Chapter 17 Carbonyls PDF

Organic chem Chapter 17 Carbonyl chemistry 1  Compounds Containing Carbonyl Groups Two broad classes of compounds contain the carbonyl group: Compounds that have only carbon and hydrogen atoms bonded to the carbonyl. Compounds that contain an electronegative at...

Organic chem Chapter 17 Carbonyl chemistry 1  Compounds Containing Carbonyl Groups Two broad classes of compounds contain the carbonyl group: Compounds that have only carbon and hydrogen atoms bonded to the carbonyl. Compounds that contain an electronegative atom bonded to the carbonyl. 2  Carbonyl Group Structure Carbonyl carbons : like other double bonded carbons sp2 hybridized, trigonal planar, bond angles that are ~120 degrees. 3  Polarity of Carbonyl Groups Note the resonance structures…carbonyls can be reactive because of the charges 4  General Reactions Carbonyl carbons are electrophilic and react with nucleophiles. Nucleophilic addition Nucleophilic Substitution Carbonyl chemistry is important because many reactions can occur around the functional group Some reactions have previously been discussed 5 nucleophilic addition: nucleophile attacks the carbon; a proton then quenches the negative on oxygen The net result is that the π π bond is broken, two new σ bonds are formed bond is broken, two new σ bonds are formed, and the elements of H and Nu are added across the π bond. 6 Aldehydes are more reactive than ketones towards nucleophilic attack for both steric and electronic reasons. 7  Nucleophilic Substitution Carbonyl compounds with leaving groups react with nucleophiles to form substitution products by a two-step process: nucleophilic attack, followed by loss of the leaving group. Nu replaces Z ; nucleophilic acyl substitution. Z must be a good leaving group 8 Reactivity to Nucleophilic Substitution 9 Aldehydes and ketones cannot undergo substitution because they do not have a good leaving group bonded to the newly formed sp3 hybridized carbon. 10  Oxidation and Reduction Generalization: 11 Summary: oxidation and reduction reactions 12  Reduction of Aldehydes and Ketones Use of metal hydride reagents to make alcohols….note the carbonyl oxygen becomes an OH …. carbon gains a H …basically H2 is added… 13 The metal adds a hydride (H- ) the carbon the water or alcohol adds a proton (H+) 14 Catalytic hydrogenation reduces using H2 and a catalyst (normally Pd supported on a carbon matrix…Pd-C) When a compound contains both a carbonyl group and a carbon– carbon double bond, selective reduction of one functional group can be achieved by proper choice of the reagent. A C=C is reduced faster than a C=O with H2 (Pd—C). A C=O is readily reduced with NaBH4 and LiAlH4, but a C=C is inert. 15 Selective reduction can occur depending on the metal-hydride system A C=C is reduced faster than a C=O with H2 (Pd—C). A C=O is readily reduced with NaBH4 and LiAlH4, but a C=C is inert. a compound that contains both a carbonyl group and a carbon–carbon double bond, can be selectively reduced 16 Example of selective reduction three different compounds can be made depending upon the reagent used. 17  Sodium Borohydride Reductions in Synthesis Figure 17.2 Note: alcohol forms; C=C doesn’t react 18  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. Both enantiomers are formed in equal amounts. 19 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. 20 Basically: One B–H bond affords a hydride in this reduction. (S)-CBS reagent generally forms the R alcohol as the major product. (R)-CBS reagent generally forms the S alcohol as the major product. 21 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, etc….some reagents can be completely selective (examples in In text fr your interest) 22  Lithium Aluminum Hydride type agents Reactivity of the hydride reduction is affected by the groups on the agent LiAlH4 reacts with all carboxylic acid derivatives. Diisobutylaluminum hydride [(CH3)2CHCH2]2AlH, DIBAL-H, has two bulky isobutyl groups which makes this reagent less reactive than LiAlH4. Lithium tri-tert-butoxyaluminum hydride, LiAlH[OC(CH3)3]3, has three electronegative O atoms bonded to aluminum, which makes this reagent less nucleophilic than LiAlH4. These allow selectivity in the type of compound formed (example on next page…mild vs strong reduction) 23 Example of selectivity: acid chloride reduction Strong….carbonyl is reduced to as far as it can be Mild…carbonyl is reduced only part of the total possible Down to alcohol Loss of Cl 24 Example of selectivity: Ester reduction Strong….carbonyl is reduced to as far as it can be Mild…carbonyl is reduced only part of the total possible 25 Mechanism of acid chloride or ester reduction 1. Hydride adds to partially reduce with loss of Z 2. Second hydride adds to further reduce the carbonyl 26 Figure 17.4 The DIBAL-H mild reduction of an ester to an aldehyde in the synthesis of the marine neurotoxin ciguatoxin CTX3C Note: regardless of the size of molecule…. only the carbonyl is reduced 27  LiAlH4 …strong agent that allows all carboxylic acid derivatives to be reduced to an alcohol except amides which become amines as shown (−NH2 is a very poor leaving group) example Mechanism for amide reduction is more complicated than that for the other carbonyls 28 A Summary of Metal Hydride Reducing Agents 29  Alcohols can be oxidized to aldehydes and ketones (Chapter 9) Aldehydes can be further oxidized to carboxylic acids ……………ketones cannot (lack of H on the carbonyl carbon) oxidizing agents: CrO3, Na2Cr2O7, K2Cr2O7, KMnO4 & silver(I) oxide in aqueous ammonium hydroxide (Tollen’s reagent). Tollen’s reagent, selectively only reduces the aldehyde 30 Next part of chapter deals with organometallic reactions: Basic general concepts: 1. an organic compound is bonded to a metal atom or complex; 2. The organic portion acts as a base or nucleophile (has a negative charge)…..as a carbanion; 3. Follow the basic concepts that deal with reactions as we have discussed: Reaction occur because of electrons (and density) movement; Keep an eye on how charges are pushed on molecules during a reaction Note the partial charges 31  Organometallic Reagents Li, Mg, and Cu are the most common organometallic metals. Sn, Si, Tl, Al, Ti, Hg also used General structures of common organometallic reagents are shown: The organometallic reagent reactivity is based polarity of the carbon-metal bond: The more polar the carbon-metal bond, the more reactive the reagent. 32 organolithium (RLi) and organomagnesium (RMgX) reagents contain very polar carbon-metal bonds …..very reactive. Organocopper reagents (R2CuLi) have a less polar carbon–metal bond and are therefore less reactive. So the reactivity is affected by the “carbanion” that’s formed 33 Organolithium compounds: prepared by halogen and metal exchange R-X + 2 Li R-Li + LiX Variety of reagents that can be made www.google.com/url?sa=i&url=https%3A%2F%2Fen.wikipedia.org%2Fwiki%2FOrganolithium_reagent&psig=AOvVaw36QkC7Uj45t4w9UIMLw B12&ust=1645885097718000&source=images&cd=vfe&ved=0CAgQjRxqFwoTCKCq8feFm_YCFQAAAAAdAAAAABAT 34 Organomagnesium compounds: Prepared by magnesium insertion into the carbon-halogen bond (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….. R generally can be any group https://cdn.masterorganicchemistry.com/wp-content/uploads/2019/12/2-formation-of-grignard-reagents-from-alkyl-or-alkenyl-halides.gif 35 Organic compounds with acidic hydrogens can be used to make reagents Acetylene compounds as an example + RC C H RC C M 36 Organometallic reagents are strong bases that readily abstract a proton from water, alcohols and amines to form hydrocarbons. The metal “wants” the oxygen 37 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 from previous slide These will react further with water 38 Overall general reaction then is: The reaction of an organic molecule that contains a halide or acidic hydrogen is 1. reacted with a metal to form an organometallic compound; which is then 2. Reacted with water to produce a molecule that has a proton 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) M = metal ion The R group is a “carbanion” which can react with electrophiles before the water work up. 39 What does all this mean or how does it work in a reaction? Once an organometallic compound is made: 1. The metal atom represents a “H” R-M……..R-”H” 2. In any reaction the “M” is always with 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 3. The metal is replaced by a “H” upon work up with water (or acid) or alcohol R-M + HOH R-H + (MOH or Mox) (other workups with different results may be possible) 40 Basic (general) reaction of an organometallic with a carbonyl compound: These are nucleophilic addition to the carbonyl by the R group 1. The formation of an alcohol after reaction of the carbanion with the carbonyl and then a workup R’ HOH R’ R-M + C=O R-C-OH R” R” 2. The formation of a different carbonyl compound after reaction and workup (or an alcohol if reaction continues) Z R-M + C=O R-C = O R” R” (see next slide from text) 41 More specific from last slide 1. Reaction of R—M with aldehydes and ketones to afford alcohols 42 Mechanism example: aldehyde & ketone 43 Actual examples: M= Li, Mg (note different R groups) 44 2. Reaction of R—M with carboxylic acid derivatives These are acid chlorides or esters (OR’): Z is a leaving group 45 Example: esters and acid chlorides; note two equivalents of either Grignard or organolithium reagents allows the reaction to go to the alcohol (the first step forms the new carbonyl compound..see previous and next slides) 46 General synthesis & mechanism 47 3. Reaction of R—M with other electrophilic functional groups 48 Grignards react with CO2 to give carboxylic acids after protonation with aqueous acid. Note carbon dioxide is “like” a carbonyl 49 organometallic reagents—RLi, RMgX, and R2CuLi—open epoxide rings to form alcohols: nucleophilic attack 50  Retrosynthetic Analysis of Grignard Products what carbonyl and Grignard components are needed to prepare a specific product? Ex. An alcohol 1. Take the R group and attach it to the metal: R-Mg-X 2. The rest of the molecule becomes the carbonyl: keeps the “O” 51 Retrosynthetic Analysis of pentan-3-ol (textbook) 52 Pentan-3-ol synthesis reaction (continued) 53  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 as these undergo acid–base reaction with organometallic reagents, not nucleophilic addition. The hydroxy group reacts first…… 54 Note: the OH (previous slide) can be protected so the carbonyl can be reacted first. Ex: A common OH protecting group is a silyl ether. OH is reacted with a silane to make the silyl ether , which can be removed later in the process 55 organocopper…basically similar reactions as the other metals, but less reactive and more selective ….concentrate on lithium and magnesium α,β-Unsaturated carbonyl compounds will be covered in other chapters. We will deal with specific carbonyl functional groups in the other chapters 56 Summary 1. Organometallic reagents (R—M) attack electrophilic atoms, especially the carbonyl carbon. 57 2. After an organometallic reagent adds to the carbonyl group, the fate of the intermediate depends on the presence or absence of a leaving group. 3. The polarity of the R—M bond determines the reactivity of the reagents: RLi and RMgX are very reactive reagents. R2CuLi is much less reactive. 58 Review of using various reactions to make different products: example 59 Sample problem 17.7 pg 819 Synthesize 2,4-dimethylhexan-3-one from four carbon alcohols. 1. Form the ketone by oxidation of a 2o alcohol 2. Make the 2o alcohol by Grignard addition to an aldehyde. Both of these compounds have 4 C’s, and each must be synthesized from an alcohol. 60 Example continued: first make both compounds needed for the Grignard reaction: complete the synthesis with Grignard addition, followed by oxidation of the alcohol to the ketone. 61 Chapter 17 HW 4, 5, 10a, 11a,b; 18, 19bd, 25a, 30a, 41a, 43d 62