Organic Chemistry 2 Chapter 21

Treatment of an aldehyde or a ketone with a 1° amine affords what product?

Treatment of an aldehyde or a ketone with a 1° amine affords an imine (also called a Schiff base).

Nucleophilic Addition of ⁻CN

Treatment of an aldehyde or ketone with NaCN and a strong acid such as HCl adds the elements of HCN across the C-O pi bond, forming a cyanohydrin. This is also a C-C bond forming reaction.

Treatment of 2° amine with an aldehyde or ketone to results in what product?

*A 2° amine reacts with an aldehyde or ketone to give an enamine. *Enamines have a nitrogen atom bonded to a C-C double bond. *Like imines, enamines are also formed by the addition of a nitrogen nucleophile to a carbonyl group followed by elimination of water. In this case, however, elimination occurs across two adjacent carbon atoms to form a new carbon-carbon π bond.

Acetals as protecting groups

*Acetals are valuable protecting groups for aldehydes and ketones. *Suppose we wish to selectively reduce the ester to an alcohol in compound A, leaving the ketone untouched. *Because ketones are more readily reduced, methyl-5-hydroxyhexanoate is formed instead. *To solve this problem, we can use a protecting group to block the more reactive ketone carbonyl.

IR Spectra of Aldehydes and ketones

*Aldehydes and ketones exhibit a strong peak at ~1700 cm-1 due to the C=O. *The sp2 hybridized C-H bond of an aldehyde shows one or two peaks at ~2700 -2830 cm−1

Physical Properties of Aldehydes and Ketones

*Aldehydes and ketones have strong dipoles, but lack hydrogen bonding, resulting in boiling points between nonpolar molecules and alcohols of similar size. *Water solubility mimics that of alcohols and ethers of similar size.

Aldehydes and ketones react with two equivalents of alcohol to form what product?

*Aldehydes and ketones react with two equivalents of alcohol to form acetals. *Acetal formation is catalyzed by acids, such as TsOH. Note that acetals are not ethers.

What is the advantage of the Wittig reaction over elimination methods used to synthesize alkenes?

*An advantage of the Wittig reaction over elimination methods used to synthesize alkenes is that the Wittig reaction always gives a single constitutional isomer.

Hydrolysis of Acetals

*Because conversion of an aldehyde or ketone to an acetal is a reversible reaction, an acetal can be hydrolyzed to an aldehyde or ketone by treatment with aqueous acid. *Since the reaction is also an equilibrium process, it is driven to the right by using a large excess of water for hydrolysis.

Hydrolysis of Imines and enamines

*Because imines and enamines are formed by a reversible set of reactions, both can be converted back to carbonyl compounds by hydrolysis with mild acid. *The mechanism of hydrolysis is the exact reverse of the mechanism written for formation of imines and enamines.

Imine Properties

*Because the N atom of an imine is surrounded by three groups (two atoms and a lone pair), it is sp² hybridized, making the C-N-R bond angle 120°, (not 180°). *Imine formation is fastest when the reaction medium is weakly acidic (pH 4-5).

Base catalyzed hydration of an aldehyde or ketone

*Both acid and base catalyze the addition of H₂O to the carbonyl group. *With base, the nucleophile is ¯OH, and the mechanism follows the usual two steps: nucleophilic attack followed by protonation. *The reaction rate increases under basic conditions because of the higher concentration of ¯OH, a stronger nucleophile.

Carbohydrates

*Carbohydrates, commonly referred to as sugars and starches, are polyhydroxy aldehydes and ketones, or compounds that can be hydrolyzed to them. *Many carbohydrates contain cyclic acetals or hemiacetals. Examples include glucose and lactose.

Naming Enals and Enones

*Compounds containing both a C-C double bond and an aldehyde are named as enals. *Compounds that contain both a C-C double bond and a ketone are named as enones. The chain is numbered to give the carbonyl the lower number.

Formation of cyclic hemiacetals

*Cyclic hemiacetals are formed by intramolecular cyclization of hydroxy aldehydes. *Such intramolecular reactions to form five- and six-membered rings are faster than the corresponding intermolecular reactions. *The two reacting functional groups (OH and C=O), are held in close proximity, increasing the probability of reaction.

Cyclic hemiacetals can be converted to acetals by treatment with what reagents?

*Cyclic hemiacetals can be converted to acetals by treatment with an alcohol and acid. *This converts the OH of the hemiacetal into the OR group of an acetal.

Electronic factors affecting hydrate stability

*Electron-donating groups near the carbonyl carbon stabilize the carbonyl group, decreasing the amount of the hydrate at equilibrium. *Electron-withdrawing groups near the carbonyl carbon destabilize the carbonyl group, increasing the amount of hydrate at equilibrium. *This explains why chloral forms a large amount of hydrate at equilibrium. *Three electron-withdrawing Cl atoms result in a partial positive charge on the carbon of the carbonyl, destabilizing the carbonyl group, and therefore increasing the amount of hydrate at equilibrium.

Nomenclature of Aldehydes

*If the CHO is bonded to a chain of carbons, find the longest chain containing the CHO group, and change the -e ending of the parent alkane to the suffix -al. *If the CHO group is bonded to a ring, name the ring and add the suffix -carbaldehyde. *Number the chain or ring to put the CHO group at C1, but omit this number from the name. *Apply all the other usual rules of nomenclature.

Naming of Ketones

*In the IUPAC system, all ketones are identified by the suffix "one". *Find the longest continuous chain containing the carbonyl group, and change the -e ending of the parent alkane to the suffix -one. *Number the carbon chain to give the carbonyl carbon the lowest number. *Apply all of the usual rules of nomenclature. *With cyclic ketones, numbering always begins at the carbonyl carbon, but the "1" is usually omitted from the name. *The ring is then numbered clockwise or counterclockwise to give the first substituent the lower number.

Mechanism for the formation of cyclic acetal from cyclic hemiacetal

*In the conversion of hemiacetals to acetals, the overall result is the replacement of the hemiacetal OH group by an OCH3 group. *This reaction occurs readily because the carbocation formed in step 2 is stabilized by resonance, making the hemiacetal OH group different from the hydroxy group in other alcohols. *Thus, when a compound with both an alcohol OH and a hemiacetal OH is treated with an alcohol and acid, only the hemiacetal OH reacts to form the acetal.

Hydration Level Versus Stability

*Increasing the number of alkyl groups on the carbonyl carbon decreases the amount of hydrate at equilibrium.

Common names of ketones

*Most common names for ketones are formed by naming both alkyl groups on the carbonyl carbon, arranging them alphabetically, and adding the word "ketone". *Three widely used common names for some simple ketones do not follow this convention:

What nucleophiles add to carbonyl groups?

*Only some of the nucleophiles that react well in nucleophilic substitution at sp3 hybridized carbons give reasonable yields of nucleophilic addition products. *Cl¯, Br¯, and I¯ are good nucleophiles in substitution reactions at sp3 hybridized carbons, but they are ineffective nucleophiles in addition. *When these nucleophiles add to the sp2 carbonyl carbon, they cleave the C-O bond, forming an alkoxide. *Since X¯ is a much weaker base than the alkoxide formed, equilibrium favors the starting materials, not the addition product.

Resonance of Wittig Reagants

*Since phosphorus is a second-row element, it can be surrounded by more than eight electrons. *Thus, a second resonance structure can be drawn that places a double bond between carbon and phosphorus. *Regardless of which resonance structure is drawn, a Wittig reagent has no net charge. *However, in one resonance structure, the carbon bears a net negative charge, making it nucleophilic.

Describe a Whittig Reagent

*The Wittig reagent is an organophosphorus reagent. *A typical Wittig reagent has a phosphorus atom bonded to three phenyl groups, plus another alkyl group that bears a negative charge. *A Wittig reagent is an ylide, a species that contains two oppositely charged atoms bonded to each other, with both atoms having octets. *Phosphorus ylides are also called phosphoranes.

¹H and ¹³C NMR absorptions

*The sp2 hybridized C-H proton of an aldehyde is highly deshielded and absorbs far downfield at 9-10 ppm. *Splitting occurs with protons on the carbon, but the coupling constant is often very small (J = 1-3 Hz). *Protons on the carbon to the carbonyl group absorb at 2-2.5 ppm. *Methyl ketones, for example, give a characteristic singlet at ~2.1 ppm. *In a ¹³C NMR spectrum, the carbonyl carbon is highly deshielded, appearing in the 190-215 ppm region.

¹³C NMR absorptions

*There are three signals due to the three different kinds of carbons, labeled Ca, Cb, and Cc. *The deshielded carbonyl carbon absorbs downfield at 203 ppm.

¹H NMR of Propanal

*There are three signals due to the three different kinds of hydrogens, labeled Ha, Hb, and Hc. *The deshielded CHO proton occurs downfield at 9.8 ppm. *The Hc signal is split into a triplet by the adjacent CH₂ group, but the coupling constant is small.

What happens with treatment of a carbonyl compound with H₂O in the presence of an acid or base catalyst?

*Treatment of a carbonyl compound with H2O in the presence of an acid or base catalyst adds the elements of H and OH across the C-O pi bond, forming a gem-diol or hydrate.

When a diol such as ethylene glycol is used in place of two equivalents of ROH, what is formed?

*When a diol such as ethylene glycol is used in place of two equivalents of ROH, a cyclic acetal is formed. *Like gem-diol formation, the synthesis of acetals is reversible, and often, the equilibrium favors the reactants. *In acetal synthesis, since water is formed as a by-product, the equilibrium can be driven to the right by removing H2O as it is formed using distillation or other techniques. *Driving an equilibrium to the right by removing one of the products is an application of Le Châtelier's principle.

Formation of imines versus enamines

*With a 1° amine, the intermediate iminium ion still has a proton on the N atom that may be removed to form a C=N. *With a 2° amine, the intermediate iminium ion has no proton on the N atom. A proton must be removed from an adjacent C-H bond, and this forms a C=C.

Formation of Imine mechanism

1 - 2. Nucleophilic attack of the amine followed by proton transfer forms the carbinolamine. 3. Protonation of the OH group forms a good leaving group. 4. Loss of H2O forms a resonance-stabilized iminium ion. 5. Loss of a proton forms the imine.

Formation of enamine mechanism

1 - 2. Nucleophilic attack of the amine followed by proton transfer forms the carbinolamine. 3. Protonation of the OH group forms a good leaving group. 4. Loss of H2O forms a resonance-stabilized iminium ion. 5. Loss of a proton from the adjacent CH bond forms the enamine.

Nucleophilic addition of CN mechanism

1 Nucleophilic attack of -CN forms a new carbon-carbon bond with cleavage of the CO π bond. 2 Protonation of the negatively charged oxygen by HCN forms the addition product. The HCN used in this step is formed by the acid-base reaction of -CN with the strong acid, HCl. *This reaction does not occur with HCN alone. The cyanide anion makes addition possible because it is a strong nucleophile that attacks the carbonyl group.

Acid-catalyzed Nucleophilic Addition

1 Protonation of the carbonyl oxygen forms a resonance-stabilized cation. 2 - 3 Nucleophilic attack and deprotonation form the neutral addition product. The overall result is addition of H and Nu to the carbonyl group.

General Mechanism—Nucleophilic Addition

1 The nucleophile attacks the electrophilic carbonyl. The π bond is broken, moving an electron pair out on oxygen and forming an sp³hybridized carbon. 2 Protonation of the negatively charged oxygen by H₂O forms the addition product. In this mechanism nucleophilic attack precedes protonation. This process occurs with strong neutral or negatively charged nucleophiles.

Aldehydes and ketones are also both obtained as products of:

Aldehydes and ketones are also both obtained as products of the oxidative cleavage of alkenes.

Preparation of Aldehydes from alkynes:

Aldehydes can be prepared by hydroboration and oxidation of alkynes

Preparation of Aldehydes from 1° alcohols:

Aldehydes can be prepared by oxidation of of 1° alcohols using PCC.

Preparation of Aldehydes from esters and acid chlorides:

Aldehydes can be prepared by reduction of esters and acid chlorides.

Amines

Amines are organic nitrogen compounds that contain a nonbonded electron pair on the N atom. Both 1° and 2° amines react with aldehydes and ketones.

How does conjugation impact IR spectra?

Conjugation leads to a somewhat weaker C=O bond, thus shifting the carbonyl absorption to longer wavelengths and lower wave numbers.

How are cyanohydrins reconverted to carbonyl compounds?

Cyanohydrins can be reconverted to carbonyl compounds by treatment with base. This process is just the reverse of the addition of HCN: deprotonation followed by elimination of -CN.

Cyclic hemiacetals

Cyclic hemiacetals containing five- and six-membered rings are stable compounds that are readily isolated.

Gem-diol product yields are good only when?

Gem-diol product yields are good only when unhindered aldehydes or aldehydes with nearby electron withdrawing groups are used.

Acid-Catalyzed Hemiacetal Formation

Hemiacetal formation is catalyzed by both acid and base.

Intramolecular cyclization of a hydroxy aldehyde forms what product?

Intramolecular cyclization of a hydroxy aldehyde forms a hemiacetal with a new stereogenic center, so that an equal amount of two enantiomers results.

Preparation of ketones via Friedel-Crafts acylation.

Ketones can be formed from acid chlorides by Friedel-Crafts acylation.

Preparation of ketones from alkynes

Ketones can be prepared by hydration of an alkyne.

Preparation of ketones from 2° alcohols:

Ketones can be prepared by oxidation of 2° alcohols with Cr6+ reagents.

Preparation of ketones from acid chlorides

Ketones can be prepared by reaction of acid chlorides with organocuprates.

Witting Reaction

The Wittig reaction uses a carbon nucleophile (the Wittig reagent) to form alkenes—the carbonyl group is converted to a C=C.

Most aldehydes have a carbonyl peak around 1730 cm−1, whereas for ketones, it is typically around 1715 cm−1. Ring size affects the carbonyl absorption in what manner?

The carbonyl absorption of cyclic ketones shifts to higher wavenumber as the size of the ring decreases and the ring strain increases.

How is the cyano group (CN) of a cyanohydrin is readily hydrolyzed to a carboxy group (COOH)?

The cyano group (CN) of a cyanohydrin is readily hydrolyzed to a carboxy group (COOH) by heating with aqueous acid or base. Hydrolysis replaces the three CN bonds by three CO bonds.

Addition of Alcohols—Hemiacetal Formation

The mechanism for acetal formation can be divided into two parts, the first of which is addition of one equivalent of alcohol to form the hemiacetal.

Acid Catalyzed Hydration of an aldehyde or ketone

The reaction rate increases in the presence of acid because the acid protonates the carbonyl group, making it more electrophilic and thus more susceptible to nucleophilic attack.

Acetal formation from a hemiacetal

The second part of the mechanism involves conversion of the hemiacetal into the acetal.

Protecting-deprotecting process

[1] Protect the interfering functional group—the ketone carbonyl. [2] Carry out the desired reaction. [3] Remove the protecting group.

As the number of R groups around the carbonyl carbon increases how does it impact reactivity towards nucleophiles,

he reactivity of the carbonyl compound decreases, resulting in the following order of reactivity:

Any reaction involving a carbonyl group and a strong acid begins with the same first step:

protonation of the carbonyl oxygen

Hydrolysis

results in cleaving bonds with water.

Examples of Nucleophilic Addition with Nucleophile and Addition Product

the picture lists nucleophiles that add to a carbonyl group, as well as the products obtained from nucleophilic addition using cyclohexanone as a representative ketone. In cases in which the initial addition adduct is unstable, it is enclosed within brackets, followed by the final product.