LEARNINGLEARNING OUTCOMESOUTCOMES LECTURE 8 DAMIETTA LECTURE 8 UNIVERSITY (1) [2 + 2] photocycloaddition Regioselectivity in photochemical [2 + 2] cycloadditions (2) Thermal [2 + 2] cycloaddition
CHEM-405:CHEM-405: The ketene–alkene cycloaddition (Regioselectivity) The isocyanate-alkene cycloaddition PERICYCLICPERICYCLIC REACTIONSREACTIONS Cycloadditions involving more than six electrons. Not all cycloadditions are pericyclic
LECTURE 8 Zwitterionic and biradical intermediates
[2s + 2s + 2s] cycloadditions Dr Ali El-Agamey ٢ Sigmatropic Reactions ١
Thermal [2 + 2] cycloaddition1 [2 + 2] cycloaddition1
Orbital overlap in the TS for the theoretically allowed [2s + 2a] reaction There are basically 3 situations in which concerted [2 + 2] cycloadditions would be extremely poor, and the reaction would initially give rise to a badly are seen: twisted cyclobutane.1 (1) Reaction is promoted by light
(2) Thermal reaction between alkene and a ketene (R2C=C=O) or another cumulene.
(3) Thermal reaction between alkene and a component, which has a pi bond
between C and a second-row or heavier element (e.g., Ph3P=CH2 or R2Ti=CH2).
1 Therefore, [2s + 2a] reactions are also rare, if they exist at all. The component that is undergoing an antarafacial mode of addition would result in inversion of the geometry about that bond.1 ٤ ٣ (1) [2 + 2] photocycloaddition (1) [2 + 2] photocycloaddition
The [2 + 2] photocycloaddition of two alkenes is widely used to form cyclobutanes. The [2 + 2] photocycloaddition reaction is highly stereospecific and suprafacial in each of the reacting partners.1,2
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(1) [2 + 2] photocycloaddition [2 + 2] photocycloaddition
Homework: Draw all possible products of the following reaction: The photochemical reaction of ketone or an aldehyde with alkene to form an oxetane is called Paterno–Büchi reaction.1
٨ ٧ Regioselectivity in photochemical [2 + 2] cycloadditions Regioselectivity in photochemical [2 + 2] cycloadditions
If we had combined the HOMO of the alkene with the LUMO of the The easiest way to work it out quickly is to draw the product you do not enone, as we should in a thermal reaction, we would expect the opposite expect from a normal HOMO/LUMO reaction.1 orientation. But we are not doing a thermal reaction.1
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[2 + 2] photocycloaddition Why!!!!!!!!!!
The light-induced [2 + 2] cycloaddition can occur in vivo. Two adjacent thymidine residues in DNA can undergo a [2 + 2] cycloaddition to give Why does [2 + 2] cycloaddition reaction work at all, given the strain in a a thymine dimer with endo selectivity.1 four-membered ring: why doesn’t the product just go back to the two starting materials?1,2 DNA repair enzymes remove the dimer and usually repair it correctly, but occasionally they make a mistake, and a mutation occurs. The mutation can lead to skin cancer.1 This reverse reaction is governed by the Woodward–Hoffmann rules, just like the forward one, and to go back again the four-membered ring products would have to absorb light. But since they have now lost their pi bonds they cannot absorb light of the wavelengths that the starting material can absorb. i.e. the reverse photochemical reaction is simply not possible because there is no mechanism for the compounds to absorb light.1,2
١٢ ١١ (2) [2 + 2] cycloaddition (2) [2 + 2] cycloaddition
The ketene–alkene cycloaddition gives cyclobutanones in a thermal The structures of cumulenes have two pi bonds at right angles and they reaction. Most ketenes are not kinetically stable, so they are usually have a central sp carbon atom.1 generated in situ, either by E1cB elimination of HCl from an acyl chloride or by a Wolff rearrangement of an -diazoketone.1,2
Wolff rearrangement of an -diazoketone.3
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(2) [2 + 2] cycloaddition (2) [2 + 2] cycloaddition
Ketenes (R C=C=O) undergo concerted cycloadditions to alkenes 2 The antarafacial nature of the ketene does not have any stereochemical under thermal conditions because the ketene can react antarafacially with an consequences, as there is no cis–trans relationship in the ketene to preserve alkene that reacts suprafacially. The two termini of the C=C pi bond of the in the product.1 ketene react from opposite faces of the pi bond.1 The alkene component of the [2 + 2] cycloaddition with ketenes, however, Because the ketene must react antarafacially, the alkene approaches the reacts suprafacially, and its stereochemistry is preserved in the product.1 ketene with the two pi bonds nearly perpendicular to each other.1
١٦ ١٥ (2) [2 + 2] cycloaddition (2) [2 + 2] cycloaddition1,2
The stereospecificity of cycloaddition of dichloroketene to olefins has been Why do ketenes have the ability to react antarafacially, and alkenes do not? demonstrated by its reaction with cis- and trans-cyclooctene. In each case the cycloadduct is formed with very high stereospecificity clearly indicating that the There are many explanations: olefin adds in a suprafacial manner.1 (a) In ketenes, one of the C atoms has only the sterically undemanding O atom attached to it. Common alkenes have sterically demanding substituents on both ends of the antarafacial component. The substituents at one end of the antarafacial alkene jut directly into the path of the other alkene in the TS, which sterically inhibits the reaction.
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(2) [2 + 2] cycloaddition1,2 (2) [2 + 2] cycloaddition1,2
There are many explanations:
(b) The other explanation is that the ketene uses both the C=C and C=O p-orbitals in the reaction, through a ‘twisted’ transition state.
٢٠ ١٩ Regioselectivity Dimerization of ketenes Regioselectivity for the reaction of ketene with alkene can be predicted using the ionic approach and taking into consideration that the carbonyl carbon of In the absence of other substrates, ketenes dimerize by a [2 + 2] 1 ketenes is very electrophilic or by using orbital coefficients approach. cycloaddition. The electron-rich C=C pi bond combines with the electron-poor C=O pi bond to give a -lactone.1
The reaction of ketene with alkene is a very efficient regio- and stereospecific [2 + 2] cycloaddition.2
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Disconnection of a four-membered ring Synthesis of -lactams by [2 + 2] cycloadditions1,2
Other cumulenes such as isocyanates (RN=C=O) can also undergo thermal The disconnection of a four-membered ring is very simple—you just split in [2 + 2] cycloadditions. The [2 + 2] cycloaddition of an isocyanate and an half and draw the two alkenes. There may be two ways to do this.1 alkene is a useful route to -lactams, the key functional group in the penicillin and cephalosporin antibiotics, as is the [2 + 2] cycloaddition of a ketene and an imine.
However, we prefer the second one because we can control the stereochemistry by using cis-butene as the alkene.1
-lactams
٢٤ ٢٣ Synthesis of -lactams by [2 + 2] cycloadditions1 Homework: Write the product of this reaction
As we expect, the more nucleophilic nitrogen atom attacks the carbonyl group of the ketene so that the regioselectivity is right to make -lactams.
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1 Homework GI (3) [2 + 2] cycloaddition
Write the mechanism of the following reaction? This type involves thermal reaction between alkene and a component, which has a pi bond between C and a second-row or heavier element
(e.g., Ph3P=CH2 or R2Ti=CH2).
The most important example of the third type of [2 + 2] cycloaddition is the Wittig reaction.
٢٨ ٢٧ GI (3) [2 + 2] cycloaddition1 Cycloadditions involving more than six electrons
The phosphorane adds to the ketone to give a phosphaoxetane, either by a concerted, [2 + 2] cycloaddition or by a two-step, polar process involving a betaine intermediate. The phosphaoxetane then undergoes [2 + 2] retrocycloaddition to give Ph3P=O and R2C=CH2.
Metal alkylidenes (M=CR2) undergo thermally allowed [2 + 2] cycloadditions with alkenes during olefin metathesis.
[8 + 2] cycloaddition
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Homework Homework
Complete the following equations and (1) define the type of cycloaddition? (2) Will the pericyclic reaction proceed under thermal or photochemical conditions?
٣٢ ٣١ Not all cycloadditions are pericyclic1 (A) Zwitterionic intermediate
Stepwise cycloaddition reactions, in which one bond forming in a separate step from the second, are still cycloadditions but they are no Stepwise cycloadditions can proceed via zwitterionic intermediate. In this longer pericyclic.1 case, a very electron-rich alkene (enamine, vinyl ether) is allowed to react with a very electron-poor alkene (nitro- or polycyanoalkene).1,2 Stepwise cycloaddition reactions can proceed via zwitterionic or biradical intermediate. A cation-stabilizing group on one component and an anion-stabilizing group on the other can make a stepwise reaction feasible.3 Cycloadditions that proceed by a stepwise mechanism are nonstereospecific.2 D D D
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(A) Zwitterionic intermediate (A) Zwitterionic intermediate
There are several facts that can suggest that the reaction is not concerted but proceed via zwitterionic intermediate:1
(1) The reaction is not completely stereospecific.
(2) The rate of reaction increases with increasing solvent polarity.
(3) Formation of open-chain products in addition to cycloaddition adducts .
٣٦ ٣٥ (B) Biradical intermediate1-3 (B) Biradical intermediate
In addition, cycloaddition reactions of polyfluoroalkenes yield mixtures of Biradical mechanism seems more likely. stereoisomers. These reactions often require rather high temperatures.1,2
Why????????
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(B) Biradical intermediate [2s + 2s + 2s] cycloadditions
Although thermal [2s + 2s + 2s] cycloadditions are theoretically allowed, the simultaneous combination of three molecules would suffer from a large, negative, entropy effect. This would be particularly unfavorable at the high temperatures necessary for many cycloaddition reactions. Thus there appear to be no examples of concerted thermal cycloadditions of three molecules.1 Several examples of thermal cycloaddition reactions of unconjugated dienes with alkenes are known e.g. the reaction of norbornadiene with acrylonitrile.1
[2+2+2]
The radical centers in the intermediate 2.162 are stabilized by -chlorines 4n+2 electron + process. and by electron-delocalization. Therefore, all that is required is enough 1 radical-stabilizing substituents. N N N Because the two pi bonds in the norbornadiene are not conjugated, each is designated separately in the description of the reaction so this is a ٤٠ ٣٩ 2 [2s + 2s + 2s] cycloadditions. Pericyclic Reaction III A bond is broken in the reactant, a new bond is formed in the product, and the bonds rearrange
A sigmatropic rearrangement produces a new sigma bond at the expense of a sigma bond, so this reaction is the most inherently reversible of all pericyclic reactions. The position of the equilibrium depends on the relative thermodynamic and kinetic stabilities of the starting material and products.1 ٤٢ ٤١
Sigmatropic Reactions Sigmatropic Reactions1
Sigmatropic reactions: A concerted reaction in which a group migrates To identify the type of a particular sigmatropic reaction, the two atoms with its sigma bond within a pi framework, an ene or a polyene, and the forming the bond being broken are both numbered as atom 1. migration is accompanied by a shift in pi bonds.1 Then the atoms in each direction from the bond being broken, up to and Since in these reactions a change in the position of one sigma bond takes including the atoms that form the new sigma bond in the product, are place, Woodward and Hofmann coined the term “sigmatropic shifts” to numbered consecutively as atoms 2,3, and so on. describe them.2-4 The numbers assigned to the atoms forming the new bond, separated by In a sigmatropic reaction, a sigma bond that breaks is bonded to an allylic commas, are placed within brackets to designate the reaction type. carbon.2-3
٤٤ ٤٣ Sigmatropic Rearrangements Homework Indicate the order of each of the sigmatropic shifts shown in the equations below.
In the designations [1,3] and [1,5] the “3” and “5” refer to the number of the carbon to which migrating group is moved to (the migration terminus). The “1” does not refer to the migration source; instead it specifies that in both reactant ٤٦ 1 ٤٥.and product bonding is to the same atom (number 1) in the migrating group