(O-CHEM 2) Mechanisms

103 flashcards · Other · by John Mark Webb

Mechanism of Fischer esterification. The reaction is an acid-catalyzed, nucleophilic acyl substitution of a carboxylic acid. In the Fischer mechanism there is a proton transfer.
know this mechanism
the product = ester
Fischer
Mechanism of amide formation by reaction of a carboxylic acid and an amine with dicyclohexylcarbodiimide (DCC).
know this mechanism
We said that carboxylic acids are reduced by LiAlH4 to give primary alcohols, but we deferred a discussion of the reaction mechanism at that time. In fact, the reduction is a nucleophilic acyl substitution reaction in which –H replaces –OH to give an aldehyde, which is further reduced to a primary alcohol by nucleophilic addition.
As with hydrolysis, alcoholysis of acid halides reactions are usually carried out in the presence of pyridine or NaOH to react with the HCl formed.
buffer?
know this mechanism
notice the less hindered alcohol and what it does
Which method would you choose if you wanted to prepare cyclohexyl benzoate—Fischer esterification or reaction of an acid chloride with an alcohol? Explain.
simple, low boiling alcohols are for Fischer reactions acid chloride and alcohol should be used
Note that the diorganocopper reaction occurs only with acid chlorides. Carboxylic acids, esters, acid anhydrides, and amides do not react with lithium diorganocopper reagents.
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Carboxylic acids, esters, acid anhydrides, and amides do not react with lithium diorganocopper reagents.
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None of the label remains with the propanoic acid, indicating that saponification occurs by cleavage of the C–OR' bond rather than the CO–R' bond.
notice where the marked 18O bond is located
Mechanism of base-induced ester hydrolysis (saponification).
notice the lone pair of the alcohol attach the carbonyl carbon forming an alkoxide ion
Mechanism of acid-catalyzed ester hydrolysis. The forward reaction is a hydrolysis; the back-reaction is a Fischer esterification.
involves protonation of carbonyl group (not the carbon)
The aldehyde intermediate can be isolated if 1 equivalent of diisobutyl-aluminum hydride (DIBAH, or DIBAL-H) is used as the reducing agent instead of LiAlH4.
it gives you the aldehyde intermediate
Amides are usually prepared by reaction of an acid chloride with an amine. Ammonia, monosubstituted amines, and disubstituted amines all undergo this reaction.
notice which kind of amines can do this reaction
Acidic hydrolysis reactions of amides occurs by nucleophilic addition of water to the protonated amide, followed by proton transfer from oxygen to nitrogen to make the nitrogen a better leaving group, and subsequent elimination.
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Basic hydrolysis reactions of amides occurs by nucleophilic addition of OH- to the amide carbonyl group, followed by elimination of amide ion (-NH2) and subsequent deprotonation of the initially formed carboxylic acid by ammonia.
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Amide reduction occurs by nucleophilic addition of hydride ion to the amide carbonyl group, followed by expulsion of the oxygen atom as an aluminate anion leaving group to give an iminium ion intermediate. The intermediate iminium ion is further reduced by LiAlH4 to yield the amine.
this one is very different
The aldehyde intermediate is much more reactive than the starting acid, so it reacts immediately and is not isolated (unless you use DIBAH).
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Reaction of an acid with BH3/THF occurs rapidly at room temperature, and the procedure is often preferred to reduction with LiAlH4 because if the reduction of p-nitrophenylacetic acid were done with LiAlH4, both the nitro and carboxyl groups would be reduced.
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This is a polyamine (nylon).
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What would happen, though, if a diamine and a diacid chloride were allowed to react? Each partner would form two amide bonds, linking more and more molecules together until a giant polyamide resulted. In the same way, reaction of a diol with a diacid would lead to a polyester.
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This is a polyester.
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This is a polyester.
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Acid chlorides are easily detected by their characteristic absorption near 1810 1/cm.
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Acid anhydrides can be identified by a pair of absorptions in the carbonyl region, one at 1820 1/cm and another at 1760 1/cm.
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Esters are detected by their absorption at 1735 1/cm, a position somewhat higher than that for either aldehydes or ketones.
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General mechanism of a carbonyl alpha-substitution reaction. In step 3, the initially formed cation loses H+ to regenerate a carbonyl compound.
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A particularly common alpha-substitution reaction in the laboratory is the halogenation of aldehydes and ketones at their a positions by reaction with Cl2, Br2, or I2 in acidic solution. Bromine in acetic acid solvent is often used.
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Mechanism of the acid-catalyzed bromination of acetone.
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If an aldehyde or ketone is treated with D3O+, the acidic alpha hydrogens are replaced by deuterium.
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The alpha bromination of carbonyl compounds by Br2 in acetic acid is limited to aldehydes and ketones because acids, esters, and amides don’t enolize to a sufficient extent. Carboxylic acids, however, can be a brominated by a mixture of Br2 and PBr3 in the Hell–Volhard–Zelinskii (HVZ) reaction.
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notice how the each method is limited
Many types of carbonyl compounds, including aldehydes, ketones, esters, thioesters, acids, and amides, can be converted into enolate ions by reaction with LDA.
The higher the pKa the greater the basicity. The lower the pKa the greater the acidity.
The enolate ion of 2,4-pentanedione, for instance, has three resonance forms. Similar resonance forms can be drawn for other doubly stabilized enolate ions.
If excess base and halogen are used, a methyl ketone is triply halogenated and then cleaved by base in the haloform reaction. The products are a carboxylic acid plus a so-called haloform (chloroform, CHCl3; bromoform, CHBr3; or iodoform, CHI3). Note that the second step of the reaction is a nucleophilic acyl substitution of -CX3 by -OH. That is, a halogen-stabilized carbanion acts as a leaving group.
Alkylation occurs when the nucleophilic enolate ion reacts with the electrophilic alkyl halide in an SN2 reaction and displaces the leaving group by backside attack.
Alkylation reactions are subject to the same constraints that affect all SN2 reactions. Thus, the leaving group X in the alkylating agent R–X can be chloride, bromide, iodide, or tosylate. The alkyl group R should be primary or methyl, and preferably should be allylic or benzylic.
One of the oldest and best known carbonyl alkylation reactions is the malonic ester synthesis, a method for preparing a carboxylic acid from an alkyl halide while lengthening the carbon chain by two atoms.
On heating with aqueous hydrochloric acid, the alkylated (or dialkylated) malonic ester undergoes hydrolysis of its two ester groups followed by decarboxylation (loss of CO2) to yield a substituted monocarboxylic acid.
Decarboxylation is not a general reaction of carboxylic acids. Rather, it is unique to compounds that have a second carbonyl group two atoms away from the –COOH. That is, only substituted malonic acids and b-keto acids undergo loss of CO2 on heating. It is like a conjugated carbonyl group. There is only one carbon in between the two carbonyl groups.
Malonic ester synthesis can also be used to prepare cycloalkanecarboxylic acids. For example, when 1,4-dibromobutane is treated with diethyl malonate in the presence of two equivalents of sodium ethoxide base, the second alkyl- ation step occurs intramolecularly to yield a cyclic product. Hydrolysis and decarboxylation then give cyclopentanecarboxylic acid. Three-, four-, five-, and six-membered rings can be prepared in this way, but yields decrease for larger ring sizes.
Just as malonic ester synthesis converts an alkyl halide into a carboxylic acid, acetoacetic ester synthesis converts an alkyl halide into a methyl ketone having three more carbons.
On heating with aqueous HCl, the alkylated (or dialkylated) acetoacetic ester is hydrolyzed to a beta-keto acid, which then undergoes decarboxylation to yield a ketone product.
The three-step sequence of (1) enolate ion formation, (2) alkylation, and (3) hydrolysis/decarboxylation is applicable to all beta-keto esters with acidic alpha hydrogens, not just to acetoacetic ester itself. For example, cyclic beta-keto esters, such as ethyl 2-oxocyclohexanecarboxylate, can be alkylated and decarboxylated to give 2-substituted cyclohexanones.
Ketones, esters, and nitriles can all be alkylated using LDA or related dialkylamide bases in THF. Aldehydes, however, rarely give high yields of pure products because their enolate ions undergo carbonyl condensation reactions instead of alkylation.
The general mechanism of a carbonyl condensation reaction. One partner becomes a nucleophilic donor and adds to the second partner as an electrophilic acceptor. After protonation, the final product is a beta-hydroxy carbonyl compound. The alpha carbon of one carbonyl group forms a bond with the carbonyl carbon. There should one carbon between the two connecting compounds' carbonyl groups.
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DIFFERENCE BETWEEN ALPHA SUBSTITUTION AND CARBONYL CONDENSATION REACTIONS Alpha-substitution reactions require a full equivalent of strong base and are normally carried out so that the carbonyl compound is rapidly and completely converted into its enolate ion at a low temperature. An electrophile is then added rapidly to ensure that the reactive enolate ion is quenched quickly.
DIFFERENCE BETWEEN ALPHA SUBSTITUTION AND CARBONYL CONDENSATION REACTIONS Carbonyl condensation reactions require only a catalytic amount of a relatively weak base, rather than a full equivalent, so that a small amount of enolate ion is generated in the presence of unreacted carbonyl compound. Once a condensation occurs, the basic catalyst is regenerated.
Under basic conditions, an acidic a hydrogen is removed, yielding an enolate ion that expels the –OH leaving group in an E1cB reaction. Under acidic conditions, an enol is formed, the –OH group is protonated, and water is expelled in an E1 or E2 reaction.
If one of the carbonyl partners contains no alpha hydrogens (and thus can’t form an enolate ion to become a donor), but does contain an unhindered carbonyl group (and so is a good acceptor of nucleophiles), then a mixed aldol reaction is likely to be successful.
If one of the carbonyl partners is much more acidic than the other, and is thus transformed into its enolate ion in preference to the other, then a mixed aldol reaction is likely to be successful.
When certain dicarbonyl compounds are treated with base, however, an intramolecular aldol reaction can occur, leading to the formation of a cyclic product.
The only difference between the aldol condensation of an aldehyde or ketone and the Claisen condensation of an ester involves the fate of the initially formed tetrahedral intermediate. The tetrahedral intermediate in the aldol reaction is protonated to give an alcohol product—exactly the behavior previously seen for aldehydes and ketones.
Mechanism of the Claisen condensation reaction.
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This reaction between two ester molecules is known as the Claisen condensation reaction.
Mixed Claisen reactions are successful only when one of the two ester components has no alpha hydrogens and thus can’t form an enolate ion.
Mixed Claisen-like reactions can also be carried out between an ester and a ketone, resulting in the synthesis of a beta-diketone. The reaction works best when the ester component has no alpha hydrogens and thus can’t act as the nucleophilic donor.
Called the Dieckmann cyclization, this reaction works best on 1,6 diesters and 1,7-diesters. Intramolecular Claisen cyclization of a 1,6-diester gives a five-membered cyclic beta-keto ester, and cyclization of a 1,7-diester gives a six-membered cyclic beta-keto ester.
Mechanism of the Dieckmann cyclization of a 1,7-diester to yield a cyclic beta-keto ester product.
notice the leaving group takes a H atom, creating an enolate ion which is then protonated by aqueous acid
The cyclic beta-keto ester produced in a Dieckmann cyclization can be further alkylated and decarboxylated by a series of reactions analogous to those used in the acetoacetic ester synthesis.
Certain nucleophiles, such as amines, react with a,b-unsaturated aldehydes and ketones to give a conjugate addition product, rather than a direct addition product.
The best Michael reactions are those that take place when a particularly stable enolate ion, such as that derived from a beta-keto ester or other 1,3-dicarbonyl compounds, adds to an unhindered a,b-unsaturated ketone.
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In addition to enolate ions, other kinds of carbon nucleophiles also add to a,b-unsaturated acceptors in Michael-like reactions. Among the most important and useful of such nucleophiles, particularly in biological chemistry, are enamines, which are readily prepared by reaction between a ketone and a secondary amine
In the Stork reaction, for example, an enamine adds to an a,b-unsaturated carbonyl acceptor in a Michael-like process. The initial product is then hydrolyzed by aqueous acid to yield a 1,5-dicarbonyl compound.
The overall result of an enamine reaction is the Michael addition of a ketone as donor to an a,b-unsaturated carbonyl compound as acceptor, yielding a 1,5-dicarbonyl product. The C–C bond formed in the Michael addition step is the one between the alpha carbon of the ketone donor and the beta carbon of the unsaturated acceptor.
The Robinson annulation is a two-step process that combines a Michael reaction with an intramolecular aldol reaction. It takes place between a nucleophilic donor (such as a beta-keto ester; an enamine, or a beta-diketone) and an a,b-unsaturated ketone acceptor, such as 3-buten-2-one. The product is a substituted 2-cyclohexenone.
The first step of the Robinson annulation is simply a Michael reaction. An enamine or an enolate ion from a beta-keto ester or beta-diketone effects a conjugate addition to an a,b-unsaturated ketone, yielding a 1,5-diketone.
Mechanism of the Michael reaction between a beta-keto ester and an a,b-unsaturated ketone. The reaction is a conjugate addition of an enolate ion to the unsaturated carbonyl compound
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secondary amines > tertiary amines > primary amines > ammonia > cyclic amines
order the amines
In contrast with amines, amides (RCONH2) are nonbasic.
they are not a white girl!
Arylamines are less basic than alkylamines because the nitrogen lone-pair electrons are delocalized by interaction with the aromatic ring’s p electron system and are less available for bonding to H+. In resonance terms, arylamines are stabilized relative to alkylamines because of their five resonance forms.
–NH2, –OCH3, and –CH3 make the aniline more basic
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The two-step sequence of SN2 displacement with CN- followed by reduction thus converts an alkyl halide into a primary alkylamine having an additional carbon atom. Amide reduction converts carboxylic acids and their derivatives into amines with the same number of carbon atoms.
Catalytic hydrogenation over platinum works well but is often incompatible with the presence elsewhere in the molecule of other reducible groups, such as C=C bonds or carbonyl groups. Iron, zinc, tin, and tin(II) chloride (SnCl2) are also effective when used in acidic aqueous solution. Tin(II) chloride is particularly mild and is often used when other reducible functional groups are present.
If ammonia is used, a primary amine results; if a primary amine is used, a secondary amine results; and so on. Even tertiary amines react rapidly with alkyl halides to yield quaternary ammonium salts, R4N X- .
Use NaN3 to prepare primary amines.
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Another alternative for preparing a primary amine from an alkyl halide is the Gabriel amine synthesis, which uses a phthalimide alkylation. An imide (–CONHCO–) is similar to a beta-keto ester in that the acidic N–H hydrogen is flanked by two carbonyl groups.
Amines can be synthesized in a single step by treatment of an aldehyde or ketone with ammonia or an amine in the presence of a reducing agent, a process called reductive amination. Typically, NaBH4 is used.
Mechanism for reductive amination of a ketone to yield an amine.
notice the reduction agents
Ammonia, primary amines, and secondary amines can all be used in the reductive amination reaction, yielding primary, secondary, and tertiary amines, respectively.
Mechanism for Hofmann rearrangement of an amide to an amine.
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Curtius rearrangement, like Hofmann rearrangement, involves migration of an –R group from the C=O carbon atom to the neighboring nitrogen with simultaneous loss of a leaving group. The reaction takes place on heating an acyl azide that is itself prepared by nucleophilic acyl substitution of an acid chloride.
Also like Hofmann rearrangement, Curtius rearrangement is often used commercially.
Both Hofmann and Curtius rearrangements convert a carboxylic acid derivative—either an amide (Hofmann) or an acid chloride (Curtius)—into a primary amine with loss of one carbon, RCOY ==> RNH2.
know the difference
In the Hofmann elimination reaction, an amine is completely methylated by reaction with an excess amount of iodomethane to produce the corresponding quaternary ammonium salt. This salt then undergoes elimination to give an alkene on heating with a base, typically silver oxide, Ag2O.
An amino group is strongly activating and ortho- and para-directing in electrophilic aromatic substitution reactions
Treatment of an amine with acetic anhydride yields the corresponding acetyl amide, or acetamide.
know this, look at the green reagent
Friedel–Crafts alkylations and acylations of N-arylamides also proceed normally.
Sulfa drugs are prepared by chlorosulfonation of acetanilide, followed by reaction of p-(N-acetylamino)benzenesulfonyl chloride with ammonia or some other amine to give a sulfonamide. Hydrolysis of the amide then yields the sulfa drug. Note that hydrolysis of the amide can be carried out in the presence of the sulfonamide group because sulfonamides hydrolyze very slowly.
Primary arylamines react with nitrous acid, HNO2, to yield stable arene diazonium salts, Ar–N≡N X-, a process called a diazotization reaction.
The overall sequence of (1) nitration, (2) reduction, (3) diazotization, and (4) nucleophilic substitution is perhaps the single most versatile method of aromatic substitution.
this is important
Aryl chlorides and bromides are prepared by reaction of an arene-diazonium salt with the corresponding copper(I) halide, CuX, a process called the Sandmeyer reaction. Aryl iodides can be prepared by direct reaction with NaI without using a copper(I) salt. Yields generally fall between 60% and 80%.
Reduction of a diazonium salt to give an arene occurs on treatment with hypophosphorous acid, H3PO2. This reaction is used primarily when there is a need for temporarily introducing an amino substituent onto a ring to take advantage of its directing effect.
Mechanistically, these diazonio replacement reactions occur through radical rather than polar pathways.
VERY IMPORTANT