sign in sign up
<<
Home , Chugaev elimination, Electrophilic addition, Nucleophilic addition

Chapter 10 Mechanisms, Part 1: Reactions Involving Additions and/or Eliminations Addition reactions 10.2 Hydration of carbonyl structures

RO OR R R 1 10.2.1 Acid-base

See section 9.3 2 10.2.2 The thermodynamics of the formation of geminal and hemiacetals

1. and aryl : less than unity, favoring the 2. Aliphatic aldehydes, carbonyl structures with EWG, and carbonyls in strained rings: greater than unity 3. Aldehydes are more hydrated than ketones because steric congestion in the geminal is less. 4. EWG destabilize the already electrophilic carbonyl, leading to greater hydration. 5. Strained rings such as cyclobutanone prefer the sp3 hybridization of a hemiacetal carbon over the sp2 hybridization of a carbonyl carbon. -> smaller bond angle of an sp3 center3 better matches the bond angles in small rings. pyranose

0.003%

2-pyridone

4 10.3 of to and : hydration

No scrambling of deuteriums -> the first step is not reversible

General acid catalysis: all forms of acid in the medium are reactive, and the protonation is rds

5 10.3.3 Regiochemistry H H

more stable; less activation energy

less stable product EDG: increase hydration rates EWG (Cl or CN): retard hydration rates

enamine

vinyl ether

6 involvement of a localized carbenium ion on the more substituted carbon 10.3.4 hydration very similar to hydrations

7 10.4 Electrophilic addition of hydrogen halides to alkenes and alkynes Two cases A

rearrangement

The product ratio depends on neither [HCl] nor [added Cl-]. If Cl- and HOAc compete for addition to a transient carbenium ion, one would expect increasing chloride concentrations to divert the intermediate to the formation of alkyl chloride products, but this is not seen.

Cl- diffusion is slower than rearrangement -> added Cl- does not affect the product ratio.

8 B The product ratio from the addition of HCl to cyclohexene in HOAc does depend on [added Cl-].

- Increase in added Cl ->this product Why? Consider of this reaction.

Second order reaction

9 Added Cl- increases in this product ratio. 10 10.4.3 Addition to alkynes Cl+

vinyl carbocation major product -> lower stability than trigonal sp2 carbenium ions -> addition of HX to alkynes is slower than with alkenes

Because of the lower stability of vinyl cations relative to alkyl carbenium ions, concerted reactions occur.

Anti addition product; predominantly

11 10.5 Electrophilic addition of halogens to alkenes

halonium ions

anti addition

F2; so exothermic, explosive Cl2; exothermic by 44 kcal/mol Br2; exothermic by 29 kcal/mol I2; near thermoneutral or endothermic -> readily reversible

12 anti addition 10.5.3 Other evidence supporting a σ complex

1. kinetics

hydration rates

If a non-bridging carbenium ion were formed, one would expect substituent effects similar to that seen for alkene hydration. -> but this is not the case. -> σ complex formation

13 2. Kinetic isotope effects

kH/kD = 0.53 (large inverse KIE -> significant rehybridization of both alkene carbons in rds) sp2 -> sp3

3. Addition of other other than bromide

Br Br

δ+ δ+ MeOH

4. Isolation of bromonium ions Steric hindrance impedes nucleophilic attack

14 anti syn

anti syn

Carbenium ions can be stabilized by resonance

15 the complex is formed rapidly prior to rds. 10.5.4 Mechanistic variants at low concentrations of bromine or in water and

In of lower polarity, even acetic acid, the reaction is second order in bromine.

F2 addition -> syn addition

Carbocation rapidly combines with F- before dissociation of the ion pair. 16 10.5.5 Addition to alkynes Alkyl-substituted alkynes show anti addition products with bromine, again supporting a brominium ion intermediate. However, alkynes generally react 103 to 107 times slower than alkenes.

ring strain and positive charge on sp2 orbital

Aryl alkynes

ρ = -5.17 (large negative value) -> EDG 반응속도 증가-> vinyl cation intermediate

17 10.6

THF

diborane borane

H2O2, NaOH

OH H syn addition

Addition of boron to a less hindered carbon

Addition; anti-Markovnikov product

18 10.7 Epoxidation mCPBA (m-chloroperbenzoic acid)

syn addition

The more electron rich the , the faster it will react with the peracid. Sterics are the primary factor directing the epoxidation stereochemistry. The least hindered face of a double bond is predominantly epoxidized.

carbocation charater가크다; sp2 -> sp2 Almost no secondary KIE sp2 -> sp3 A relatively large inverse KIE

19 10.8 Nucleophilic additions to carbonyl compounds

Cyanohydrin formation

Aldehydes are more reactive than ketones because steric congestion in the cyanohydrin is less.

CN- is a very good -> protonation is not required prior to or at rds rate = k[CN-][C=O] -> no dependence on acid 20 Grignard addition Extremely fast even at -85 oC

two electron nucleophile

For some carbonyl compounds

electron transfer mechanism: carbonyl structures that lead to stabilized ketyl anions will favor this mechanism, such as conjugate enones, phenyl ketones, and phenyl aldehydes. -> evidence; hydrogen abstraction products (B 첫번째) or radical coupling products (B 두번째) are formed.

21 Lithium aluminum reduction

A lithium-specific cryptand

A lithium cation is involved in the reaction. 22 10.8.6 Conformational effects in additions to carbonyl compounds The addition of nucleophiles to carbonyl compounds is often found to occur faster with six-membered ring cyclic ketones than with acyclic ketones or cyclopentanones.

o Why? The dihedral angle between the Heq and the carbonyl oxygen is only 4 . This near eclipsing interaction produces a conformational strain of around 4 kcal/mol that raises the ground state energy of cyclohexanones relative to acyclic systems. Upon nucleophilic attack, this near eclipsing interaction is relieved, but we introduce a 1,3-diaxial interaction with an oxygen anion. However, the diaxial interaction is estimated to be only 0.7 kcal/mol destabilizing (the A value for an OH), and so the net effect is that a significant amount of strain has been released in this reaction.

Release of eclipsing interaction (4 kcal/mol) but increase in 1,3 diaxial interaction (0.7 kcal/mol) -> a significant amount of strain has been released

near eclipsing interaction

23 10.8.7 Stereochemistry of nucleophilic additions

Rs O Rs OH Rs OH Rm Rm R Nu + m R Rl R Rl R Rl Nu major minor

S기 쪽으로 공격

Cram’s model S기 쪽으로 공격 Karabatsos’ model

Felkin-Ahn model

24 Cram’s model

Felkin-Ahn model

25 Cyclic carbonyl structures

LAH reduction; trans -> major

Due to these strains, H- attacks more sterically hindered face of the

1. 3번위치에H 이외의 치환기가 있으면 hydride 반응시 cis가 major 2. Larger Nu -> cis product as a major

due to steric hindrance

26 Meerwein-Pondorrf-Verley reduction (the reverse reaction is called the Oppennauer ocidation)

equilibrium

More stable

less stable

27 FAD: one electron and two electron reactions NADH(P): two electron (or hydride) reactions

28 10.9 Nucleophilic additions to alkenes

Much less favorable than a carbonyl. But when strongly EWG are placed on an alkene, can occur.

Michael addition (1,4 addition)

29 10.9.4 Baldwin’s rule

These rules allow chemists to predict the ease of ring closure reactions. Three factors are considered: 1. ring size, 2. hybridization of the carbon undergoing attack, 3. whether the bond undergoing attack will be endocyclic or exocyclic to the forming ring in the product.

The ease of intramolecular formation of a particular ring size generally followed the trend, 5> 6 > 3 > 7 > 4 > 8-10. This holds for intramolecular nucleophilic, as well as radical and cationic ring closures.

sp = digonal, sp2 = trigonal, sp3 = tetragonal

30 Nu

Nu Nu trigonal large distortion -> unfavorable

digonal Nu Nu

favorable

31 10.11 Carbene additions and insertions

Triplet states should be preferred at the linear geometry (Hund’s rule), and indeed it is. H-C-H angle becomes small enough -> singlet states Angle is 136o for the triplet and 105o for the singlet.

While simple carbenes have a triplet ground state, approapriate substituents can reverse this preference. -> carbenes with lone-pair donating substituents such as N, O, and halogens can have singlet ground states because of such an interactions

32 Singlet carbene addition to alkenes Triplet carbene addition to alkenes

Singlet carbene insertion into a C-H bond Triplet carbene insertion goes via radical abstraction followed by recombination

33 Carbene generation Thermal decomposition of diazoalkanes

Base-induced eleimination of nitrosourea N-nitrosourea

Base-induced eleimination of tosylhydrazone

Decomposition of diazirine

Base-induced alpha eleimination of haloform

All the thermal protocols described above initially form singlet carbenes, as do the photolysis of 34 and diazirine compounds. The Simmons-Smith reagent (ICH2ZnI) also act as a carbene source. However, the reaction between CH2I2 and Zn does not generate a full-fledged free carbene, but instead a carbenoid.

Carbenoid is a carbene that is stabilized by complexation to a metal.

35 Mechanism Singlet carbenes give 100% stereospecific reactions (syn addition). Triplet carbenes give mixtures. spin flip

Triplet carbenes

triplet biradical

spin flip

- Stereochemistry of the alkene is typically not completely lost in the product, which indicates that the spin inversion and bond rotation rates must be comparable. - The more electron rich the alkene, the faster the carbene addition. - The dialkylcarbenes (more unstable) are less selective than dihalocarbenes or carbenes with neighboring N, O atoms. (more stable carbenes are more selective) - Carbenes are highly reactive species, and if an olefin or other addition partner is not available,36 carbenes will indiscriminately insert into C-H bonds. Eliminations 10.12 Eliminations to form carbonyls or carbonyl-like intermediates

acetal

Correct; 1. stereocenter in R -> retention 2. -18OR -> release in solution after reaction

37 10.12.3 Catalysis of the of

Specific-acid catalyzed pathway: OR -> poor leaving groups

Not plausible pathway

General-acid catalyzed pathway: OR -> good leaving groups

38 10.12.4 Stereoelectronic effects

two antiperiplanar

39 10.12.5 CrO3 oxidation – The Jones reagent

(ClCO)2,DMSO H R OH pyridine R O Swern oxidation 40 10.14 Elimination reactions for aliphatic systems–formation of alkenes

E1 and E2 reactions E2: 1,2-elimination (β-elimination) and 1,4-elimination

E1:

1,2-elimination or β-elimination

l l 4 1,4-elimination 4 41 Acid-catalyzed 1,4-elimination Other types of elimination

of Zn to C-X bond

elimination of 1,2-dihaloalkanes

elimination of 1,4-dihaloalkanes

Reverse

Reverse

42 10.13.3 Contrasting elimination and substitution

1. Elimination will dominate if the carbon with the leaving group (LG) is not susceptible to nucleophilic attack, such as a tertiary R group. 2. E1 involves carbenium ion intermediates, and thus are facilitated by all the factors that stabilize carbenium

ions. These are the same factors that facilitate SN1 reactions. 3. In highly ionizing solvents and with R groups that readily form carbenium ions, the ratio of substitution to elimination products is typically independent of the LG. 4. In solents of lower ionizing power, the ratio of substitution to elimination products does depend on the LG.

43 10.13.4 E1cB

Any elimination that first form the conjugate base of the reactant is referred to as E1cB (elimination, unimolecular, conjugate base).

α-CH

44 10.13.7 Regiochemistry of elimination

- Saytzeff’s rule: the more substituted double bond will dominate, a common observation for both E2 and E1 reactions. -> Saytzeff elimination - : the product with the less substituted double bond is formed.

- Saytzeff’s rule: the more substituted double bond will dominate, a common observation for both E2 and E1 reactions. -> Saytzeff elimination - Hofmann elimination: the product with the less substituted double bond is formed. - With E1 reaction, Saytzeff elimination dominates because the transition state for proton removal from the carbenium ion has double bond character. - The rationalization for Sayzeff elimination in E2 reactions is similar to the reasoning for E1 reactions.

E1 E2

45 If there are severe steric factors that make the hydrogen on the more substituted carbon inaccessible, Hofmann elimination will dominate the product mixture.

H H

Elimination reactions with quaternary ammonium and sulfonium LG give preferential Hofmann elimination. 1. Steric hindrance by bulk quaternary ammonium and sulfonium LG, 2. The number of hydrogens to be removed 3. Electronic effects; a strongly electron withdrawing cationic LG creates a significant amount of positive charge on the neighboring hydrogens. However, electron donating alkyl group diminish this charge on the neighboring hydrogens, and thus the most positive hydrogens are those on the less substituted carbon -> preferential deprotonation of the less substituted carbon.

3H 1H

2H 3H

46 10.13.8 Stereochemistry of eliminations-orbital considerations

E1; in the low-ionizing such as nitromethane -> gives only elimination products via a syn pathways; a contact ion pair is formed and the tosylate is the base that removes the proton. in more ionizing solvents such as aqueous ethanol, all four possible products are formed. 47 E2; anti elimination is preferred 1. conformational preferences, 2. orbital effect

eclipsed

(Bs = SO2C6H4Br)

48 E2; syn elimination can occur when one or more of the following circumstances occurs 1. a synperiplanar arrangement can be achieved but an an antiperiplananr one cannot

120o 2. The counterion of the base is ion paired with the base and the leaving group.

13% Addition of 18-crown-6 0%

3. Strong steric factors favor the syn pathway.

49 Antiperiplanar elimination

one product is observed

50 Two products are observed 10.13.9 Dehydration

10.13.10 Thermal elimination (pyrolysis) Only syn elimination

heat Cope elimination

N-oxides

Xanthate esters

Esters (400-450 oC) 51 52 Combining addition and elimination reactions (substitutions at sp2 centers)

53 10.15 The addition of nitrogen nucleophiles to carbonyl structures, followed by elimination Schiff base; unstable to be isolated. However, when aromatic groups are placed on either C or N, are stable to be often isolated. In addition, oximes (R’ = OH), semizarbazones (R’ = NHCONH2) Schiff base and hydrazone (R’ = NHR) are very stable.

54 10.15.2 Acid-base catalysis

Commonly bell-shaped pH versus rate profiles for and enamine formation.

55 carbinolamine

Strongly nucleophilic (hydroxylamines and alkylamines): A -> amines add directly at all pHs, but below pHs around 4 this direct addition becomes rds. This is because there is a low concentration of unprotonated present at low pHs. At the high pHs where the carbinolamine breakdown is rds, kobs decreases as the pH is increased. The rate has a maximum where the amine is present in high enough concentrations as the free base form to react with a reasonable rate, but there is also enough acid present to catalyze the elimination of water from the carbinolamine, hence the bell-shaped pH-rate profile. weakly nucleophilic amines (aryl amines): B -> the amines are not nucleophilic enough to directly add to the carbonyl, and general-acid catalysis is found for this step. The amines should be in its free base form, and therefore the rate still increases with increasing pH. At higher pHs, the dehydration becomes rds (step 3), and it involves general-acid catalysis. Therefore, in this reaction both the addition and elimination steps are general-acid catalyzed, but enough free56 base form of the amine still needs to be present to produce a reasonable rate. 10.16 The addition of carbon nucleophiles, followed by elimination- the

P=C or P=O can be acceptable, but the d orbitals on P are too high in energy to participate in a significant manner in the bonding to phosphorus. Thus, the zwitterion forms (ylide) are more representative of the true chemical structure.

57 10.17 Acyl transfers

10.17.1 General electron-pushing schemes

tetrahedral intermediate

58 Other possible pathways, however, the most common pathway is addition-elimination via a tetrahedral intermediate.

highly acidic conditions

59 10.17.2 Isotope scrambling

O 18 O18 O H O18 HO OH 2 + R OR' R OR' R OR' R OR'

Apparently all the derivatives (esters, acyl halides, anhydrides and ) can proceed through tetrahedral intermediates during acyl transfers.

Caution: observation of isotope exchange -> a good evidence for a tetrahedral intermediates the lack of isotope exchange -> we do not know which is correct because if nucleophilic

attack is rds (k2 >> k-1), little exchange into the starting material will be seen. Amides display such behavior under acidic conditions.

rds little exchange

60 10.17.4 Catalysis

a better nucleophile than ROH or H2O

a highly reactive carbonyl Reaction of an alcohol or water with an acid halide in the presence of trialkyl amine -> not only base neutralizes the HX, but also significantly enhances the rate of the reaction. Other species such as anhydrides and esters are also susceptible to this form of catalysis.

Amide hydrolysis under basic conditions not very effective very bad LG

rds base-initiated reaction, not base-catalyzed reaction very rapid 18O scrambling is observed.

61 Base-mediated reaction is not very effective for hydrolysis. Amide hydrolysis under acidic conditions effective

Since amides are so unreactive toward nucleophilic attack, specific-acid catalysis is most commonly observed. Little to no 18O scrambling into reactants is observed, but still tetrahedral intermediate exists. acidic conditions

extremely acidic conditions

62 Ester hydrolysis under basic conditions very effective

base-initiated reaction, not base-catalyzed reaction

- - k2 ~ k-1 (the rate of departure of OH ~ the rate of departure of OR) However, a good LG departs much faster.

Ester hydrolysis under acidic conditions very effective

An addition-elimination process

63 Serine proteases: the catalytic triad eg) chymotrypsin

Catalytic triad

64 Metalloproteases: Zn(II) catalysis eg) carboxypeptidase A

65 Peptide synthesis

66