Chapter 11. Reactions of carbonyl compounds

Transcription

1 hapter 11. eactions of carbonyl compounds The most important mechanistic feature of all reaction involving = (aldehydes, ketones, derivatives of carboxylic acids) is the addition of a nucleophile = formation of the tetracoordinate intermediate: tetrahedral intermediate. ' u ' ' u Addition of heteroatom nucleophiles to carbonyl compounds: umerous nucleophiles can add to the = compound. The mechanism for these reaction is essentially the same. ucleophiles that are known to add readily: water (hydration), alcohols (acetalization, -acetalization), thiols (-acetalization), amines (-acetals). or u u ' Acetalization-one example fits all: - emiacetal - Acetal Acetalization (,-acetalization) The transition states, energy profiles (surfaces) depend largely on the structure of the carbonyl component. The ammet treatment offers a very good description (more accurate for the first step-hemiacetal formation). W: read this section in the arey-undberg textbook. ydration and acetalization reactions compared hydration is slow / unfavored (= is an exception); acetalization does not proceed too well either (the equilibrium needs to be pushed by removing water; azeotropic removal; ean- tark appts). The actual equilibrium constants differ very much from derivative to derivative. hydration may be both acid/base catalyzed; acetalization is different: both acid/base catalyzed to the stage of hemiacetal (ketal). The second step hemiacetal acetal is specifically acid-catalyzed. this makes possible to synthesize hemiacetals and acetals selectively this makes possible to use the acetals in organic synthesis in the presence of bases and organometallic reagents. ATE 11/ page 1

2 Acetalization and -acetalization reactions compared The most important feature is that,-acetals are pretty inert to bases, while,-acetals react with bases readily (orey-eebach synthesis). acid or Lewis A. u X u ' X ' acid or Lewis A. u ' X ' g 2 l 2, a 3, water-acetone ',-Acetalization and the chemistry of the iminium ion Ammonia, primary and secondary amines add to the =. The mechanism is the same like in the addition of the - or -nuclophiles: the hemiacetal structure is formed and the next step (protonation and elimination of water) proceeds fast to give the iminium ion. A ' acid or Lewis A. A ' - 2 ' A iminium ion = = ' acid or Lewis A. - ' A ' ',-acetal ' A chiff base A enamine Addition of -nucleophiles to carbonyl compound with subsequent E1 elimination ondensation of = compounds with primary amines chiff bases ote: 1) acid catalyzed, 2) deprotonation during the basic workup. 2 - chiff base same mechanism as in acetalization during workup ATE 11/ page 2

3 ondensation of = compounds with secondary amines enamines ote: 1) acid catalyzed, 2) azeotropic distillation / 2 steps in one - 2 α β same mechanism as in acetalization Enamine imilar condensations = compound with hydroxylamine (or hydroxylamine.l) oxime = compound with hydrazine hydrazone Addition of ylides to = etaine, Ylide and Ylene betaine trong base ammonium ylide ylene - and -ylides Are generated by strong bases (e.g. u) from the respective phosphonium, sulfonium or sulfoxonium salts. h h 3 u h h 2 h h 2 hosphonium ylide h r h h h 2 u h h 2 ulfonium ylide h I h h 3 u ulfoxonium ylide I ATE 11/ page 3

4 Addition of -ylides to =: Wittig reaction hosphonium salts that are usually used in the W.r. are h salts. chanism: 1. tarts with a [22] cycloaddition of the ylide to thye = (aldehydes react much faster) to form two oxaphopshetane isomers (cis- and trans-). 2. xaphopshetanes are in an equilibrium with an open metal-stabilized oxoylides. 3. xaphopshetanes decompose to the respective olefin: (cis-oxaphopshetane gives exclusively Z-olefin and trans-oxaphopshetane gives exclusively E-olefin). E/Z-tereoselectivity depends on the sterical demands of the 1 and 2 and the presence of the cation (lithium favorizes E-olefin). ote: the cis-oxaphopshetane can revert back (reversible reaction) and irreversibly form the trans-oxaphopshetane. This isomerization is called stereochemical drift. h 3 X 1 2 X k cis h 3 Z- k drift ex ex 1 2 cis-oxaphosphetane h 3 xaphosphetanes h h h 1 2 h 3 E- ex k trans 1 2 trans-oxaphosphetane X ex h 3 X 1 2 ATE 11/ page 4

5 Addition of -ylides to =: formation of three-membered rings Two-step mechanism: 1. tarts with nucleophilic attack of the carbanionic ylide carbon on the electrophilic carbon of the (δ)= to produce zwitterion. This is rate-limiting step. 2. The negatively charged moiety of the zwitterions then attacks in the fashion the carbon to which the positively charged sulfonium salt is attached. zwitterion -ylides can react also w0ith = bonds: regioselectivity in α,β-unsaturated ketones. ulfoxonium ylide gives cyclopropane, while the sulfonium ylide gives epoxide. 2 enolate alcoxide The reason is different nucleophilicity of the ylide carbon(-). The sulfoxonium ylide has more of an ylene character preference for the softer center. less nucleophilic more nucleophilic ATE 11/ page 5

6 orner-wadsworth-emmons reaction with achiral substrates WE reaction is an addition of α-(alkoxycarbonyl)phosphonic acids or β-ketophosphonic acids to the =. WE reagents (the respective phosphonates) are obtained via the Arbuzov reaction (Lecture 22, p.4): the Arbuzov reaction: ' ' ' ' 2 X ' X ' ' 'X () () ' The WE reaction mechanism: Advantages over Wittig reaction: easy preparation of phosphonates by Arbuzov reaction, phosphates are inexpensive, stable phosphonate carbanions are more nucleophilic than the corresponding phosphorous ylides react with aldehydes and ketones at mild conditions react even with hindered ketones the α-carbon of phosphonates may be derivatized prior to WE (not possible with ylides) dialkylphosphate by-products are water-soluble () ' ' X () ' 1. It starts with a formation of the delocalized phosphonate anion ' -ase ' ' ' ase hosphonate carbanion = trifluoroalkyl = alkyl 2. In the next step the phosphonate anion adds to the =. It is not known, whether the first intermediate is the alkoxide ion A, or whether the oxaphosphetane is formed directly in onestep cycloaddition (analogy to Wittig r.). 3. The decomposition of the oxaphosphetane proceeds via one-step [22]-cycloreversion and yields E-olefin. A '' ' ' () '' ' ' () '' ' ' () '' () ATE 11/ page 6

7 WE: E/Z-egioselectivity = E strongly prevalent E-selectivity is maximized by: large of the phosphite (isopropyl is the best) Z-selectivity may be increased by using small and strongly dissociated base ( t uk)) 3 ' k syn addition (slow) ' hosphonate carbanion 3 Aldehyde k syn addition (slower) 3 ' T (anti) T (syn) 3 k anti (faster) ' k cis (slower) ' cis oxaphosphetane 2 ' (Z)-Alkane minor 3 (E)-Alkane major 2 ' 3 trans oxaphophetane k trans (slow) 3 2 ' k syn (fast) ' Example-synthesis of a cephalosporine analogue: t-u- 2 ()(Et) 2 a, TF 85% t-u- 2 oc t-u- 2 3-(hydroxymethyl)carbacepahalosporin ATE 11/ page 7

8 orner-wadsworth-emmons reaction, till-gennari modification (Gm)was developed in 1983 by W.. till and. Gennari to generate selectively Z-alkenes. Features: -2F3 esters of the phosphonate. the phosphonate residue must have electronegative/anion stabilizing functionality on α- otherwise the carbanion decomposes base must be dissociated and the metal cation must be non-coordinating, or trapped effectively by a crown ether (e.g. 18-crown-6 for K). Examples: K, K 2 as a phosphonate residue gives excellent Z-selectivity (as opposed to normal WE) chanism: key point = the rearrangement from the chelated adduct to form the oxaphosphetane is favored and the elimination step is faster than the initial addition 3 ' k syn addition (slow) ' 3 k syn addition (slower) 3 ' hosphonate carbanion Aldehyde k anti (fast) k syn (fast) 3 ' k cis (fast) 3 3 cis oxaphophetane 2 ' 2 ' (Z)-Alkane major 3 (E)-Alkane minor 2 ' 3 trans oxaphophetane 2 ' k trans (fast) 3 ' slow in WE, fast in WE-G Example: F 3 2 F n K 2 3, 18-crown-6 toluene, -25 o, then T n 2 T 65% ATE 11/ page 8

9 Addition of organometallic -nucleophiles to carbonyl compounds umerous organometallic -nucleophiles add to = compounds, for example -, -gx, enolates, etc. The addition goes through the tetrahedral adduct (stable with aldehydes and ketones, less stable with carboxylate-derived =s). Kinetics: depends on the degree of aggregation of the -nucleophile!!!! Example: addition of to ketone rate=k[] 1.[ketone] 4 oordination luster - bond formation (rate determining) eorganisation Alcoxide complex formation δ- δ δ- δ δ- δ δ- δ δ δ - Aggregate imilar reactivity is observed with Grignard reagents tereoselectivity of nucleophiles addition ram s rule (see ) Addition of hydride donors to carbonyl compounds umerous -donors add to = compounds. Typical example: a 4. The same for Al 4. Aldehydes react much faster than ketones (steric reasons more than electronic). Lewis acid a 4 a a a Lewis base Acid workup imilar, yet different is the mechanism of addition of ibal-: Lewis base (=) coordinates to the aluminum (Lewis acid) Lewis Acid δ Al δ Lewis ase Al Al ydride transfer Al Acid workup ATE 11/ page 9

10 iastereoselective dddition of hydride donors to carbonyl compounds ydride-donor addition to α-chiral carbonyl compounds aldehydes: hydrogen donor has to be deuteride to create the second stereocenter Two products are possible: product according to ram s rule and product with opposite configuration of the second (just created) stereocenter (=anti-ram product) Al 4 Al 4 ram product >> Anti-ram product t t u u ram product >> Anti-ram product Larg d u d d u Larg Larg u ram product >> Anti-ram product In the cases when the α-chiral center is a σ-, different diastereoselectivity was observed, depending on the nature of itrogen xygen (n) 2 (n) 2 (n) 2 n n n Al4 Al 4 ram product << Anti-ram product ram product >> Anti-ram product (n) 2 Al 4 (n) 2 (n) 2 n n n Et Et Et ram product << Anti-ram product Et Al 4 Et Et ram product >> Anti-ram product 1 2 u 1 u 1 u ram-chelate product 2 2 Felkin-Anh product (Anti-ram product) ow do we explain the different stereoselectivity? Analysis of the respective transition states ote: nucleophile attacks in 103 o to the =. This is so-called ürgi-unitz angle. ATE 11/ page 10

11 1. Additions of hydride donor to α-chiral carbonyl compounds do not have to reflect the preferred conformations of the subtrate 2. Additions to α-chiral carbonyl compounds do not have a heteroatom on α-stereocenter proceed according to ram s rule (see chapter about conformations). u approached from opposite side to the large alkyl residue. 3. Additions α-chiral carbonyl compounds that have a heteroatom on α-stereocenter and the hereoatom does not form five-membered chelate with metal ion present in the medium proceeds via Felkin-Anh transition state (u approaches from opposite side to the ). 4. Additions α-chiral carbonyl compounds that with a hereoatom that does form fivemembered chelate with metal ion proceeds via ram-chelate transition state (u approaches from opposite side to the 1). Larg d u 1, 2 1 = chelator u u 2 δ u urgi-unitz angle 103 o Larg d ram transition state u Larg δ d 2 u δ 1 Felkin-Anh transition state u 2 urgi-unitz angle 103 o u 2 urgi-unitz angle 103 o δ () ram-chelate transition state u () u d 2 u 2 u Larg 1 1 = d u 1 Larg u = = 2 2 ram product Felkin - Anh product ram - chelate product 1 u ATE 11/ page 11

12 Examples: n n n ram - chelate product Zn( 4 ) 2 95 : 5 K (sec-u) 3 10 : 90 Felkin - Anh product = n = T ram - chelate product 98 : 2 5 : 95 Felkin - Anh product ATE 11/ page 12

13 Enantioselective addition of hydride donors to carbonyl compounds ydride-donor addition to ketones with 2 different subst. and deuteroaldehydes results in the formation of a chiral center. orane reductions:.. rown, 1979 obel rize in hemistry yn-addition Alpine-orane (idland, hem. ev. 1989, 89, 1553) educes aryl-ketones and aldehydes with -selectivity LAGE ALL tert or Ar Ar Ar () -()-Alpine-orane T tert or Ar Ar al al Ar al tert or Ar Ar Ar The mechanism of Alpine-orane reduction of aromatic ketones and aldehydes: L L L LAGE ALL Unfavored T* Favored T* ATE 11/ page 13

14 oyori reduction (2001 obel rize in hemistry) This reaction utilizes an axially chiral ligand 2,2 -binaphthol (1), which upon treatment with Al 4 gives an intermediate dihydride structure (2). ihydride (2) has two homotopic hydrogens, a and b, and therefore it makes no difference which one is replaced by the reaction with aliphatic alcohol. Treatment of dihydride (2) with one equivalent of aliphatic alcohol (Et, ) yields oyori s ydride (IAL-) (3) eq. of LA 1eq. of TF a Al Al (10) (11) b (5) inal- reduces unsaturated ketones with at least one unsaturated chain connected to the carbonyl group with high -enantioselectivity. ' prim -IAL- ' ' ' prim -IAL- ' ' ' prim -IAL- ' ' hair-like six-membered transition states (12a and 12b) were proposed by oyori to explain the stereochemical course of the reduction. These transition states involve co-ordination of lithium cation (from AL 4 ) to the highest basicity oxygen of Et group. Unsaturated and saturated chains are then differentiated on electronic grounds. elative magnitude of electronic repulsion with a phenolic oxygen lone pair is following the order: aryl > alkenyl, alkynyl > alkyl > methyl > long chain alkyl. Et group henolic oxygen Al favourable Un (12a) Un Al electronic repulsion (12b) unfavourable destabilised by electronic repulsion ATE 11/ page 14

15 therwise the mechanism of reduction is the same as above for IAL-. ATE 11/ page 15