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
