Chapter 21 Carboxylic Acid Derivatives: Nucleophilic Acyl Substitutution Reactions Suggested Problems – 1-26,31-4,45-6,48-53,56,65-66.

Chapter 21 Carboxylic Acid Derivatives: Nucleophilic Acyl Substitutution Reactions Suggested Problems – 1-26,31-4,45-6,48-53,56,65-66

Carboxylic Compounds Carboxylic acid derivatives are compounds in which the acyl group is bonded to an electronegative atom or substituent that can act as a leaving group in the nucleophilic acyl substitution reaction. Acid halides, acid anhydrides, esters, and amides are the four most common carboxylic acid derivatives. Thioesters and acyl phosphates are encountered primarily in biological chemistry. Note the similarities between esters and thioesters and between acid anhydrides and acyl phosphates.

Naming Carboxylic Acid Derivatives
Acid halides, RCOX Derived from carboxylic acid name by replacing the –ic acid or –oic acid ending with –oyl or –carboxylic acid ending with –carbonyl Acid halides are named by identifying first the acyl group and then the halide. The acyl group name of most carboxylic acids is derived from the carboxylic acid name by replacing the –ic acid or –oic acid ending with –oyl. Thus the acyl group for benzoic acid becomes benzoyl and the acyl group for pyruvic acid becomes pyruvoyl. If the acid is named as a –carboxylic acid, the suffix acyl substituent becomes –carbonyl as in cyclobutane carboxylic acid becoming cyclobutane carbonyl. Note – some notable exceptions to this nomenclature exist for simple acids such as formic acid and acetic acid. Here the –ic is replaced with a –yl rather than an –oic when naming the acyl derivative.

Acid anhydrides, RCO2COR’ Symmetrical anhydrides of unsubstituted monocarboxylic acids and cyclic anhydrides of dicarboxylic acids are named by replacing acid with anhydride Unsymmetrical anhydrides are named by listing the two acids alphabetically and then adding anhydride Acetic anhydride is thus the condensation product (loss of one molecule of water) of two molecules of acetic anhydride.

Esters, RCO2R’ Named by identifying the alkyl group attached to oxygen and then the carboxylic acid, replacing –ic acid with –ate For esters name the alkyl group attached to the singly bonded oxygen first. Then name the carboxylic acid have replacing –ic acid with –ate.

Amides, RCONH2 With an unsubstituted –NH2 group, –oic acid or –ic acid is replaced with –amide –carboxylic acid ending is replaced with –carboxamide If the N is further substituted, identify the substituent groups and then the parent amide Benzoic acid translates to benzamide where the nitrogen contains two hydrogens. If the nitrogen is further substituted, the substituent groups on the nitrogen are named followed by the name of the parent amide. The substituents are preceded by the letter N to identify them as being directly attached to the nitrogen.

Thioesters, RCOSR’ Named similarly to the corresponding esters Prefix thio- is added to carboxylate if ester has a common name –oate or carboxylate is replaced by –thioate or carbothioate if ester has a systematic name

Acyl phosphates, RCO2PO32- and RCO2PO3R’– Named by citing the acyl group and adding the word phosphate Identified after acyl group, if an alkyl is attached to the phosphate oxygen

Worked Example Draw structures corresponding to the following names:
a) 4-Methylpentanoyl chloride b) Isopropyl cyclopentanecarboxylate Solution: a) b)

Nucleophilic Acyl Substitution Reactions
When a nucleophile adds to a carboxylic acid derivative, the initially formed tetrahedral intermediate eliminates one of the two substituents originally bonded to the carbonyl carbon Leads to a net nucleophilic acyl substitution reaction Carboxylic acid derivatives have an acyl carbon bonded to a group –Y that can act as a leaving group

The General Mechanisms of Nucleophilic Addition and Nucleophilic Acyl Substitution Reactions
In carboxylic acid derivatives, as soon as the tetrahedral intermediate is formed, the leaving group –Y is expelled to generate a new carbonyl compound. (Bottom of slide) Aldehydes and ketones do not have a good leaving group (H or C) and therefore cannot undergo substitution, affording only alcohols as products. The net effect of the addition/elimination sequence in nucleophilic acyl substitution reactions is a substitution of the nucleophile for the –Y group originally bonded to the acyl carbon.

Worked Example Show the mechanism of the following nucleophilic acyl substitution reaction Use curved arrows to indicate the electron flow in each step Solution:

Relative reactivity of carboxylic acid derivatives Nucleophiles react more readily with unhindered carbonyl groups Electrophilic carbonyl groups are more reactive to addition The intermediate with the best leaving group decomposes fastest While both the initial addition step and the subsequent elimination step can affect the overall rate of a nucleophilic acyl substitution, the addition is generally the rate-limiting step. Thus, any factor that makes the carbonyl group more reactive toward nucleophiles favors the substitution process. Steric and electronic factors are both important. The more hindered the carbonyl group, the slower the reaction.

Strongly polarized acyl compounds react more readily than less polar ones Acid chlorides are the most reactive because the electronegative chlorine withdraws electrons from the carbonyl carbon Amides are the least reactive The way in which various substituents affect the polarization of a carbonyl group is similar to the way they affect the reactivity of an aromatic ring toward electrophilic substitution. A chlorine substituent, for example, inductively withdraws electrons from an acyl group in the same way that it withdraws electrons from and thus deactivates an aromatic ring. Similarly, amino, methoxyl, and methylthio substituents donate electrons to acyl groups by resonance in the same way that they donate electrons to, and thus activate, aromatic rings.

A more reactive acid derivative can be converted into a less reactive one Acid halides and acid anhydrides react rapidly with water Acid chlorides, for instance, can be directly converted into anhydrides, thioesters, esters, and amides, but amides can’t be directly converted into esters, thioesters, anhydrides, or acid chlorides. A consequence of the reactivity differences is the fact that only the less reactive acyl phosphates, thioesters, esters, and amides are commonly found in nature. Acid halides and acid anhydrides react so rapidly with water that they can’t exist for long in living organisms. It is useful to remember the reactivity order of carboxylic acid derivatives.

Hydrolysis - Water is used as a reagent to make carboxylic acids Alcoholysis – Alcohol is used as reagent to make esters Aminolysis - Ammonia or an amine is used to make an amide Reduction – A hydride source is used to make an aldehyde or an alcohol Grignard reaction – An organometallic reagent is used to make a ketone or an alcohol

Some General Reactions of Carboxylic Acid Derivatives

Worked Example Predict the products of the following nucleophilic acyl substitution reaction Solution: Identify the nucleophile and the leaving group and replace the leaving group with the nucleophile in the product

Reactions of Carboxylic Acids
Direct nucleophilic acyl substitution of a carboxylic acid is difficult –OH is a poor leaving group Reactivity of the acid can be increased by: Using a strong acid catalyst to protonate the carboxyl group Converting –OH into a better leaving group Under the right conditions, acid chlorides, anhydrides, esters, and amides can be prepared from carboxylic acids

Conversion of carboxylic acids into acid chlorides Reaction with thionyl chloride, SOCl2 Carboxylic acid is first converted into an acyl chlorosulfite intermediate which replaces the –OH of the acid with a much better leaving group Chlorosulfite then reacts with a nucleophilic chloride ion This reaction is only possible in the laboratory and not in living systems owing to the extreme reactivity of acid chlorides with water and other nucleophiles.

Occurs by a nucleophilic acyl substitution pathway Carboxylic acid is converted into a chlorosulfite which then reacts with chloride

Conversion of carboxylic acids into acid anhydrides Acid anhydrides can be derived from two molecules of carboxylic acid by heating to remove water Because of the high temperatures needed to effect this reaction, only acetic acid is commonly prepared this way.

Conversion of carboxylic acids into esters Through reaction of a carboxylate anion with a primary alkyl halide Perhaps the useful reaction of carboxylic acids is their conversion into esters. The reaction of a carboxylate anion with a primary alkyl halide is only one way to effect this conversion.

Fischer esterification reaction: Synthesis of esters by an acid-catalyzed nucleophilic acyl substitution reaction of a carboxylic acid with an alcohol Esters can also be synthesized by an acid-catalyzed nucleophilic acyl substitution reaction of a carboxylic acid with an alcohol, a process called the Fischer esterification reaction. The need for an excess of a liquid alcohol as solvent effectively limits the method to the synthesis of methyl, ethyl, propyl, and butyl esters.

Mechanism of the Fischer Esterification
All steps are reversible; the reaction can be driven in either direction When 18O-labeled methanol reacts with benzoic acid, the methyl benzoate produced is 18O-labeled but the water produced is unlabeled Carboxylic acids are not reactive enough to undergo nucleophilic addition directly, but their reactivity is greatly enhanced in the presence of a strong acid such as HCl or H2SO4. The mineral acid protonates the carbonyl group oxygen atom, thereby giving the carboxylic acid a positive charge and rendering it much more reactive. Subsequent loss of water from the tetrahedral intermediate yields the ester product. The net effect of Fischer esterification is substitution of an –OH group by –OR’. All steps are reversible, and the reaction typically has an equilibrium constant close to 1. Thus, the reaction can be driven in either direction by the choice of reaction conditions. Ester formation is favored when a large excess of alcohol is used as solvent, but carboxylic acid formation is favored when a large excess of water is present. Evidence in support of the mechanism comes from 18O labeling experiments with labeled methanol. Since the radiolabel is transferred to the product ester, the oxygen in the ester product is derived from that contained in the alcohol. Thus it is the C-O bond in the acid derivative that breaks.

Worked Example How is the following ester prepared from the corresponding acid? Solution:

Conversion of carboxylic acids into amides Amides are difficult to prepare by direct reaction of carboxylic acids Amides can be prepared by activating the carboxylic acid with dicyclohexylcarbodiimde, followed by addition of the amine Amides are difficult to prepare by direct reaction of carboxylic acids with amines because amines are bases that convert acidic carboxyl groups into their unreactive carboxylate anions. Thus, the –OH must be replaced by a better, nonacidic leaving group. In practice, amides are usually prepared by activating the carboxylic acid with a reagent such as dicyclohexylcarbodiimide (DCC). The acid first adds to a c=N double bond of DCC, and nucleophilic acyl substitution by amine then ensues. The DCC method of amide formation is the key step in the laboratory synthesis of small proteins.

Conversion of carboxylic acids into alcohols Carboxylic acids are reduced by LiAlH4 to give primary alcohols The aldehyde intermediate in the reaction of an acid with LiAlH4 is much more reactive than the starting acid, so it reacts immediately and is not isolated.

Reduction is a nucleophilic acyl substitution reaction in which –H replaces –OH to give an aldehyde Reduction to the primary alcohol occurs by a second nucleophilic addition of H- Because LAH serves as a base, the actual nucleophilic acyl substitution step takes place on the carboxylate ion rather than on the free carboxylic and gives a high-energy dianion intermediate. In this intermediate, the two oxygens are undoubtedly complexed to a Lewis acidic aluminum species. Thus, the reaction is relatively difficult, and acid reductions require higher temperatures and extended reaction times. An alternative to the use of LAH is the use of borane in THF (BH3/THF) which reduces acids rapidly at room temperature to primary alcohols. Because of its relative ease and safety borane reduction of acids is often preferred over that employing LAH. Moreover, borane reacts with carboxylic acids faster than with any other functional group, thereby allowing selective transformations such as that a nitro-substituted carboxylic acid. Lithium aluminum hydride would reduce the nitro group as well as the acid function; borane only reduces the carboxylic acid leaving the nitro group intact.

A safer way to effect reduction of carboxylic acids is with borane in THF Selective reductions are possible An alternative to the use of LAH is the use of borane in THF (BH3/THF) which reduces acids rapidly at room temperature to primary alcohols. Because of its relative ease and safety borane reduction of acids is often preferred over that employing LAH. Moreover, borane reacts with carboxylic acids faster than with any other functional group, thereby allowing selective transformations such as that a nitro-substituted carboxylic acid. Lithium aluminum hydride would reduce the nitro group as well as the acid function; borane only reduces the carboxylic acid leaving the nitro group intact.

Direct conversion of a carboxylic acid to an acyl derivative by nucleophilic acyl substitution does not occur in biological chemistry. As in the laboratory, the acid must first be activated by converting the –OH group into a better leaving group.

Activation is accomplished in living organisms by reaction of the acid with ATP to give an acyl adenylate phosphate, a mixed anhydride combining a carboxylic acid and AMP.

In the biosynthesis of fats, a long chain acid reacts with ATP to give an acyl adenylate, followed by subsequent nucleophilic acyl substitution of a thiol group from coenzyme A to give the corresponding acyl CoA The fatty acid acyl CoA serves as an acylating agent in other biological reactions.

Chemistry of Acid Halides
Preparation of acid halides Acid chlorides are prepared from carboxylic acids by reaction with SOCl2 Reaction of a carboxylic acid with PBr3 yields the acid bromide

Reaction of acid halides Nucleophilic acyl substitution mechanisms Halogen replaced by –OH, by –OR, or by –NH2 Reduction yields a primary alcohol Grignard reagent yields a tertiary alcohol Acid halides are among the most reactive of carboxylic acid derivatives and can be converted into many other kinds of compounds by nucleophilic acyl substitutution mechanisms. The halogen can be replaced by –OH to yield an acid, by –OCOR to yield an anhydride, by –OR to yield an ester, by –NH2 to yield an amide, or by R’ to yield a ketone. In addition the reduction of an acid halide yields a primary alcohol, and reaction with a Grignard reagent yields a tertiary alcohol.

Conversion of acid halides into acids: Hydrolysis Acid chlorides react with water to yield carboxylic acids HCl is generated during the hydrolysis: A base, such as pyridine or NaOH, is typically added to remove the HCl

Conversion of acid halides into anhydrides Nucleophilic acyl substitution reaction of an acid chloride with a carboxylate anion gives an acid anhydride Both symmetrical and unsymmetrical acid anhydrides can be prepared in this reaction.

Conversion of acid halides into esters: Alcoholysis Esters are produced in the reaction of acid chlorides with alcohols in the presence of pyridine or NaOH The reaction of an acid chloride with an alcohol to form esters is probably the most common method for preparing esters in the laboratory. As with hydrolysis, alcoholysis reactions are usually carried out in the presence of pyridine or NaOH to react with the HCl formed. The reaction of an alcohol with an acid chloride is strongly affected by steric hindrance. Bulky groups on either partner slow down the reaction considerably, resulting in a reactivity order among alcohols of primary > secondary > tertiary. As a result, its often possible to selectively esterify an unhindered alcohol in the presence of a more hindered one.

Worked Example How is ethyl benzoate prepared using a nucleophilic acyl substitution reaction of an acid chloride? Solution:

Aminolysis Acid chlorides react rapidly with ammonia and amines to give amides Both monosubstituted and disubstituted amines can be used Trisubstituted amines (R3N) cannot be used This method is the most commonly used laboratory method for preparing amides. Because HCl is formed during the reaction, two equivalents of the amine must be used. One equivalent reacts with the acid chloride, and one equivalent reacts with the HCl by-product to form an ammonium chloride salt. If the amine component is valuable, amide synthesis is often carried out using one equivalent of the amine plus one equivalent of an inexpensive base, such as NaOH.

Worked Example How is propanamide prepared using an acid chloride and an amine or ammonia Solution:

Conversion of acid chlorides into alcohols: Reduction and Grignard reaction LiAlH4 reduces acid chlorides to yield aldehydes and then primary alcohols in a second step Reduction occurs via a nucleophilic acyl substitution mechanism

Grignard reagents react with acid chlorides to yield tertiary alcohols with two identical substituents Reduction occurs in two steps via a nucleophilic acyl substitution mechanism

Formation of Ketones from Acid Chlorides
Conversion of acid chlorides into ketones: Diorganocopper reaction Reaction of an acid chloride with a lithium diorganocopper (Gilman) reagent, Li+ R’2Cu Addition produces an acyl diorganocopper intermediate, followed by loss of RCu and formation of the ketone While a Grignard addition to an acid chloride will result in the addition of two alkyl substituents and the formation of a primary alcohol, conversion to a ketone can be achieved employing a Gilman reagent. This reaction is typically carried out at -78 oC in ether solution and yields are excellent. The Gilman reagent is not sufficiently reactive with the ketone carbonyl and the reaction can be stopped at the ketone stage. Note that diorganocopper reaction occurs only with acid chlorides. Carboxylic acids, esters, acid anhydrides, and amides do not reaction with lithium diorganocopper reagents.

Worked Example How is the following ketone prepared by reaction of an acid chloride with a lithium diorganocopper reagent?

Worked Example Solution:

Chemistry of Acid Anhydrides
Preparation of acid anhydrides Nucleophilic acyl substitution of a carboxylate with an acid chloride Acetic anhydride is prepared by the high temperature condensation of acetic acid. The method in this slide is more general and avails itself to the synthesis of symmetrical and unsymmetrical anhydrides.

Reactions of Acid Anhydrides
Anhydrides react similarly to acid halides. Anhydrides are a little less reactive however.

Reactions of Acid Anhydrides
Conversion of acid anhydrides into esters Acetic anhydride forms acetate esters from alcohols Conversion of acid anhydrides into amides Acetic anhydride is used to prepare N-substituted acetamides from amines In the case of the bottom reaction, the more nucleophilic NH2 group reacts preferentially over the OH group. Notice that in both of these cases, only “half” of the anhydride is used; the other half acts as a leaving group. As a result, anhydrides are inefficient and acid halides are normally preferred for introducing acyl substituents other than acetyl groups.

Worked Example What product is expected from reaction of one equivalent of methanol with a cyclic anhydride, such as phthalic anhydride (1,2-benzenedicarboxylic anhydride)? Solution:

Chemistry of Esters Esters are pleasant-smelling liquids
Fragrant odors of fruits and flowers Also present in fats and vegetable oils Industrially used esters include: Ethyl acetate (a solvent) Dialkyl phthalates (plasticizers) Esters are used in the fragrance industry.

Chemistry of Esters Preparation of esters
Esters are usually prepared from carboxylic acids Acid chlorides are converted into esters by treatment with an alcohol in the presence of base Esters are typically prepared from carboxylic acids under acidic and basic conditions or from acid chlorides.

Chemistry of Esters Reactions of Esters
Less reactive toward nucleophiles as compared to acid chlorides or anhydrides Cyclic esters are called lactones and react similarly to acyclic esters

Chemistry of Esters Conversion of esters into carboxylic acids: Hydrolysis An ester is hydrolyzed by aqueous base or aqueous acid to yield a carboxylic acid plus an alcohol Saponification: Ester hydrolysis in basic solution “Sapo” means soap. Soap is made by boiling animal fat with aqueous base to hydrolyze the ester linkages.

Mechanism of Base-induced Ester Hydrolysis

Chemistry of Esters Hydrolysis: Conversion of esters into carboxylic acids Acid-catalyzed ester hydrolysis can occur by different mechanisms Depends on the structure of the ester This mechanism is simply the reverse of the Fischer esterification reaction.

Chemistry of Esters Conversion of esters into amides: Aminolysis
Ammonia reacts with esters to form amides Conversion of esters into alcohols: Reduction Reaction with LiAlH4 yields primary alcohols Esters also react with amines to form amides. Both primary and secondary amines react to afford N-substituted and N,N-disubstituted amides, respectively. Esters typically are not the preferred starting materials to form amides, however, as acid chlorides are considerably more reactive. Esters are easily reduced with LiAlH4 to afford alcohols.

Chemistry of Esters Hydride ion adds to the carbonyl group, followed by elimination of alkoxide ion to yield an aldehyde Reduction of the aldehyde gives the primary alcohol

Chemistry of Esters Aldehyde intermediate can be isolated if 1 equivalent of diisobutylaluminum hydride (DIBAH, or DIBAL-H) is used as a reducing agent DIBAL only has one hydride that it can transfer DIBAL reactions are typically carried out at -78oC to avoid further reduction to the alcohol.

Worked Example Show the products that would be obtained by reduction of the following ester with LiAlH4: Solution:

Chemistry of Esters Conversion of esters into alcohols: Grignard reaction Esters react with two equivalents of a Grignard reagent to yield a tertiary alcohol The intermediate, following addition of one equivalent of the Grignard reagent, is a ketone which reacts with a second equivalent of Grignard. The reaction cannot typically be stopped at the ketone stage because the ketone is more reactive than the starting ester.

Worked Example What ester and what Grignard reagent might be required to prepare the alcohol given below?

Worked Example Solution:
Grignard reagents can only be used with esters to form a tertiary alcohol that has two identical substituents

Chemistry of Amides Amides are abundant in living organisms
Proteins, nucleic acids, and other pharmaceuticals have amide functional groups Amides are the least reactive of the common acid derivative Because amides are the least reactive of the common acid derivatives, they undergo relatively few nucleophilic acyl substitution reactions.

Preparation of Amides Chemistry of amides
Prepared by reaction of an acid chloride with ammonia, monosubstituted amines, or disubstituted amines This is the ideal way to prepare amides.

Reactions of Amides Conversion of amides into carboxylic acids: Hydrolysis Heating in either aqueous acid or aqueous base produces a carboxylic acid and amine Acidic hydrolysis by nucleophilic addition of water to the protonated amide, followed by loss of ammonia Steps in the acid catalyzed hydrolysis of amides are reversible.

Reactions of Amides Basic hydrolysis is difficult in comparison to analogous acid-catalyzed reaction because amide ion is a very poor leaving group Addition of hydroxide and loss of amide ion In biological chemistry, amide hydrolysis is common The base catalyzed hydrolysis involves reversible steps as well. The hydrolysis of amides is the initial step in the digestion of dietary proteins. The reaction is catalyzed by protease enzymes and occurs by a mechanism almost identical to that for fat hydrolysis.

Reactions of Amides Conversion of amides into amines: Reduction
Reduced by LiAlH4 to an amine rather than an alcohol Converts C=O  CH2

Reactions of Amides Addition of hydride to carbonyl group
Loss of the oxygen as an aluminate anion to give an iminium ion intermediate which is reduced to the amine The reaction is effective with both acyclic and cyclic amides, or lactams Good route for preparing cyclic amines

Worked Example How can N-ethylbenzamide be converted into benzoic acid? Solution:

Chemistry of Thioesters and Acyl Phosphates: Biological Carboxylic Acid Derivatives
Nucleophilic carboxyl substitution in nature often involves a thioester or acyl phosphate Acyl CoA’s are most common thioesters in nature Neither a thioester nor an acyl phosphate is as reactive as an acid chloride or acid anhydride, yet both are stable enough to exist in living organisms while still reactive enough to undergo acyl substitution.

Worked Example Write the mechanism of the reaction shown between coenzyme A and acetyl adenylate to give acetyl CoA

Worked Example Solution:
Since this problem only concerns the –SH group, the remainder of the structure is represented as “R”

Worked Example Step 1 Step 2
Nucleophilic addition of the –SR group of CoA to acetyl adenylate to form a tetrahedral intermediate Step 2 Loss of adenosine monophosphate

Polyamides and Polyesters: Step-Growth Polymers
Reactions occur in distinct linear steps, not as chain reactions (ie. not like other polymerizations) Reaction of a diamine and a diacid chloride gives an ongoing cycle that produces a polyamide A diol reacting with a diacid leads to a polyester

Main classes of synthetic polymers are: Chain-growth polymers - Produced in chain-reaction processes (eg. polyethylene) Step-growth polymers: Each bond in the polymer is independently formed in a discrete step Key bond-forming step is often a nucleophilic acyl substitution of a carboxylic acid derivative Polyethylene resulting from polymerization of ethylene is a chain-growth polymer. Polyamides and polyesters are step-growth polymers because each bond in the polymer is independently formed in a discrete step.

Polyamides (Nylons) Heating a diamine with a diacid produces a polyamide called nylon Example - Nylon 66 is prepared from adipic acid and hexamethylene-diamine at 280°C Used in engineering applications and in making fibers

Most useful type made by reaction between dimethyl terephthalate and ethylene glycol Tensile strength of poly(ethylene terephthalate) film is nearly equal to that of steel Dacron is used to make clothing fiber or tire cord. Mylar is the trade name used to make recording tape.

Sutures and biodegradable polymers Common biodegradable polymers include: Poly(glycolic acid) (PGA) Poly(lactic acid) (PLA) Poly(hydroxybutyrate) (PHB) Susceptible to hydrolysis of their ester links Poly(glycolic acid) and poly(lactic acid) copolymers are employed in biodegradable sutures. These are typically hydrolyzed and absorbed by the body within 90 days following surgery. Poly(hydroxybutyrate) which can be made into films for packaging as well as into molded items degrades within four weeks in landfills. Presently, the cost of the monomer limits its use.

Worked Example Draw structures of the step-growth polymers expected from the following reaction: Solution:

Spectroscopy of Carboxylic Acid Derivatives
Infrared spectroscopy Acid chlorides absorb near 1810 cm1 Acid anhydrides absorb at 1820 cm1 and also at 1760 cm1 Esters absorb at 1735 cm1, higher than aldehydes or ketones Amides absorb near the low end of the carbonyl region (around cm-1) All carbonyl-containing compounds have intense IR absorptions in the range cm-1. The inductive withdrawal of electron density shortens the C=O bond, thereby raising its stretching frequency. The delocalization of electron density (resonance) from nitrogen into the carbonyl lengthens the C=O bond and lowers its stretching frequency.

Worked Example What kinds of functional groups might compounds have if they show the following IR absorptions? a) Absorption at 1735 cm–1 b) Absorption at 1810 cm–1 Solution: Absorption Functional group present 1735 cm–1 1810 cm–1 Saturated ester or 6-membered ring lactone Saturated acid chloride

Nuclear Magnetic Resonance Spectroscopy
Hydrogens on the carbon next to a C=O are near 2  in the 1H NMR spectrum Acid derivatives absorb in the same range so NMR does not distinguish them from each other The net result is you can’t use NMR to distinguish between acid derivatives based on the absorption of the protons on the alpha carbon.

13C NMR Useful for determining the presence or absence of a carbonyl group in a molecule of unknown structure Carbonyl carbon atoms of the various acid derivatives absorb from 160  to 180 

Saturated and Unsaturated Fatty Acids
Fatty acids can be saturated with hydrogen (and therefore have no carbon-carbon double bonds) or unsaturated (and have carbon-carbon double bonds). Fatty acids with more than one double bond are called polyunsaturated fatty acids. The melting points of saturated fatty acids increase with increasing molecular weight because of increased van der Waals interaction between the molecules. The melting points of unsaturated fatty acids with the same number of double bonds also increase with increasing MW. The double bonds in naturally occurring unsaturated fatty acids have the cis configuration and are always separated by one CH2 group. The cis double bond creates a bend in the molecule, which decreases packing between molecules relative to saturated fatty acids. As a result, unsaturated fatty acids have fewer intermolecular interactions and therefore have lower melting points than saturated fatty acids with comparable molecular weights.

Fats and Oils are Formed by Esterifying Glycerol with Fatty Acids
Triglycerides are compounds in which each of the three OH groups of glycerol has formed an ester with a fatty acid. If the three fatty acids are the same, the compound is called a simple triglyceride. Mixed triglycerides contain two or three different fatty acid components and are more common than simple triglycerides.

Fats and Oils Triglycerides that are solids or semisolids at room temperature are called fats. Most fats are obtained from animals and are composed largely of triglycerides with fatty acid components that are either saturated or have only one double bond. The saturated fatty acid tails pack closely together, giving these triglycerides relatively high melting points – they are solids at room temperature. Liquid triglycerides are called oils. Oils typically come from plant products such as corn, soybeans, olives, and peanuts. They are comprised primarily of triglycerides with unsaturated fatty acids and therefore cannot pack tightly together. Consequently, they have relatively low melting points and so are liquids at room temperature. The fatty acid chains pack more tightly together in fats. Fats are solids at room temperature. Oils are liquids at room temperature.

Hydrogenation of a Fat Some or all of the double bonds of polyunsaturated oils can be reduced by catalytic hydrogenation. Margarine and shortening are prepared by hydrogenation vegetable oils until they have the desired consistency. Reducing all of the double bonds would produce a hard fat - as a result hydrogenation must be carefully controlled. Fats, oils, waxes, and fatty acids are all lipids. Lipids are naturally occurring organic compounds that are soluble in nonpolar solvents.

Hydrolysis of Fat or Oil in a Basic Solution Forms a Soap
Soap comes from the hydrolysis of fats. The reaction is termed saponification. The sodium salts of the fatty acids obtained in this reaction is called soap. A soap is a sodium or potassium salt of a fatty acid. The reaction is called saponification.

Common Soaps

A Micelle Long-chain carboxylate ions form micelles.
By nature of it’s long non-polar tail, and charged acidic head, soaps can form micelles Micelles resemble large balls. The polar heads of the carboxylic ions, each accompanied by a counterion, are on the outside of the ball because of their attraction for water, whereas the nonpolar tails are buried in the interior of the ball to minimize their contact with water. The hydrophobic interactions between the nonpolar tails increase the stability of the micelle. Water by itself is not a very effective cleaning agent because dirt is carried by nonpolar molecules. Soap has cleansing ability because the nonpolar oil molecules dissolve in the nonpolar interior of the micelles and are washed away with the micelle during rinsing. Long-chain carboxylate ions form micelles.

Phosphoglycerides Phosphoglycerides are the major components of cell membranes. Phosphoglycerides are similar to triglycerides except that a terminal OH group of glycerol is esterified with phosphoric acid rather than with a fatty acid. Phosphoglycerides form membranes by arranging themselves in a lipid bilayer. The fluidity of a membrane is controlled by the fatty acid components of the phosphoglycerides. Saturated fatty acids decrease membrane fluidity because their hydrocarbon chains pack closely together. Unsaturated fatty acids increase fluidity because they pack less closely together. Cholesterol also decreases fluidity – only animal membranes contain cholesterol, so they are more rigid than plant membranes.

An Enzyme in Snake Venom Catalyzes the Hydrolysis of Phospholipids
An enzyme in snake venom hydrolyzes the ester group of a phosphoglyceride. This causes the membranes of red blood cells to rupture.

If the Incoming Nucleophile (Z) is a Stronger Base
Than the Base in the Reactant (Y) The weakest base is eliminated from the tetrahedral intermediate. If the incoming nucleophile (Z) is a stronger base than the base in the reactant (Y), a new product will be formed.

If the Incoming Nucleophile (Z) is a Weaker Base
Than the Base in the Reactant (Y) The weakest base is eliminated from the tetrahedral intermediate. If the incoming nucleophile (Z) is a weaker base than the base in the reactant (Y), the reactants will be reformed.

If the Two Groups Have Similar Basicities
A mixture of reactants and products is obtained.

The Relative Reactivities Depend on the Basicity of the Substituent Attached to the Leaving Group

A Carboxylic Acid Derivative Can Be Converted
Only into a Less Reactive Carboxylic Acid Derivative

Chapter 21 Carboxylic Acid Derivatives: Nucleophilic Acyl Substitutution Reactions Suggested Problems – 1-26,31-4,45-6,48-53,56,65-66.

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Chapter 21 Carboxylic Acid Derivatives: Nucleophilic Acyl Substitutution Reactions Suggested Problems – 1-26,31-4,45-6,48-53,56,65-66.

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