens, the reaction between ketones and esters can be successful.
• Some crossed Claisen condensations can be seen in the following examples.

• There are a variety of difunctional and trifunctional compounds that can be produced with appropriate choices of esters.

• Predict the major products of the Claisen condensations.

• Predicting product structures and drawing mechanisms until you gain confidence.

• Many alkylation and acylation reactions use anions of b@dicarbonyl compounds that can be completely deprotonated and converted to their enolate ion by common bases.

• Most ester condensations use alkoxides to form enolate ion.

• A small amount of enolate is formed with simple esters.
• The equilibrium favors the alkoxide.
• The desired reaction is often interfered with by the alkoxide.
• If we want an alkyl halide to alkylate an enolate, alkoxide ion in the solution will attack the alkyl halide and form an ether.

• B@dicarbonyl compounds are more acidic than alcohols.
• The deprotonated enolates are easily alkylated and acylated.
• One of the carbonyl groups can be removed by decarboxylation at the end of the synthesis, leaving a compound that is difficult or impossible to make.

• We compare the acidity advantages of b@dicarbonyl compounds and then look at how they can be used in synthesis.

• Table 22-1 compares the acidities of carbonyl compounds with alcohols and water.
• There is an increase in acidity for compounds with two carbonyl groups.
• The b@dicarbonyl compounds are more acidic than water and alcohols.

• The electron-donating nature of the alkoxy group is reflected in the difference.

• Diethyl malonate is alkylated or acylated on the more acidic carbon that is a to both carbonyl groups and the resulting derivative is allowed to decarboxylate.

• Malonic ester is completely deprotonated.
• A alkyl halide, tosylate, or other reagent is used to alkylate the enolate ion.

• A good S N 2 is required for this step.

• A malonic acid derivative is given by hydrolysis of the diethyl malonate.

• Any carboxylic acid with a carbonyl group in the b position is prone to decarboxylate.

• A substi tuted derivative of acetic acid is created when the alkylmalonic acid loses CO2 at the temperature of the hydrolysis.
• A substituted acetic acid is quickly tautomerized to the product when decarboxylation takes place.

• A substituted acetic acid is used in the synthesis of a malonic ester.
• The second carboxyl group allows the ester to be easily deprotonated and alkylated.
• The substituted acetic acid is removed by hydrolysis and decarboxylation.

• The second acidic protons can be removed by a base.

• A dialkylated malonic ester is created by removing the enolate with another alkyl halide.

• Some cycloalkanecarboxylic acids, which are not easily made by any other method, can be made with the malonic ester synthesis.
• The ring is formed from a dihalide.
• Even though most other condensations cannot form four-membered rings, the synthesis of cyclobutanecarboxylic acid shows that a strained four-membered ring system can be generated by this ester alkylation.

• An organic chemist wouldn't use the malonic ester synthesis.
• The method that cells use to synthesise long-chain fatty acids is similar to it.
• The thioester with coenzyme A is activated by the growing acid derivative.
• Two of the three carbons of malonic acid are added by a malonic ester acylation.
• The acyl group has been lengthened by two carbon atoms after the reduction of the ketone, dehydration and reduction of the double bond.
• When the acid has reached the required length, the cycle is repeated until there is an even number of carbon atoms.

• Malonyl-CoA is acylates in a malonic ester when activated as its coenzyme A thioester.
• Two carbon atoms are added.
• Dehydration, further reduction, and zymatic reduction shorten the length of a fatty acid.

• The malonic ester synthesis is used to make 2-benzylbutanoic acid.

• Adding these substituents to the malonic ester gives the correct product.

• The malonic ester synthesis can't form the following substituted acetic acid.

• The use of LDA to depro tonate a ketone was shown in Sections 22-2B and 22-3.

• Show how a modern alternative to the malonic ester synthesis can be used to make acid.
• You can use the ester shown in part (b) as your starting material.

• In the acetoacetic synthesis ester, substituents are added to the enolate ion of ethyl acetoacetate, followed by hydrolysis and decarboxylation to produce an alkylated derivative of acetone.

• acetone is a molecule of acetone with a temporary ester group attached to enhance its acidity Ethoxide deprotonates acetoacetic ester.

• The enolate is alkylated by an alkyl halide or tosylate.
• The alkylating agent needs to be a good S N 2.

• The b position promotes decarboxylation to form a substitute for acetone.

• A six-membered transition state splits out carbon dioxide to make the substitute acetone.
• The decarboxylation usually happens at the temperature of the hydrolysis.

• The following general synthesis shows that disubstituted acetones are formed by alkylating acetoacetic ester a second time before the decarboxylation steps.

• The disubstituted acetone product is given by hydrolysis.

• An acetoacetic synthesis goes toketo esters.

• The acetoacetate decarboxylase is made by these strains.

• The b carbon has a partial positive charge of the carbonyl carbon atom.

• At either the carbonyl group or the b position, a nucleophile can attack an a,b@unsaturated carbonyl compound.

• The net result is the addition of a hydrogen atom and a carbonyl group across a double bond.

• The mechanisms of 1,2-addition and 1,4-addition are different.
• There is a resonance-stabilized enolate ion in the 1,4-addition.

• The standard addition to a carbonyl group is 1,2-addition.

• The enolate ion is created when the b carbon atom of an a,b@unsaturated system is added to the nucleophile.
• Oxygen or carbon may be used to give an enol.

• There are many compounds that can serve as Michael donors and acceptors.
• Michael donors are stable by two strong electron-withdrawing groups such as carbonyl groups, cyano groups, or nitro groups.
• There are acceptors that have a double bond with a carbonyl group, a cyano group, or a nitro group.

• Adding a,b-unsaturated ketone to the double bond of a,b-vinylcuprate creates a Michael donor.
• The b carbon atom is added to give an enolate ion.
• The product is given by the presence of a carbon.

• The lithium dialkylcuprate can undergo additional reactions if it is used as a Michael donor.
• A product with one substituent at the a position and another at the b position is shown in the example above.

• The enolate at the carbon is the crucial step.
• The resulting enolate is very basic.

• The product of this Michael addition may be treated the same as any other substituted malonic ester.
• It is difficult to imagine other ways to make this acid.

• A new bond at the b carbon of the acceptor would have been formed by a Michael addition.

• At the b,g bond, we break this molecule apart.

• The top fragment, where we broke the b bond, must have come from the Michael acceptor.
• A simple ketone is the bottom fragment.
• It is likely that this ketone was used with some sort of stabilizing group.
• Adding a temporary ester group to the ketone will give us the correct product.

• Consider a Michael addition to a compound with three carbons.

• An acetoacetic synthesis ester can be used to form a d@diketone.

• A mechanism for the conjugate addition of a nucleophile to acrylonitrile six-membered rings is proposed.
• You can use resonance forms to show the structure.
• The double bond is activated by the female hormone estra nitro groups.

• The following products could be made from suitable Michael donors and acceptors.

• Adding a ketone enolate to an a,b@unsaturated ketone gives a d@diketone.
• A new six-membered ring can be created if the d@diketone undergoes a conjugate addition under strongly basic or acidic conditions.
• An example would be to use a substitution of cyclohexanone as the Michael donor and a substitution ofMVK as the Michael acceptor.

• A d@diketone is formed by the Michael addition of the cyclohexanone enolate.

• The d@diketone is ideally suited for the formation of a six-membered ring.
• The cyclohexanone carbonyl is attacked by the enolate of the methyl ketone.
• The product gives a cyclohexenone.

• A six-membered ring is formed by Cyclic aldol.

• If you remember that the Michael addition is first, followed by an aldol condensation with dehydration, you can draw the mechanisms for the Robinson annulation.

• The system for proposing mechanisms summarized in Appendix 3A is used in this problem-solving example.
• The problem is to come up with a mechanism for the base-catalyzed reaction.

• Determine the type of mechanism first.
• The use of a basic catalyst suggests that the reaction involves strong nucleophiles.
• We expect to see anionic intermediates, but no strong acids, or free radicals.

• The product must be made from ethyl acetoacetate.
• The carbon from the C " C double bond" should be derived from the ethyl acetoacetate.
• The structure can be seen in the four remaining carbons.

• Consider if one of the reactants is strong enough to react without being activated.
• Both reactants are strong enough to attack the other.
• The enolate ion can be given by ethoxide ion because acetoacetate is more acidic.

• The product of this bond formation can be drawn.
• The carbonyl group ofMVK might be attacked by the enolate of acetoacetic ester.

• One of the bonds needed in the product is a Michael addition.

• The ethyl acetoacetate group needs to be converted to a C " C double bond in the a,b position.

• This conversion is related to aldol condensation.
• The enolate that is needed to give the observed product is formed by the removal of the most acidic protons.

• Use curved arrows to draw out the steps.
• Don't show more than one step at a time.

• Combining the preceding equations gives the complete mechanism.
• You can review the steps by writing out the mechanism.
• The point of a mechanism problem is not that we can draw other mechanisms, but that we can't draw other products.
• Even though other products are likely formed as well, and possibly in higher yields, the question asked for a mechanism to explain only this one product.

• The approach shown will help you propose mechanisms for multistep condensations.

• The mechanism for the reaction should be proposed.

• There is a mechanism for the Perkin condensation.

• Show how you would make the following compounds.

• The cyclohexenone is the new ring and the double of Robinson is formed by dehydration, so you can usually spot a product Work backward.
• The double has a new ring.

• A full summary of additions and condensations would take a long time.
• The major classes of condensations are covered in this summary.

• The anion is the initial form of the product.

• The carbanions are stable enough to exist in solution.

• Many of the nucleophilic reaction types have been covered previously.
• Enolates are strong bases and usually need an acidic workup to supply H+.

• Dehydration often leads to the formation of aldol condensations.

• Chapter 22 has reactions shown in red.
• Reactions are shown in blue.

• A ring is formed by Claisen condensation.

• The carbon atom is deprotonated next to a carbonyl group.

• Such a hydrogen may be lost and regained through tautomerism.

• The acylation of malonic ester is followed by the hydrolysis and decarbox ylation.

• Robinson is followed by an aldol condensation with dehydration.

• The acylation of a ketone or aldehyde involves the use of an enamine derivative.

• The alkylated or acylated ketone or aldehyde can be regenerated.

• An isomerism involves the movement of a double bond and a protons.

• tautomerism is related to the isomers.

• condensations take on a wide variety of forms in this chapter.
• To gain confidence in working out new variations of the standard mechanisms, you need to work enough problems.
• Make sure you can propose condensations that form new rings.

• Each skill is followed by problem numbers.

• Predict the reactions of aldol before and after dehydration.
• Acid-catalyzed and base-catalyzed reactions have mechanisms.

• The compounds should be ranked in order of increasing acidity.

• List the compounds that would be more than 99% deprotonated by a solution of sodium ethoxide.

• There is a mixture of 8% keto and 92% enol forms.
• Explain the stability of the stable enol tautomer.

• In order to increase acid strength, rank these compounds.

• In order to increase enol content, rank these compounds.
• Draw the most stable enol.

• Show how you would use Robinson to make these compounds.

• You can show how you would make each compound with aldol, Claisen, or another type of condensation.

• How would you accomplish the following conversions?
• You can use any necessary reagents.

• The following compounds would be made using the malonic ester synthesis.

• The acetoacetic ester synthesis would be used to make the following compounds.

• The following compounds can be made using aldol condensations.

• In the case of the aldol condensation, an active methylene compound reacts with an aldehyde or ketone, in the presence of a secondary amine as a basic catalyst, to produce a new C.

• The following enamine alkylation and acylation reactions have expected products.
• After the iminium salts are hydrolysis, give the final products.

• The following multistep conversions would be accomplished by showing how you would accomplish them.
• You can use any additional reagents.

• Many of the condensations we studied are not permanent.
• There are mechanisms to account for the reactions.

• The chemistry lab students added an excess of ethylmagnesium bromide to methyl furoate, expecting the Grignard reagent to add twice and form the tertiary alcohol.
• The product was a mixture of two compounds.
• The expected product had two ethyl groups, but the unexpected product had three.
• There is a mechanism to explain the formation of the unexpected product.

• The splitting of fructose-1,6-diphosphate to give glyceraldehyde- 3-phosphate is a reaction involved in the metabolism of sugars.
• The base-catalyzed reaction can be proposed.