Chapter 6 Reactions of Carbonyl Compounds 羰基化合物的反应 6-1 Nucleophilic Addition Reacitions 亲核加成反应 6-2 Nucleophilic Addition-Elimination Reactions 亲 核加成消除反应 6-3 Condensation Reactions 缩合反应 6-4 The Nucleophilic Substitutions of Carbonyl Acid and Their Derivatives 羧酸及其衍生物的亲核 取代

Key Terms Involved in This Chapter carbonyl ( 羰基 ) aldehyde( 醛 ) ketone ( 酮 ) nucleophilic( 亲核的 ) nucleophile ( 亲核试剂 ) electrophilic ( 亲电的 ) electrophile( 亲电试剂 ) carbanion （碳负离子） diastereomer （非对映体）

Introduction Several functional groups contain the carbonyl group.  Structure of the Carbonyl Group The carbonyl carbon is sp 2 hybridized and is trigonal planar. All three atoms attached to the carbonyl group lie in one plane.

.. : ++ -- :: - + electrophilic at carbon nucleophilic at oxygen Nu: nucleophiles attack here H + or E + electrophiles add here O C O C Nu: nucleophile 亲核试剂 The carbonyl group is polarized. There is substantial  + charge on the carbon.

6-1 Nucleophilic Addition Reactions （亲核加成反应） Carbonyl groups can undergo nucleophilic addition. The nucleophile adds to the  + carbon. The  electrons shift to the oxygen. The carbon becomes sp 3 hybridized and therefore tetrahedral.

or adding acid A strong nucleophile attacks the carbonyl carbon, forming an alkoxide ion that is then protonated. An alkoxide ion  Mechanisms in Basic or Neutral Solutions An alcohol

 Acid Catalyzed Mechanisms Acid catalysis speeds the rate of addition of weak nucleophiles and weak bases (usually uncharged). more reactive to addition than the un- protonated precursor ACIDIC SOLUTIONpH 5-6 stronger acid protonates the nucleophile

Typical Nucleophilies Nu - : - CN, C  C -, RMgX, RLi, RZnBr, Witting Reagents, H -, - OH, RO -, HSO 3 -, Nu: H 2 O, ROH, RNH 2, NH 2 OH, H 2 NNHR

1. Cyanides act as nucleophiles toward C=O Buffered to pH 6-8 In acid solution there would be little CN -, and HCN (g) would be a problem (poison). a cyanohydrin

(1) Reactivity of Aldehydes and Ketones Aldehydes are generally more reactive than ketones in nucleophilic additions. formaldehydeacetaldehyde acetone Methyl ketones

 Electronic effects of alkyl groups Electron-donating group makes C=O less electrophilic less reactive Electron-withdrawing group makes C=O more electrophilic more reactive (2) Factors affecting the nucleophilic addition HCN: hydrocyanic acid

 Steric effect Hybridization: sp 2 sp 3 The bond angle: 120° 109.5° The crowding in the products is increased by the larger group

Watch out for the possibility of optical isomerism in hydroxynitriles CN¯ attacks from above CN¯ attacks from below (3) Sterochemistry Enantiomers

CN¯ attacks from below CN¯ attacks from above Enantiomers

Cram’s Rule How does this center control the direction of attack at the trigonal carbon? CX * diastereomeric X = C, O, N Chiral center 非对映体

R M S L O L RNu OH M S L NuR OH M S Nu: Less steric Major product Nu: Minor product O MS R L More steric Perspective drawing

2. Grignard reagents act as nucleophiles toward C=O Grignard reagents are prepared by the reaction of organic halides with magnesium turnings

 Aldehydes and ketones react with Grignard reagents to yield different classes of alcohols depending on the starting carbonyl compound

 Esters react with two molar equivalents of a Grignard reagent to yield a tertiary alcohol The final product contains two identical groups at the alcohol carbon that are both derived from the Grignard reagent. A ketone is formed by the first molar equivalent of Grignard reagent and this immediately reacts with a second equivalent to produce the alcohol.

 Planning a Grignard Synthesis Example : Synthesis of 3-phenyl-3-pentanol

 Restrictions on the Use of Grignard Reagents Grignard reagents are very powerful nucleophiles and bases.  They react as if they were carbanions.  Grignard reagents cannot be made from halides which contain acidic groups or electrophilic sites elsewhere in the molecule.

The substrate for reaction with the Grignard reagent cannot contain any acidic hydrogen atoms. Two equivalents of Grignard reagent could be used, so that the first equivalent is consumed by the acid-base reaction, while the second equivalent accomplishes carbon-carbon bond formation.

1 RMgX 2 H 2 O + minor R major minor CH : 1 C 6 H 5 > 4 : 1 (CH 3 ) 2 CH 5 : 1 (CH 3 ) 3 C 49 : 1 major Sterochemistry-Cram’s rule

Organolithium act as nucleophiles toward C=O 3. Organolithium act as nucleophiles toward C=O Organolithium reagents react with aldehydes and ketones in the same way that Grignard reagents do.

Sodium alkynidesact as nucleophiles toward 4. Sodium alkynides act as nucleophiles toward C=O NaNH 2 : sodium amide propine Sodium alkynide

5. Reformatskii Reactions (Organozinc Addition to C=O ) Grignard reagent, Organozinc is not as reactive as Grignard reagent, so it will not reactive with esters so it will not reactive with esters

Ylide A compound or intermediate with both a positive and a negative charge on adjacent atoms. XY Betaine or Zwitterion A compound or intermediate with both a positive and a negative charge, not on adjacent atoms, but in different parts of the molecule. X - Y + : BOND MOLECULE 内铵盐 两性离子 6. Wittig reaction (Ylides addition to C=O ) Synthetic method for preparing alkenes.

(C 6 H 5 ) 3 P C +AB – + + CC R R' A B (C 6 H 5 ) 3 P O + – CORR' triphenyl phosphine oxide （三苯基氧膦） An alkene

Preparation of a Phosphorous Ylide strong base : O-CH Triphenylphosphine ( Ph = C 6 H 5 ) :.. ( WITTIG REAGENT ) an ylide benzene phosphonium salt ether S N 2 reaction Substrates: 1°, 2°Alkyl halides

.. INSOLUBLE very thermodynamically stable molecule ylidebetaine + - The Wittig Reaction MECHANISM synthesis of an alkene oxaphosphetane (UNSTABLE) 内磷盐

+ : + - ylide SYNTHESIS OF AN ALKENE - WITTIG REACTION

ANOTHER WITTIG ALKENE SYNTHESIS Br - + PhLi ylide : triphenylphosphine oxide (insoluble)..

Georg F. K. Wittig received the Nobel Prize in Chemistry in Georg F. K. Wittig received the Nobel Prize in Chemistry in Synthesis of β-Carotene （ β- 胡萝卜素）

Georg Wittig 1/2 of the prize University of Heidelberg Heidelberg, Federal Republic of Germany b d German chemist whose method of synthesizing olefins (alkenes) from carbonyl compounds is a reaction often termed the Wittig synthesis. For this achievement he shared the 1979 Nobel Prize for Chemistry. In the Wittig reaction, he first demonstrated 1954, a carbonyl compound (aldehyde or ketone) reacts with an organic phosphorus compound, an alkylidene- triphenylphosphorane, (C 6 H 5 ) 3 P=CR 2, where R is a hydrogen atom or an organic radical. The alkylidene group (=CR 2 ) of the reagent reacts with the oxygen atom of the carbonyl group to form a hydrocarbon with a double bond, an olefin (alkene). The reaction is widely used in organic synthesis, for example to make squalene (the synthetic precursor of cholesterol) and vitamin D 3 German chemist whose method of synthesizing olefins (alkenes) from carbonyl compounds is a reaction often termed the Wittig synthesis. For this achievement he shared the 1979 Nobel Prize for Chemistry. In the Wittig reaction, he first demonstrated 1954, a carbonyl compound (aldehyde or ketone) reacts with an organic phosphorus compound, an alkylidene- triphenylphosphorane, (C 6 H 5 ) 3 P=CR 2, where R is a hydrogen atom or an organic radical. The alkylidene group (=CR 2 ) of the reagent reacts with the oxygen atom of the carbonyl group to form a hydrocarbon with a double bond, an olefin (alkene). The reaction is widely used in organic synthesis, for example to make squalene (the synthetic precursor of cholesterol) and vitamin D 3

7. Hydride Addition to C=O Sources of hydride ("H - "), such as NaBH 4, LiAlH 4, all convert aldehydes and ketones to the corresponding alcohols by nucleophilic addition of hydride to C=O, followed or concurrently with protonation of the oxygen

Ethyl ether LiAlH 4 H2OH2O + 75%25%

20% CH 3 H3CH3CH3CH3CO 80% OHOHOHOH H H3CH3CH3CH3C OHOHOHOH H H3CH3CH3CH3C NaBH 4

this methyl group hinders approach of nucleophile from top H 3 B—H – preferred direction of approach is to less hindered (bottom) face of carbonyl group preferred direction of approach is to less hindered (bottom) face of carbonyl group Steric Hindrance to Approach of Reagent

Biological reductions are highly stereoselective pyruvic acid  S-(+)-lactic acidO CH 3 CCO 2 H NADH H+H+H+H+ enzyme is lactate dehydrogenase CO 2 H HO H CH 3

One face of the substrate can bind to the enzyme better than the other.

Change in geometry from trigonal to tetrahedral is stereoselective. Bond formation occurs preferentially from one side rather than the other.

8. Hydration of C=O hydrates or gem-diols

steric hindrance in the product

Very electrophilic C=O carbon because of nearby highly electronegative atoms favorable

Knock out drops

Hydrate formation relieves some ring strain by decreasing bond angles