Electron Withdrawing Groups

Transcription

1 Electron Withdrawing Groups If an α-carbon has more than one electron withdrawing group, the α-proton becomes increasingly acidic as the number of groups attached to the carbonyl increases. The pk a of is 0 whereas the pk a of is 6.5, and that of 5 is 5. The electronegativity of the chlorine atom makes it electron withdrawing, so the α-proton in is expected to be more polarized and more acidic relative to the α-proton in, leading to an increase in acidity of about.5 pk a units. The second electron withdrawing chlorine atom in 5 makes the α-proton even more acidic, but the effect on pk a is not as large. In general, the more powerful the electron withdrawing properties of a substituent at the α- carbon, the more acidic the α-proton, and the more powerful the electron releasing properties of the substituents, the weaker the acidity of the α-proton. The enol content of chlorinated ketones and 5 should be much higher. Groups include C=, CN. C R, S R, halogen, etc. Cl Cl C C C C C C Cl 5

2 Acyl Addition. The aldol condensation When an aldehyde was treated with an alkoxide base in an alcohol solvent heated to reflux (heated at the boiling point of the alcohol). When the initial product was treated with dilute aqueous acid at low temperatures, a β-hydroxy aldehyde (known generically as an aldol) was isolated. This reaction has come to be called the aldol condensation. A typical example treats butanal () with NaEt in refluxing ethanol, and an aqueous acid second step (known as a reaction workup) gives in 75% yield. When the reaction is repeated, but treated in the second step with hot and concentrated acid, a conjugated aldehyde product () is formed in over 90% yield, and it also contains 8 carbons. If, is isolated and purified, and then heated with aqueous acid, is the product. C NaEt C Et + reflux dilute, 5 C +, hot, concentrated + heat C

3 Non-Nucleophilic Bases When acetone reacts with NaEt in ethanol to form enolate anion 7, it is a reversible acid-base reaction. Unreacted ketone or aldehyde always remains in the reaction, and this fact allows self-condensation to occur. Amide bases (R N: ), derived from secondary amines (R N), will generate the enolate anion, but the equilibrium is pushed far to the right (towards the enolate anion product). A typical and highly useful amide base is lithium diisopropylamide (0; commonly abbreviated as LDA), formed by the acid-base reaction of a powerful base such as butyllithium and the hydrogen atom attached to nitrogen in the parent amine, diisopropylamine (9). Diisopropylamine is an acid in this reaction and diisopropylamide is its conjugate base, with a pk a of about 5. N n-buli TF, -78 C N : Li + n-bu 9 0

4 Non-Nucleophilic Bases If lithium diisopropylamide (0) reacts with the carbonyl carbon of acetone (), the acyl addition product via path a would be. The carbon groups around nitrogen (the basic atom) provide quite a bit of steric hindrance, which makes it difficult for the nitrogen to approach the sp hybridized carbon atom via path a. Acyl addition to give is very slow to the point of not being competitive with an acidbase reaction. This poor reactivity of the amide base in acyl addition is expressed by saying that nitrogen is a poor nucleophile in this reaction. The acid-base reaction of 0 and (path b) proceeds smoothly to give enolate anion 7 (the conjugate base) and diisopropylamine (the conjugate acid). The acid-base reaction of 0 and proceeds readily to form the enolate anion, but acyl addition to form is so slow that virtually no is formed. Since lithium diisopropylamide is a good base but a poor nucleophile, it is termed a non-nucleophilic base. i-pr N :C 7 Me b Li N : 0 + b a C Me a N Me Me Li

5 Aldol Condensation with LDA -Pentanone () reacts first with LDA to form the enolate anion (not shown) and then with benzaldehyde (5) to form the aldol alkoxide product. Subsequent mild acid hydrolysis gives in 80% yield. Virtually no self condensation of is observed in this experiment, which suggests that the reaction is largely irreversible. 5. LDA, TF, -78 C C 7 Ph C 7 C C Ph W?

6 Aldol: Stepwise Assume that -pentanone reacts with LDA to give enolate anion (the two resonance forms are A and B). A different carbonyl compound may be added in a second chemical step to give 5. 6 C 7 LDA C 7 A C Ph C 7 C C Ph C 7 + C C Ph C 7 A C 5 5 Li

7 Aldol. Self-Condensation 7 Formation of is an acid-base reaction, and therefore an equilibrium reaction. This means that (the conjugate base) is in equilibrium with (the acid). Under these conditions there is a small amount of and a large amount of at equilibrium. As reacts with the equilibrium is reestablished and, eventually, all of reacts to give. A new carbon-carbon bond is formed in the product (heavy bond marked in blue), analogous to acyl addition of carbon nucleophile. C NaMe Me reflux B 7A C C 8 7 6

8 Unsymmetrical Ketones There are two acidic hydrogen atoms in -pentanone: the pk a of a is about 0 and that of b is about. The α-carbon that bears a (in red) has only hydrogen atoms attached to it. As noted earlier, an alkyl group is electron releasing relative to the α-carbon of a ketone or aldehyde, so b is less polarized than a (it has a smaller δ+). This observation is consistent with the observation that b is less acidic. -Pentanone () is called an unsymmetrical ketone since two different groups are attached to the carbonyl (the common name of is ethyl methyl ketone, which reflects the fact that it is unsymmetrical). In an unsymmetrical ketone with different substituents on the different α- carbons, it is possible that those two α- protons will have different pk a values and one may be more acidic than the other. 8 LDA b a

9 Unsymmetrical Ketones: Why is it a Problem? 9 LDA, TF C + 78 C Add a different C= compound In a nd step A mixed aldol Unsymmetrical ketones pose a different problem two enolate anions can be formed from an unsymmetrical ketone + a more highly substituted C=C so thermodynamically more stable TERMDYNAMIC a b a is more acidic than b b Removal of more acidic a leads to first formed product KINETIC on less substituted C is more acidic and n more substituted C is less acidic since C groups are electron releasing

10 Equilibrium and Enolate Anion Stability The stability of the conjugate base plays a major role in the magnitude of K a. The structure of the enolate anion must be considered as a major influence on the position of the equilibrium. An equilibrium reaction is under thermodynamic control, which will favor the more stable (lower energy) product. Assume that the more highly substituted enolate anion will be more stable and will be the major product in an equilibrium reaction. 0 Et Et Base Et Base Et Et a b a 6 K K a a a b b

11 LDA versus Na When LDA (the base) reacts with 6 (the acid) the acid-base reaction shown leads to the conjugate base (enolate anion ) and the conjugate acid (diisopropylamine, 9). The reaction of with Na (the base) leads to and the conjugate acid water (). -Butanone has a pk a for a of about 0, and diisopropylamine has a pk a of about 5. -Pentanone is the stronger acid when compared to diisopropylamine, so the equilibrium to the right and K a is larger). LDA is a stronger base than the enolate anion, which also favors a larger K a. If -pentanone is compared with the conjugate acid of Na, water (pk a, 5.7) in the second reaction, water is the stronger acid. nce is formed, it will react with water to regenerate and the hydroxide ion. Since water is the stronger acid, it is anticipated that the equilibrium is shifted to the left, which is consistent with a smaller K a. Et Et b a Li N Na ipr ipr Et Et b + a N 9 + ipr a - ipr b a b

12 Base Strength: Conjugate Acid If a strong base generates a conjugate acid that is a weaker acid than the ketone, K a will be large and the kinetic product is favored. If a strong base generates a conjugate acid that is a stronger acid than the ketone, K a will be small allowing K a to be established and the thermodynamic product will be favored.

13 Kinetic versus Thermodynamic Since is formed fastest, it is referred to as the kinetic product. Since 6 is formed under equilibrium conditions and is thermodynamically more stable, it is referred to as the thermodynamic product.

14 Kinetic versus Thermodynamic Kinetic control C 7 LDA TF -78 C C 7 C 7 A A C 7 C 7 C C + C Ph C Ph C 5 5 Li C Ph Thermodynamic control 7 NaEt, Et TF reflux Na 78 C! 5 C Na + - 8

15 Kinetic versus Thermodynamic: Reaction Conditions 5 The reaction of -pentanone with LDA in TF at 78 C constitutes typical kinetic control conditions. Thermodynamic control conditions typically use a base such as sodium methoxide or sodium amide in an alcohol solvent at reflux.

16 Mixed aldol reactions 6 If acetone () is treated with aqueous Na in the presence of another carbonyl molecule such as benzaldehyde (5), enolate (6) is formed in situ. This enolate anion may react with itself (with another molecule of in a self-condensation reaction), but it may also react with aldehyde 5 via acyl addition to give alkoxide 8. Mild hydrolysis gives the mixed aldol product, 6. There is a competition for the reaction of 7 with either or 5 so at least two products are possible in the reaction, 8 and the self-condensation product. In this reaction the second carbonyl derivative (5 in this case) does not have acidic an hydrogen atom, so 7 is the only possible enolate anion. Under these conditions, enolate 7 is formed and if an excess of 5 is added, the major product will 8 and then 6 after the aqueous acid workup. C C Ph 5 C C NaMe, Me, reflux Ph C 7 8 Ph C 6 Ph +

17 Mixed aldol: Thermodynamic 7 NaEt NaEt

18 Mixed aldol: Kinetic 8 Li LiNiPr + NiPr Li Li +

19 Intramolecular Aldol 9 Aldol condensation reaction can form a ring to give the usual alkoxide product (59). ydrolysis leads to the expected aldol product 60. It is an intramolecular aldol condensation. Note that 59 is drawn first with an peculiar looking "extended" bond in order to keep the relative shape the same, but it is then re-drawn in its proper five-membered ring form. Note that the numbers used are arbitrary, since the IUPAC name of 60 is - hydroxycyclopentanecarboxaldehyde (or carbaldehyde). 5 LDA TF -78 C aq

20 Intramolecular: Thermodynamic or kinetic 0 NaEt, Et reflux aq. + LDA, TF aq C C C.. NaEt, Et reflux aq. + C

21 Reactions C. NaMe, Me, reflux. + C. LDA, TF, 78 C. butanal. +. NaMe, Me, reflux. +. LDA, TF, 78 C Ph I did not get here on Monday but I wanted you to see examples..phc. +. NaMe, Me, reflux. +. LDA, TF, 78 C.-phenyl--pentanone. + Ph