CHM 222 Chap 17 Carbonyl Chemistry

• Chapter 17 is about carbonyl chemistry

Compounds with Carbonyl Groups

• Two classes of compounds possess the carbonyl group
• The first class has only carbon and hydrogen atoms bonded to the carbonyl
  • This includes aldehydes and ketones
• The second class contains an electronegative atom bonded to the carbonyl
  • This includes carboxylic acid, acid chloride ester, and amide

Carbonyl Group Structure

• Carbonyl carbons are like other double-bonded carbons
• Carbonyl carbons are sp² hybridized
• Carbonyl carbons are trigonal planar
• Carbonyl carbons have bond angles of ~120 degrees

Polarity of Carbonyl Groups

• Carbonyls can be reactive because of the charges

General Reactions

• Carbonyl carbons are electrophilic and react with nucleophiles
• Carbonyl carbons can undergo nucleophilic addition and substitution
• Carbonyl chemistry is important because many reactions can occur around the functional group

Nucleophilic Addition

• A nucleophile attacks the carbon, and a proton then quenches the negative on oxygen
• A π bond is broken, and two new σ bonds are formed
• In mechanism 17.1, the nucleophile attacks the electrophilic carbonyl
  • The π bond is broken to form an sp³ hybridized carbon
• Protonation of the negatively charged oxygen by H2O forms the addition product

Aldehydes vs Ketones

• Aldehydes are more reactive than ketones toward nucleophilic attacks for steric and electronic reasons
• Compared to ketones, aldehydes are less crowded, less stable, and more reactive
• Ketones are more crowded, more stable, and less reactive compared to aldehydes
• Two R groups bonded to the ketone carbonyl group makes them more crowded, making nucleophilic attacks more difficult
• Two electron-donor R groups stabilize the partial charge on the carbonyl carbon of a ketone, making it stable and less reactive

Nucleophilic Substitution

• Carbonyl compounds with leaving groups react with nucleophiles to form substitution products via a two-step process: nucleophilic attack, followed by loss of the leaving group
• In mechanism 17.2, the nucleophile attacks the electrophilic carbonyl
  • The π bond is broken, forming an sp³ hybridized carbon
• An electron pair on oxygen re-forms the π bond, Z comes off as a leaving group, with the electron pair in the C-Z bond
• Nu replaces Z in nucleophilic acyl substitution
• Z must be a good leaving group

Reactivity to Nucleophilic Substitution

• The better the leaving group Z, the more reactive RCOZ is in nucleophilic acyl substitution
• The following trend results
  • Acid chlorides (RCOCl), which have the best leaving group (Cl⁻), are the most reactive.
  • Amides (RCONH2), which have the worst leaving group (NH2), are the least reactive.
  • Carboxylic acids (RCOOH) and esters (RCOOR'), which have leaving groups of similar basicity (OH⁻ and ¯OR'), fall in the middle.
• Aldehydes and ketones cannot undergo substitution
  • They do not have a good leaving group bonded to the newly formed sp³ hybridized carbon

Oxidation and Reduction

• 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
• 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
• Reduction of aldehydes and ketones to alcohols is acheived using metal hydride reagents
  • The carbonyl oxygen becomes an OH, and the carbon gains an H, so H₂ is effectively added
• Aldehydes and ketones are reduced to 1° and 2° alcohols, respectively.
• 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 1° alcohols
• Oxidation of aldehydes forms carboxylic acids
• The most useful oxidation reaction of carbonyl compounds forms carboxylic acids

Reduction of Aldehydes and Ketones

• Accomplished using metal hydride reagents
• Carbonyl oxygen becomes an OH
• Carbon gains a H, so H₂ is added
• Mechanism 17.3 indicates the metal adds a hydride (H⁻) to the carbon
  • Water or alcohol then adds a proton (H⁺)

Catalytic hydrogenation

• Catalytic hydrogenation is achieved using H₂ and a catalyst, like palladium supported on a carbon matrix e.g. Pd-C
• When a compound contains both a carbonyl group and a carbon-carbon double bond, selective reduction of one functional group is done by proper choice of the reagent
• A C=C is reduced faster than a C=O with H₂ over Pd-C
• A C=O is readily reduced with NaBH₄ and LiAlH₄, but a C=C is inert

Selective Reduction

• Selective reduction can depend on the metal-hydride system
• An example: three different compounds can be made depending upon the reagent used
  • NaBH₄ reduces the C=O selectively forms an allylic alcohol
  • One equivalent of H₂ reduces the C=C selectively to form a ketone
  • Excess H₂ reduces both π bonds to form an alcohol
• Sodium Borohydride Reductions in Synthesis
  • Note that alcohol forms when C=C doesn't react

Stereochemistry of Carbonyl Reduction

• Planar sp² hybridized carbonyl carbon can be attacked from either side
• When an achiral reagent is used, a racemic product is obtained, with both enantiomers forming in equal amounts
• Hydride reduction of an achiral ketone with LiAlH₄ or NaBH₄ gives a racemic mixture of two alcohols when a new stereogenic center is formed
• Selective formation of one enantiomer over another can occur if a chiral reducing agent is used
  • A reduction that forms one enantiomer predominantly or exclusively is an enantioselective or asymmetric reduction
  • An example of chiral reducing agents are the enantiomeric CBS reagents (S)-CBS reagent generally forms the R alcohol as the major product and the (R)-CBS reagent generally forms the S alcohol as the major product
• These reagents are highly enantioselective
  • One enantiomer is formed in enantiomeric excess (ee)
• Enantioselective reductions are key steps in the synthesis of specific chemicals
• Pharmaceuticals can be completely selective

Lithium Aluminum Hydride Agents

• Reactivity of the hydride reduction is affected by the groups on the agent
  • LiAlH₄ reacts with all carboxylic acid derivatives
• The diisobutylaluminum hydride [(CH₃)₂CHCH₂]₂AlH, DIBAL-H has two bulky isobutyl groups, making it less reactive than LiAlH₄
• The lithium tri-tert-butoxyaluminum hydride, LiAlH[OC(CH₃)₃]₃ has three electronegative O atoms bonded to aluminum
  • It makes this reagent less nucleophilic than LiAlH₄
• These allow selectivity in the type of compound formed

Selective Reagents

• In acid chloride reduction, use of a strong reagent reduces the carbonyl as far as possible
  • A mild reagent, on the other hand, only reduces only part of the total possible
• In Ester reduction, use of a strong reagent reduces the carbonyl as far as possible
• A mild reagent , on the other hand, only reduces only part of the total possible
• In mechanism 17.4, hydride adds to partially reduce with loss of Z
• The second hydride adds to further reduce the carbonyl
• With DIBAL-H in the synthesis of the marine neurotoxin ciguatoxin CTX3C, regardless of the size of the molecule, only the carbonyl is reduced
• LiAlH₄ is a strong agent that allows all carboxylic acid derivatives to be reduced to an alcohol
  • Except amides, which become amines NH₂ is a very poor leaving group!
• The mechanism for amide reduction is more complicated than that for the other carbonyls

Hydride Reducing Agents

• Strong reducing agent: LiAlH₄
  • Aldehydes, Ketones, Carboxylic acids, Esters, Acid Chlorides, and Amides are reduced to alcohols or amines
• Milder reagents e.g. NaBH₄, LIAIH[OC(CH₃)₃]₃, and DIBAL-H
  • Aldehydes, Ketones, Esters, and Acid Chlorides are reduced to ketones and alcohols

Oxidation for carbonyls

• Alcohols are oxidized to aldehydes and ketones
• Aldehydes are further oxidized to carboxylic acids
• Ketones cannot be oxidized if they lack H on the carbonyl carbon
• Oxidizing agents for carbonyls are CrO₃, Na₂Cr₂O₇, K₂Cr₂O₇, KMnO₄ & silver(I) oxide in aqueous ammonium hydroxide (Tollen's reagent).
• Tollen’s reagent can selectively reduce aldehydes

Organometallic Reactions

• Organometallic chemistry deals with organometallic reactions
• An organic compound is bonded to a metal atom or complex
  • The organic portion acts as a base or nucleophile (has a negative charge) a carbanion
• Reactions occur due to electron movement
  • Keep an eye on how charges are pushed on molecules during a reaction
• Organometallic reagents contain a carbon atom bonded to a metal
  • Most common metals: Li, Mg, Cu

Organometallic Reagents

• Li, Mg, and Cu are the most common organometallic metals and Sn, Si, Tl, Al, Ti, Hg can be used
• Common organometallic reagents
  • R-Li: organolithium reagents
  • R-Mg-X: organomagnesium reagents or Grignard reagents
  • R₂Cu⁻Li⁺ : organocopper reagents or organocuprates
• The organometallic reagent reactivity is based on the polarity of the carbon-metal bond; the more polar the bond, the more reactive the reagent
  • Organolithium (RLi) and organomagnesium (RMgX) reagents contain very polar carbon-metal bonds, so they are very reactive
  • Organocopper reagents (R₂CuLi) have a less polar carbon-metal bond and are therefore less reactive
• Organolithium compounds are prepared by halogen and metal exchange
  • R-X + 2 Li → R-Li + LiX
• Organomagnesium compounds are prepared by magnesium insertion into the carbon-halogen bond when using Grignard reagents
  • R-X + Mg → R-Mg-X
• Grignard reagents are usually prepared in diethyl ether (CH₃ CH₂ OCH₂ CH₃) as the solvent to help stabilize them.
• Grignards can be formed from alkyl or alkenyl chlorides, bromides or iodides Organic compounds with acidic hydrogens make reagents as an Acetylene example
• Acetylene compounds
• Organometallic reagents are strong bases
• Organometallic reagents abstract a proton from water, alcohols, and amines to form hydrocarbons
• Organometallic reagents look for oxygen compounds to "quench” the charges Generally, water is used to stop the reactions and then isolate the organic molecule
• Replaces the Metal ion with a hydrogen

Overall Chemistry

• An organic molecule that contains a halide or acidic hydrogen is reacted with a metal to form an organometallic compound
• Then it is reacted with water to produce a molecule that has a proton that replace the metal on the carbon
• R-Y + M → R-M ; R-M + H₂O → R-H
• Y = halide (or a very acidic H, ex. Acetylenes) and M = metal ion
• The R group is carbanion can react with electrophiles before the water work up

Chemical Reaction

• Once an organometallic compound is made:
  • The metal atom represents a “H” R-M..............R-"H"
• In any reaction the metals always has the negative charge R-M means R is a carbanion if it reacts then the M follows as a cation R-M + R'OH → R-H + R'O M
• The metal is replaced by a “H” upon work up with water (or acid) or alcohol
• R-M + HOH → R-H + (MOH or Mox)
• Basic nucleophilic addition reaction of metal with the carbonyl by the R group
• The formation of an alcohol after reaction of the carbanion with the carbonyl and then a workup
• The formation of a different carbonyl compound after reaction and workup (or an alcohol if reaction continues)

General Scheme Reaction

• Reaction of R-M with aldehydes and ketones to afford alcohols
• Mechanism example: aldehyde & ketone
• Addition of R"MgX to formaldehyde (CH₂=O) forms a 1° alcohol
• Addition of R"MgX to all other aldehydes forms a 2° alcohol
• Addition of R"MgX to ketones forms a 3° alcohol
• Reaction of R-M with carboxylic acid derivatives gives ketone or 3° alcohol These are acid chlorides or esters (OR'): Z is a leaving group

Ester and Acid Halides

• Reacting esters and acid chlorides with two equivalents of either Grignard or organolithium reagents allows the reaction to make alcohols. The metal replaces and oxygen or alcohol through substitution, then the carbonyl group is attacked

Synthesis

• Grignards are reacted with carbon dioxide to give carboxylic acids after protonation via aqueous acid
  • Carbon dioxide acts likes a carbonyl
• Organometallic reagents-RLi, RMgX, and R₂CuLi-open epoxide rings to form alcohols
• Reaction problems with organometallic reagents
  • Organometallic reagents cannot be used with molecules that contain both a carbonyl group and N-H or O-H bonds. Organometallic reagents cause acid-base reaction with the acidic functional groups

Protection

• The OH can be protected so the carbonyl can be reacted first
  • A common OH protecting group is a silyl ether

Summary:

• Organometallic reagents (R-M) attack electrophilic atoms, especially the carbonyl carbon O - O carbonyl
• After an organometallic reagent adds to the carbonyl group, the fate of the intermediate depends on the presence or absence of a leaving group.