Organic Chemistry chapter 17

Carboxylation reaction of RMgX with CO2

1. The nucleophilic Grignard reagent attacks the electrophilic carbon of CO2, cleaving the pi bond and forming a new carbon-carbon bond. 2. Protonation of the carboxylate anion with aqueous acid forms the carboxylic acid

More

Aldehydes are ___ reactive than ketones. The two r groups bonded to the ketone carbonyl group make it more crowded, so nucleophilic attack is more difficult. The two electron-donor R groups stabilize the partial charge on the carbonyl carbon of a ketone, making it more stable and less reactive

Reduction of Aldehydes and Ketones

-undergo reduction to form alcohols

Catalytic hydrogenation of aldehydes and ketones

Reduces them to primary and secondary alcohols, respectively, using H2 and Pd-c. H2 adds to the C=O.

Addition of R'MgX to ketones forms

Tertiary alcohol

Reduction of an amide to an amine with LiAlH4

1-2: AlH4- removes a proton from the amide to form a Lewis base that complexes with AlH3 in step [2] 3-4: Nucleophilic attack of H:- and loss of a leaving group, (OAlH3)^(2-), form an imine 5-6: Nucleophilic addition of H:- and protonation form the amine

Reduction of RCOCl and RCOOR' with a metal hydride reagent

1. Nucleophilic attack of H:- forms a tetrahedral intermediate with a leaving group Z 2. The pi bond is re-formed and the leaving group Z departs. The overall result of addition of H:- and elimination of Z:- is substitution of H for Z. 3.Nucleophilic attack of H:- forms an alkoxide with no leaving group 4. Protonation of the alkoxide by H2O forms the alcohol reduction product

The mechanism of hydride reduction

1. The nucleophile (AlH4- or NaBH4) donates H:- to the carbonyl group, breaking the pi bond and moving an electron pair out on oxygen. This forms a new C-H bond 2. Protonation of the negatively charged oxygen by H2O (Or CH3OH) forms the reduction product with a new O-H bond. The net result of adding H:- (from NaBH4 or LiAlH4) and H+ (from H2O) is the addition of the elements of H2 to the carbonyl pi bond.

Nucleophilic addition of R"MgX to RCHO and R2C=O

1. The nucleophile (R'') attacks the carbonyl group, breaking the pi bond and yielding an alkoxide. This forms a new carbon-carbon bond 2. Protonation of the alkoxide by H2O forms the addition product with a new O-H bond. The overall result is addition of R'' and H to the carbonyl group

Nucleophilic addition to aldehydes and ketones

1. The nucleophile attacks the electrophilic carbonyl. The pi bond is broken, moving an electron pair out on oxygen and forming an sp3 hybridized carbon. 2. Protonation of the negatively charged oxygen by H20 forms the addition product. The net result is that the pi bond is broken, two new pi bonds are formed, and the elements of H and Nu are added across the pi bond

Nucleophilic substitution of RCOZ (Z= leaving group)

1. The nucleophile attacks the electrophilic carbonyl. The pi bond is broken, moving an electron pair out on oxygen and forming an sp3 hybridized carbon. 2. An electron pair on oxygen re-forms the pi bond and Z comes off as a leaving group with the electron pair in the C-Z bond The net result is that NU replaces Z- a nucleophilic substitution reaction. The better the leaving group Z, the more reactive RCOZ is in nucleophilic acyl substitution

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

1. nucleophilic attack of (R"-) forms a tetrahedral intermediate with a leaving group Z 2. The pi bond is reformed and the leaving group Z departs to form a ketone. The overall result of addition of (R"-) and elimination of (Z:-) is substitution of R'' for Z 3. Nucleophilic attack of (R"-) forms an alkoxide with no leaving group 4. Protonation of the alkoxide by H2O forms a tertiary alcohol

Nucleophilic substitution of RCOZ (Z= leaving group) trend

Acid chlorides (RCOCl), which have the best leaving group (Cl-), are the most reactive carboxylic acid derivatives and amides (RCONH2), which have the worst leaving group (-NH2) are the least reactive.

Reaction of R-M with carboxylic acid derivatives

Acid chlorides and esters can be converted to ketones or tertiary alcohols with organometallic reagents. The identity of the product depends on the identity of R'-M and the leaving group X

Compounds that contain an electronegative atom bonded to the carbonyl group

Carboxylic acid, acid chloride, ester, amide. Each of these compounds contain an Atom (Cl, O, or N) more electronegative than carbon, capable of acting as a leaving group.

Reaction of RLi and RMgX with esters and acid chlorides

Form tertiary alcohols when treated with two equivalents of either Grignard or organolithium reagents

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

Forms a primary alcohol

Where does addition of R-M always occur?

From both sides of the trigonal planar carbonyl group. When a new stereogenic center is formed from an chiral starting material, an equal mixture of enantiomers results

Preparation of organocuprates

From organolithium reagents by reaction with a Cu+ salt, often CuI

How can one enantiomer be formed selectively?

From the reduction of a carbonyl group, provided a choral reducing agent is used

Reaction of Grignard reagents with carbon dioxide

Give you carboxylic acids after protonation with aqueous acid.

Reduction of Carboxylic Acids and their derivatives

Gives a variety of products, depending on the identity of Z and the nature of the reducing agent. The usual products are aldehydes or primary alcohols

Aldehyde

Has at least one H atom bonded to the carbonyl group

Ketone

Has two alkyl or aryl groups bonded to the carbonyl group

Lithium tri-tert-butoxyaluminum hydride

LiAlH[OC(CH3)3]3, has three electronegative atoms bonded to aluminum, which make this reagent less nucleophilic than LiAlH4

What strong reducing agent reacts with all carboxylic acid derivatives?

Lithium aluminum hydride (LiAlH4)

Do ketones undergo oxidation reactions?

No because they do not have H on the carbonyl carbon.

The reaction of organometallic reagents with epoxides

Nucleophilic attack from the back side of the epoxide ring, followed by protonation of the resulting alkoxide. In unsymmetrical epoxides, nucleophilic attack occurs at the less substituted carbon atom

R2CuLi

Organocopper reagents, also called organocuprates. Have a less polar carbon-metal bond and are therefore less reactive

Strong nucleophiles

Organometallic reagents are also ______ that react with electrophilic carbon atoms to form new carbon-carbon bonds

tert-butyldimethylsiyl ether (TBDMS)

Protecting group

Reaction of R-M with other electrophilic functional groups

R-M treated with 1)Co2 and 2)H3O+ forms carboxylic acid R-M treated with 1) epoxides and 2)H2O form alcohols

Epoxide

Reaction of organometallic reagents with __ rings to form alcohols

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

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

Carbonyl reactions

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 pi bond. As result, carbonyl compounds react with nucleophiles.

True

The presence or absence of a leaving group on the carbonyl carbon determines the type of reactions compounds that contain an electronegative atom bonded to the carbonyl group undergo

Reduction of Aldehydes and Ketones

The two most common metal hydride reagents are sodium borohydride (NaBH4) and lithium aluminum hydride (LiAlH4). These reagents contain a polar metal- hydrogen bond that serves as a source of the nucleophile hydride, H:- . LiAlH4 is a stronger reducing agent than NABH4, because the Al-H bond is more polar than the B-H bond

Why are organometallic reagents useful synthetically?

They react as if they were free carbanions; that is, carbon bears a partial negative charge so the reagents react as bases and nucleophiles

Preparation of organolithium reagents

With lithium, the halogen and metal exchange to form the _____.

Preparation of Grignard Reagent

With magnesium, the metal inserts in the carbon-halogen bond, forming the Grignard reagent

LiAlH4 reduction of amides

____ forms amines. Both C-O bonds are reduced to C-H bonds.

LiAlH4

_____ converts RCOCL and RCOOR' to alcohols

DIBAL-H or LiAlH[OC(CH3)3]3

_____ converts RCOCl or RCOOR' to RCHO at low temperatures

oxidation of aldehydes

_____ to carboxylic acids. A variety of oxidizing agents can be used, including CrO3, Na2Cr2O7, and KMnO4.

Carbonyl compounds that also contain N-H or O-H bonds undergo

________ an acid-base reaction with organometallic reagents, not nucleophilic addition

Organometallic reagents are

________ strong bases that readily abstract a proton from water to form hydrocarbons

nucleophilic addition

aldehydes and ketones undergo _____. Addition of a nucleophile to the electrophilic carbon of a carbonyl group followed by protonation of the oxygen

Reaction of R-M with aldehydes and ketones

are converted to primary, secondary, or tertiary alcohols with R''Li or R'MgX. This reaction is an addition reaction because the elements of R'' and H are added across the pi bond

Oxidation of aldehydes

can be oxidized to carboxylic acids by most oxidizing agents

organometallic reagents

contain a carbon atom bonded to a metal (M=Li,Mg,Cu)

(R)-CBS reagent

delivers hydride (H:-) from the backside of the C=O. This generally affords the S alcohol as the major product

(S)-CBS reagent

delivers hydride (H:-) from the front side of the C=O. This generally affords the R alcohol as the major product

R-Li

organolithium reagents

R-Mg-X

organomagnesium reagents or Grignard reagents

The product of the reduction of an aldehyde

primary alcohol

Hydride reduction of an achiral ketone with LiAlH4 or NaBH4 gives a __________

racemic mixture of two alcohols when a new stereogenic center is formed

Reduction of carboxylic acids

reduced to alcohols with LiAlH4.

Addition of R"MgX to all other aldehydes forms

secondary alcohol

The product of the reduction of an ketone

secondary alcohol

How are aldehydes oxidized?

selectively in the presence of other functional groups using Silver(I) oxide in aqueous ammonium hydroxide (Ag2O in NH4OH)

How to convert an alkyl halide to an alkane or another hydrocarbon

start with Alkyl Halide, and react with either organolithium and Grignard reagents followed by H2O

retrosynthetic analysis of Grignard products

step 1 is to find the carbon bonded to the OH group in the product. Step 2 is to 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

Carbonyl compounds that also contain N-H or O-H

step 1: convert the OH group to 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 2.Carry out the desired reaction 3. Remove the protecting group. This reaction is called deprotection

alcohol

treating an aldehyde or ketone with NaBH4 or LiAlH4, followed by water or some other proton source, affords an ___. This is an addition reaction because the elements of H2 are added across the pi bond, but it is also a reduction because the product ___ has fewer C-O bonds than the starting carbonyl compound.

faster

A C=C is reduced ___ than a C=O with H2(pd-c)

true

A C=O is readily reduced with NaBH4 and LiAlH4, but a C=c is inert

organolithium and organomagensium reagents

Because both Li and Mg are very electropositive metals, they contain very polar carbon-metal bonds and are therefore very reactive reagents

Why is the reduction of carboxylic acids and their derivatives (RCOZ) complicated?

Because the products obtained depend on the identity of both the leaving group (Z) and the reducing agent

Reduction of acid chlorides and esters

Can be reduced to either aldehydes or alcohols, depending on the reagent

Nucleophilic substitution

Carbonyl compounds that contain leaving groups undergo nucleophilic substitution

Reaction of R2 CuLi with acid chlorides

give a ketone as product

Diisobutylaluminum hydride, [(CH3)2CHCH2]2AlH, (DIBALH)

has two bulky isobutylene groups, which make this reagent less reactive than LiAlH4