question

Two broad classes of compounds contain a carbonyl group?

answer

[1] Compounds that have only carbon and hydrogen atoms bonded to the carbonyl group [2] Compounds that contain an electronegative atom bonded to the carbonyl group

question

carboxylic acid derivatives

answer

compounds containing an electronegative atom (Cl, O, or N) capable of acting as a leaving group. Acid chlorides, esters, and amides are often called carboxylic acid derivatives, because they can be synthesized from carboxylic acids. Since each compound contains an acyl group (RCO- ), they are also called acyl derivatives.

question

Aldehydes and ketones undergo what type of reaction?

answer

• Aldehydes and ketones undergo nucleophilic addition.

question

The carbonyl carbon is nucleophilic or electrophilic?

answer

The electronegative oxygen makes the carbonyl carbon electrophilic, and because it is trigonal planar, a carbonyl carbon is uncrowded. Moreover, a carbonyl group has an easily broken ? bond. The carbonyl carbon reacts with nucleophiles!

question

Carbonyl compounds that contain leaving groups undergo what type of reaction?

answer

• Carbonyl compounds that contain leaving groups undergo nucleophilic substitution.

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Nucleophilic Addition to Aldehydes and Ketones (Mechanism)

answer

The net result is that the ? bond is broken, two new ? bonds are formed, and the elements of H and Nu are added across the ? bond.

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Reactivity of Carboxylic acid derivatives?

answer

• The better the leaving group Z, the more reactive RCOZ is in nucleophilic acyl substitution.

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similarities/differences between Nucleophilic addition and nucleophilic acyl substitution

answer

involve the same first step—nucleophilic attack on the electrophilic carbonyl group to form a tetrahedral intermediate. The difference between them is what then happens to this intermediate. Aldehydes and ketones cannot undergo substitution

question

Why can't Aldehydes and ketones undergo nucleophilic substitution?

answer

Aldehydes and ketones cannot undergo substitution because they have no leaving group bonded to the newly formed sp³ hybridized carbon. Nucleophilic substitution with an aldehyde, for example, would form H:-, an extremely strong base and therefore a very poor (and highly unlikely) leaving group.

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What results from oxidation?

answer

• Oxidation results in an increase in the number of C - Z bonds (usually C - O bonds) or a decrease in the number of C - H bonds.

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What results from reduction?

answer

• Reduction results in a decrease in the number of C - Z bonds (usually C - O bonds) or an increase in the number of C - H bonds.

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Oxidation and reduction reactivity of carbonyl groups?

answer

because aldehydes fall in the middle of this scheme, they can be both oxidized and reduced. Carboxylic acids and their derivatives (RCOZ), on the other hand, are already highly oxidized, so their only useful reaction is reduction.

question

The most useful reagents for reducing aldehydes and ketones

answer

the metal hydride reagents. The two most common metal hydride reagents are sodium borohydride (NaBH?) and lithium aluminum hydride (LiAlH?). These reagents contain a polar metal-hydrogen bond that serves as a source of the nucleophile hydride, H:-. LiAlH? is a stronger reducing agent than NaBH?, because the Al - H bond is more polar than the B - H bond.

question

Reduction with Metal Hydride Reagents

answer

Treating an aldehyde or a ketone with NaBH? or LiAlH?, followed by water or some other proton source, affords an alcohol. This is an addition reaction because the elements of H? are added across the ? bond, but it is also a reduction because the product alcohol has fewer C- O bonds than the starting carbonyl compound.

question

Do you get a 1° or 2° alcohol when the starting carbonyl compound is an aldehyde? What about a ketone.?

answer

The product of this reduction reaction is a 1° alcohol when the starting carbonyl compound is an aldehyde, and a 2° alcohol when it is a ketone.

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LiAlH? Reduction of RCHO and R?C=O (Mechanism)

answer

• The net result of adding H:- (from NaBH? or LiAlH?) and H+ (from H?O) is the addition of the elements of H? to the carbonyl ? bond.

question

Catalytic Hydrogenation of Aldehydes and Ketones

answer

Catalytic hydrogenation also reduces aldehydes and ketones to 1° and 2° alcohols, respectively, using H? and Pd-C (or another metal catalyst).

question

When a compound contains both a carbonyl group and a carbon-carbon double bond, selective reduction of one functional group can be achieved how?

answer

• A C=C is reduced faster than a C=O with H? (Pd-C). • A C=O is readily reduced with NaBH? and LiAlH?, but a C=C is inert.

question

Hydride reduction of an achiral ketone with LiAlH? or NaBH? gives what kind of product when a new stereogenic center is formed?

answer

A racemic mixture of two enantiomers. Because the carbonyl carbon is sp² hybridized and planar, hydride can approach the double bond with equal probability from both sides of the plane.

question

enantioselective or asymmetric reduction

answer

A reduction that forms one enantiomer predominantly or exclusively One enantiomer can be formed selectively from the reduction of a carbonyl group, provided a chiral reducing agent is used.

question

CBS reagent

answer

formed by reacting borane (BH?) with a heterocycle called an oxazaborolidine. One B- H bond of BH? serves as the source of hydride in this reduction

question

Reacting the 2 CBS molecules with For ketones having the general structure C6H5COR gives what product(s)?

answer

• The (S)-CBS reagent delivers hydride (H:-) from the front side of the C=O. This generally affords the R alcohol as the major product. • The (R)-CBS reagent delivers hydride (H:-) from the back side of the C=O. This generally affords the S alcohol as the major product.Highly enantioselective (forms almost 97% of the correct enantiomer usually)

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Enantioselective Biological Reduction

answer

This reaction is completely enantioselective

question

NAD+

answer

the oxidized form of NADH, is a biological oxidizing agent capable of oxidizing alcohols to carbonyl compounds (it forms NADH in the process)

question

Reduction of Carboxylic Acids and Their Derivatives

answer

The reduction of carboxylic acids and their derivatives (RCOZ) is complicated because the products obtained depend on the identity of both the leaving group (Z) and the reducing agent. Metal hydride reagents are the most useful reducing reagents

question

Lithium aluminum hydride

answer

LiAlH? a strong reducing agent that reacts with all carboxylic acid derivatives

question

Diisobutylaluminum hydride, [(CH?)2CHCH?]?AlH, abbreviated as DIBAL-H,

answer

has two bulky isobutyl groups, which make this reagent less reactive than LiAlH?. The single H atom is donated as H:- in hydride reductions.

question

Lithium tri-tert-butoxyaluminum hydride, LiAlH[OC(CH?)?]?,

answer

has three electronegative oxygen atoms bonded to aluminum, which make this reagent less nucleophilic than LiAlH?.

question

Reduction of acid chlorides

answer

In the reduction of an acid chloride, Cl- comes off as the leaving group.

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Reduction of an ester

answer

In the reduction of the ester, CH?O- comes off as the leaving group, which is then protonated by H?O to form CH?OH.

question

Reduction of Carboxylic Acids

answer

Carboxylic acids are reduced to 1° alcohols with LiAlH?. LiAlH? is too strong a reducing agent to stop the reaction at the aldehyde stage, but milder reagents are not strong enough to initiate the reaction in the first place, so this is the only useful reduction reaction of carboxylic acids.

question

Reduction of Amides?

answer

Both C-O bonds are reduced to C-H bonds by LiAlH?, and any H atom or R group bonded to the amide nitrogen atom remains bonded to it in the product. Because -NH? (or -NHR or -NR?) is a poorer leaving group than Cl- or -OR, -NH? is never lost during reduction, and therefore it forms an amine in the final product.

question

Summary of Metal Hydride Reducing Agents

answer

LiAlH? is such a strong reducing agent that it nonselectively reduces most polar functional groups.

question

Oxidation of Aldehydes

answer

The most common oxidation reaction of carbonyl compounds is the oxidation of aldehydes to carboxylic acids. A variety of oxidizing agents can be used, including CrO?, Na?Cr?O?, K?Cr?O?, and KMnO?. Cr?? reagents are also used to oxidize 1° and 2° alcohols, as discussed in Section 12.12. Because ketones have no H on the carbonyl carbon, they do not undergo this oxidation reaction. Aldehydes are oxidized selectively in the presence of other functional groups using silver(I) oxide in aqueous ammonium hydroxide (Ag?O in NH?OH).

question

Organometallic reagents

answer

contain a carbon atom bonded to a metal. Lithium, magnesium, and copper are the most commonly used metals in organometallic reagents, but others (such as Sn, Si, Tl, Al, Ti, and Hg) are known

question

General structures of the three common organometallic reagents

answer

R can be alkyl, aryl, allyl, benzyl, sp2 hybridized, and with M = Li or Mg, sp hybridized. Because metals are more electropositive (less electronegative) than carbon, they donate electron density towards carbon, so that carbon bears a partial negative charge.

question

Grignard reagents

answer

organomagnesium reagents (RMgX) contain very polar carbon-metal bonds and are therefore very reactive reagents.

question

organocuprates

answer

Organocopper reagents (R?CuLi), also called organocuprates, have a less polar carbon-metal bond and are therefore less reactive. Although organocuprates contain two alkyl groups bonded to copper, only one R group is utilized in a reaction

question

Types of reactions with organometallic reagents

answer

Regardless of the metal, organometallic reagents are useful synthetically because they react as if they were free carbanions; that is, carbon bears a partial negative charge, so the reagents react as bases and nucleophiles.

question

Electronegativity of carbon and common metals

answer

in R - M reagents are C (2.5), Li (1.0), Mg (1.3), and Cu (1.8).

question

Preparation of Organometallic Reagents

answer

Organolithium and Grignard reagents are typically prepared by reaction of an alkyl halide with the corresponding metal, as shown in the accompanying equations.

question

Preparation of Organolithium reagent

answer

the halogen and metal exchange to form the organolithium reagent

question

Preparation of Grignard reagent

answer

the metal inserts in the carbon-halogen bond, forming the Grignard reagent. Grignard reagents are usually prepared in diethyl ether (CH3CH2OCH2CH3) as solvent. It is thought that two ether oxygen atoms complex with the magnesium atom, stabilizing the reagent

question

Preparation of Organocuprates

answer

Organocuprates are prepared from organolithium reagents by reaction with a Cu+ salt, often CuI.

question

Acetylide Anions

answer

acetylide anions discussed in Chapter 11 are another example of organometallic compounds. These reagents are prepared by an acid-base reaction of an alkyne with a base such as NaNH? or NaH. We can think of these compounds as organosodium reagents. Because sodium is even more electropositive (less electronegative) than lithium, the C-Na bond of these organosodium compounds is best described as ionic, rather than polar covalent.

question

preparation of sp hybridized organolithium compounds.

answer

An acid-base reaction can also be used to prepare sp hybridized organolithium compounds. Treatment of a terminal alkyne with CH?Li affords a lithium acetylide. Equilibrium favors the products because the sp hybridized C - H bond of the terminal alkyne is more acidic than the sp³ hybridized conjugate acid, CH?, that is formed

question

Organometallic reactions with water

answer

• Organometallic reagents are strong bases that readily abstract a proton from water to form hydrocarbons. Equilibrium favors the products of this acid-base reaction because H2O is a much stronger acid than the alkane product.

question

Organometallic reactions with alchohols or amines

answer

Metals Similar reactions occur for the same reason with the O- H proton in alcohols and carboxylic acids, and the N - H protons of amines.

question

Converting an alkyl halide into an alkane (or another hydrocarbon) with organometallics

answer

Because organolithium and Grignard reagents are themselves prepared from alkyl halides, a two-step method converts an alkyl halide into an alkane (or another hydrocarbon).

question

Organometallics act as an electrophile or a nucleophile?

answer

Organometallic reagents are also strong nucleophiles that react with electrophilic carbon atoms to form new carbon-carbon bonds. These reactions are very valuable in forming the carbon skeletons of complex organic molecules

question

Reaction of Organometallic Reagents with Aldehydes and Ketones

answer

Treatment of an aldehyde or ketone with either an organolithium or Grignard reagent followed by water forms an alcohol with a new carbon-carbon bond. This reaction is an addition reaction because the elements of R'' and H are added across the ? bond.

question

Addition of R"MgX to formaldehyde (CH2=O)

answer

forms a 1° alcohol reaction results in addition of one new alkyl group to the carbonyl carbon, and forms one new carbon-carbon bond

question

Addition of R"MgX to all other aldehydes

answer

forms a 2° alcohol reaction results in addition of one new alkyl group to the carbonyl carbon, and forms one new carbon-carbon bond

question

Addition of R"MgX to ketones

answer

forms a 3° alcohol. reaction results in addition of one new alkyl group to the carbonyl carbon, and forms one new carbon-carbon bond

question

Reaction of Organometallic Reagents with Aldehydes and Ketones (organolithium, Grignard reagents, and acetylide anions) 3 examples

answer

Each reaction results in addition of one new alkyl group to the carbonyl carbon, and forms one new carbon-carbon bond

question

Restrictions for reactions of Organometallic reagents with aldehydes and ketones

answer

Because organometallic reagents are strong bases that rapidly react with H?O (Section 20.9C), the addition of the new alkyl group must be carried out under anhydrous conditions to prevent traces of water from reacting with the reagent, thus reducing the yield of the desired alcohol. Water is added after the addition to protonate the alkoxide.

question

Stereochemistry of reactions of Organometallic reagents with aldehydes and ketones

answer

Addition of R -M always occurs from both sides of the trigonal planar carbonyl group. When a new stereogenic center is formed from an achiral starting material, an equal mixture of enantiomers results

question

Retrosynthetic Analysis of Grignard Products (steps)

answer

Step [1] Find the carbon bonded to the OH group in the product. Step [2] Break the molecule into two components: One alkyl group bonded to the carbon with the OH group comes from the organometallic reagent. The rest of the molecule comes from the carbonyl component.

question

Synthesize 3-pentanol [(CH?CH?)?CHOH] by a Grignard reaction

answer

locate the carbon bonded to the OH group, and then break the molecule into two components at this carbon. Thus, retrosynthetic analysis shows that one of the ethyl groups on this carbon come from a Grignard reagent (CH?CH?MgX), and the rest of the molecule comes from the carbonyl component, a three-carbon aldehyde. Then, writing the reaction in the synthetic direction—that is, from starting material to product— shows whether the analysis is correct. In this example, a three- carbon aldehyde reacts with CH?CH?MgBr to form an alkoxide, which can then be protonated by H?O to form 3-pentanol, the desired alcohol.

question

Protecting Groups

answer

• Carbonyl compounds that also contain N-H or O-H bonds undergo an acid-base reaction with organometallic reagents, not nucleophilic addition.

question

What functional groups undergo rapid acid/base reactions with organometallic reagents?

answer

ROH, RCOOH, RNH2, R2NH, RCONH2, RCONHR, and RSH.

question

Strategy for overcoming addition reactions with carbonyl compounds that contain NH or OH bonds

answer

Step [1] Convert the OH group into another functional group that does not interfere with the desired reaction. This new blocking group is called a protecting group, and the reaction that creates it is called protection. Step [2] Carry out the desired reaction. Step [3] Remove the protecting group. This reaction is called deprotection

question

silyl ether

answer

A common OH protecting group is a silyl ether. A silyl ether has a new O-Si bond in place of the O-H bond of the alcohol. The most widely used silyl ether protecting group is the tertbutyldimethylsilyl ether.

question

Preparation of tert-Butyldimethylsilyl ethers

answer

tert-Butyldimethylsilyl ethers are prepared from alcohols by reaction with tert-butyldimethylsilyl chloride and an amine base, usually imidazole.

question

Deprotection Process

answer

The silyl ether is typically removed with a fluoride salt, usually tetrabutylammonium fluoride (CH?CH?CH?CH?)?N? F?.

question

Reaction of RLi and RMgX with Esters and Acid Chlorides

answer

Both esters and acid chlorides form 3° alcohols when treated with two equivalents of either Grignard or organolithium reagents. Two new carbon-carbon bonds are formed in the product.

question

Reaction of R"MgX or R"Li with RCOCl and RCOOR' (Mechanism)

answer

Organolithium and Grignard reagents always afford 3° alcohols when they react with esters and acid chlorides. As soon as the ketone forms by addition of one equivalent of reagent to RCOZ (Part [1] of the mechanism), it reacts with a second equivalent of reagent to form the 3° alcohol.

question

Reaction of R?CuLi with Acid Chlorides

answer

To form a ketone from a carboxylic acid derivative, a less reactive organometallic reagent— namely an organocuprate—is needed. Acid chlorides, which have the best leaving group (Cl?) of the carboxylic acid derivatives, react with R'?CuLi, to give a ketone as product. Esters, which contain a poorer leaving group (?OR), do not react with R'?CuLi. This reaction results in nucleophilic substitution of an alkyl group R' for the leaving group Cl, forming one new carbon-carbon bond.

question

carboxylation

answer

Grignard reagents react with CO? to give carboxylic acids after protonation with aqueous acid. This reaction, called carboxylation, forms a carboxylic acid with one more carbon atom than the Grignard reagent from which it is prepared. Because Grignard reagents are made from alkyl halides, an alkyl halide can be converted to a carboxylic acid having one more carbon atom by a two-step reaction sequence

question

Reaction of Organometallic Reagents with Epoxides

answer

Like other strong nucleophiles, organometallic reagents—RLi, RMgX, and R?CuLi—open epoxide rings to form alcohols The reaction follows the same two-step process as the opening of epoxide rings with other negatively charged nucleophiles—that is, nucleophilic attack from the back side of the epoxide ring, followed by protonation of the resulting alkoxide

question

Reaction of Organometallic Reagents with unsymmetrical epoxides

answer

nucleophilic attack occurs at the less substituted carbon atom.

question

?, ? -Unsaturated Carbonyl Compounds

answer

?, ?-Unsaturated carbonyl compounds are conjugated molecules containing a carbonyl group and a carbon-carbon double bond, separated by a single ? bond.

question

? bonds in ?, ? -Unsaturated Carbonyl Compounds

answer

Both functional groups of ?, ?-unsaturated carbonyl compounds have ? bonds, but individually, they react with very different kinds of reagents. Carbon-carbon double bonds react with electrophiles (Chapter 10) and carbonyl groups react with nucleophiles

question

conjugation of ?, ? -Unsaturated Carbonyl Compounds and implications

answer

Because the two ? bonds are conjugated, the electron density in an ?, ? -unsaturated carbonyl compound is delocalized over four atoms. Three resonance structures show that the carbonyl carbon and the " carbon bear a partial positive charge. This means that ?, ? -unsaturated carbonyl compounds can react with nucleophiles at two different sites.

question

1,2-Addition to an ?, ?-Unsaturated Carbonyl Compound

answer

The steps for the mechanism of 1,2-addition are exactly the same as those for the nucleophilic addition to an aldehyde or ketone—that is, nucleophilic attack, followed by protonation

question

1,4-Addition to an ?, ?-Unsaturated Carbonyl Compound

answer

The mechanism for 1,4-addition also begins with nucleophilic attack, and then protonation and tautomerization add the elements of H and Nu to the ? and ? carbons of the carbonyl compound,

question

What determines the reactivity of the reagents in carbonyl reactions

answer

The polarity of the R-M bond determines the reactivity of the reagents. • RLi and RMgX are very reactive reagents. • R?CuLi is much less reactive.

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