Frontier Molecular Orbital Overlap Between n and a Orbitals
This pairing of FMOs leads to the formation of a new σ bond by permitting transfer of electrons from a filled nonbonding orbital to an empty nonbonding orbital. It is the simplest of all the nine possible HOMO-LUMO combinations, because it does not involve any antibonding orbitals. In this case, the overlap of the two nonbonding or- bitals leads to the formation of two new orbitals (one bonding, one antibonding), as shown in Figure 5.13. The reaction between trimethylborane and ammonia is a typical example. In the most common case, two electrons are transferred and the net result is the formation of a new bond without the rupture of a bond in either reactant. Overall, the reaction converts what are in essence two atomic orbitals to a σ orbital and a σ*
orbital.
When we overlap these two orbitals, the most efficient overlap is large lobe to large lobe, so we expect that the regiochemistry of the product will be most favorable when the two substituents on the six-membered ring are on adjacent carbons. The stereochemistry of the reaction follows the Alder endo rule, which places both substit- uents on the same face of the six-membered ring:
OMe CN
CN +
OMe OMe
CN
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Me Br
Me n+a
Br
(5.8)
Ph
Ph N C R
N C Ph
Ph R (5.9)
The most common occurrence of this pairing of orbitals in organic chemistry is during the fast step of the SN1 reaction, where the carbocation (the Lewis acid) reacts with the nucleophile (the Lewis base) (Example 5.8). It is noteworthy that the slow step of the SN1 reaction corresponds to the reverse of this process. This is also the key bond-forming step in the Ritter reaction of nitriles (Example 5.9).13
Cl O Al Cl Cl Cl
Cl O Al
Cl Cl Cl
Cl O Al
Cl Cl Cl
(5.10)
The free (unbound) proton does not occur in condensed media, although the reaction between a proton and a Lewis base belongs to this class of reactions. More importantly, per- haps, so do the reactions of Lewis bases with Lewis acids such as aluminum chloride (e.g., Example 5.10), titanium tetrachloride (e.g., Example 5.11), and a wide range of boron reagents (e.g., Example 5.12). These n + a reactions are often important steps in the mechanisms of key synthetic reactions. For example, the complexation of the carbonyl oxygen atom by a Lewis acid is a key step in many reactions that we most commonly categorized as nucleophilic addi- tions: magnesium in the Grignard addition, titanium in the Mukaiyama aldol addition reac- tion,14 and boron in the Evans asymmetric aldol addition,15 as well as the addition of allylboranes to carbonyl compounds. Complexation of the carbonyl oxygen of an acid chlo- ride by aluminum chloride (Example 5.10) is a key stage in the Friedel-Crafts acylation of arenes. Similar reactions of alkyl halides with Lewis acids (e.g., Example 5.13) are key steps in the Friedel-Crafts alkylation of arenes and alkenes (especially enol trimethylsilyl ethers).16
13. Krimer, L.I.; Cota, D. Org. React. 1969, 17, 213.
14. Mukaiyama, T.; Banno, K.; Narasaka, K. J. Am. Chem. Soc. 1974, 96, 7503.
15. Evans, D.A.; Bartroli, J.; Shih, T.L. J. Am. Chem. Soc., 1981, 103, 2127.
16. (a) Reetz, M.T.; Chatziiosifidis, I.; Lửwe, U.; Maier, W.F. Tetrahedron Lett. 1979, 1427. (b) Reetz, M.T.;
Chatziiosifidis, I.; Hübner, F.; Heimbach, H. Org. Syn. 1984, 62, 95.
Figure 5.13 Frontier molecu- lar orbital overlap between n and a orbitals
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O Ti Cl Cl Cl Cl
O TiCl Cl ClCl
O Ti Cl Cl ClCl
(5.11)
O O
B BR2
R R
O B R
R
(5.12)
Cl Cl AlCl Cl
Cl Cl AlClCl
Cl Cl AlClCl
(5.13)
Because this overlap of FMOs leads to the formation of a bond without requiring con- comitant bond rupture, the relative energies of the n and a orbitals are frequently of rela- tively little consequence in comparison to reactions where bond rupture is required.
Nevertheless, in general, the lower the energy of the LUMO, the more reactive the electrophile or Lewis acid is, and the higher the energy of the HOMO, the more reactive the nucleophile or base; lowering the energy of its LUMO increases the strength of a Lewis acid, and raising the energy of its HOMO increases the strength of a Lewis base. In the same reaction, however, these two effects are often incompatible with each other. Conse- quently, we seldom find a strong Lewis base involved in reactions where a strong Lewis acid is used—the Lewis acid is capable of accepting a pair of electrons from even weak electron-pair donors, and a strong Lewis base tends to be incompatible with reaction con- ditions where a strong Lewis acid is generated. Conversely, a strong Lewis acid is seldom involved in reactions where a strong Lewis base is used—the Lewis base is capable of do- nating a pair of electrons to even weak electron-pair acceptors, and a strong Lewis acid tends to be incompatible with reaction conditions that lead to the formation of a strong Lewis base.
Conjugated Systems: ap and np Orbitals OSiMe3
H2O
O
(5.14) Cl
Br
H2O OH (5.15)
Recall that conjugated π bonding systems with an odd number of atoms have a nonbond- ing orbital between the bonding and antibonding orbitals. To distinguish this type of orbital form those that are localized on a single atom, we will designate them as ap and np orbitals. The major difference between these orbitals and the localized a and n orbitals that we have been discussing is that these orbitals are delocalized, with lobes (i.e., sites for reaction) at more than one location, thus permitting regioisomers to be formed in their reactions. In a species such as the allyl cation, this nonbonding orbital is the LUMO, whereas in systems such as an enolate anion, this orbital is the HOMO. Thus, the second
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step of the SN1 reactions of allyl halides (the left-hand example in Figure 5.14) also belongs to the n + apsubclass of reactions, with ψ2 of the allyl cation as the ap orbital. The Friedel-Crafts alkylation of an enol trimethylsilyl ether16,17 (the right-hand example in Figure 5.14) belongs to the np+ a subclass or reactions, where the carbocation (a) inter- acts with ψ2 of the silyl ether as the np orbital. The interaction between an allyl cation and an enol trimethylsilyl ether or an enamine would represent the np+ ap subclass of reac- tions. As we shall see later in this chapter, systems such as the ones in Example 5.14 may also be treated as a + π overlaps.
Problems
5-3 The Friedel-Crafts acylation proceeds through an electrophile generated by the reaction between aluminum chloride and an acyl chloride. Example 5.10 above discusses one type of electrophile that can be formed by this combination of reactants. What is the other, and what FMOs are involved in its formation?
5-4 The reaction below can give more than one chloride as the product. What chlo- ride should be the major product formed, and overlap of what FMOs initiates its formation?
OH HCl
5-5 The reaction between a silyl ether and fluoride anion occurs in two stages. Write a mechanism consistent with this and specify the orbital overlap that initiates the reaction (i.e., which orbitals are involved?).
Si OR' R R
R F Si F
R R
R + OR'
17. Chan, T.H.; Paterson, I.; Pinsonnault, J. Tetrahedron Lett. 1977, 4183.
X
HOMOn LUMOψ2
+ :X
Me3SiO
LUMO2p
HOMOψ2
O + R
Figure 5.14 Reactions involv- ing conjugated cations and/
or anions with frontier mo- lecular orbital overlap be- tween n and a orbitals.
HOMO, highest energy oc- cupied molecular orbital;
LUMO, lowest energy unoc- cupied molecular orbital.
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Frontier Molecular Orbital Overlap Between n and π * Orbitals
This combination of FMOs initiates nucleophilic addition to a polar π bond, such as a carbonyl group, which means that it is the FMO overlap responsible for initiating some of the most important synthetic organic reactions available to the organic chemist. The sim- plest illustration of a reaction initiated by this pairing of FMOs is given by the addition of a heteroatom nucleophile to a carbonyl group (Figure 5.15). In this reaction, a new σ bond is formed at the expense of a π bond by overlap of a filled n orbital of the nucleophile (sulfur in the example above) with the unoccupied π * orbital of the carbonyl group. In nucleophilic addition, the HOMO-LUMO overlap that initiates the reaction puts electrons into an antibonding orbital, which results in rupture of the π bond. As their name implies, antibonding orbitals are the absolute opposite of bonding orbitals, and they destabilize the association of the two nuclei.
Whenever electrons are placed into an antibonding orbital, the bond corresponding to that orbital is broken.
Thus, the HOMO-LUMO overlap now affects three orbitals—the n orbital of the nuc- leophile and the π * and π orbitals of the electrophile—and the fate of all three must be taken into account when deciding what the overall bonding change is. In this reaction, the electrons of the nucleophile lone pair become the electrons of the new σ bond, and the electrons in the π bonding orbital become the new nonbonding electron pair. For clarity, the new σ* orbital has been omitted from Figure 5.6.
Reactions initiated by n + π* overlap are among the most important bond-forming reactions in organic chemistry, and they include a wide diversity of reactions. The π* or- bital, for example, can be the C—O π* orbital of an isolated carbonyl group; the C—N π*
orbital of an isolated nitrile group or imine; or ψ3 of an α,β-unsaturated carbonyl system, imine, or nitrile. It can also, however, be the lowest unoccupied π orbital of an electron- deficient aromatic ring system such as nitrobenzene, where it is the functional equivalent of ψ3 of an α,β-unsaturated carbonyl system, or be pyridine, where it is the functional equivalent of the C—N π* orbital of an isolated imine group.
O H
OAr
LiO OHAr
OH O
(5.16)
C O
S
C O
S
+ C—S σ*
H2C O C O
n π
π*
n
C O H H
H S + S
H H H
O σ Figure 5.15 Frontier molecu-
lar orbital overlap between n and p* orbitals
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O H
H O
H
H Me2CuLi
Et2O/0°C (5.17)
O OBPS
CHO
MeO O
OBPS
MeO MeC≡CLi
96%
OH
(5.18)
N
NaNH2 110°C
N NH2
(5.19)
When the π* orbital is the antibonding orbital of an aldehyde or ketone, the reactions include the addition of metal enolates (e.g., Example 5.16), metal alkyls (e.g., Example 5.17) and alkali metal alkynides (e.g., Example 5.18) to the carbonyl group to give alcohols, and the addition of heteroatom nucleophiles and cyanide or azide anion to the carbonyl group to give addition products. In conjugated systems, we see both 1,2- and 1,4-addition reac- tions arising from this combination of FMOs, with the regiochemistry of the reaction often being controlled by the hardness and softness of the two reacting species (i.e., the HOMO-LUMO gap), as we saw in Section 5.2, above.
This combination of FMOs also corresponds to the first step in nucleophilic substitu- tion at sp2-hybridized centers by the addition-elimination mechanism, including nucleo- philic acyl substitution and nucleophilic aromatic substitution as well as the Chichibabin reaction of pyridines (e.g., Example 5.19).
Problems
5-6 Using the curved arrow formalism, write a mechanism to account for the formation of the product in each of the four examples above.
5-7 Identify the FMOs used by each of the reactants in the examples above.
Frontier Molecular Orbital Overlap Between n and σ * Orbitals
The σ-type overlap of these two FMOs is the pairing in the SN2 reaction (Figure 5.16) and in the transfer of a proton from a Lowry-Brứnsted acid to a base. In essence, this reaction is
n
C Br
σ∗ σ
C
CH4 Br Br
σ n
N C N C
CHBr H3C H3C
+ C CH
CH3 CH3
+ Br N C N
Figure 5.16 Frontier molecu- lar orbital overlap between n and s* orbitals
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basically the same as the reactions in the previous section, except that the LUMO is now a σ * orbital rather than a π * orbital—the rupture of the σ bond produces two separate species rather than simply breaking one of the two bonds of a double bond.
All the remaining arguments remain the same. Again, the new σ* antibonding or- bital has been omitted for clarity.
The second major group of reactions that is initiated by this type of FMO over- lap is the deprotonation of organic compounds by strong bases. There are many examples of such reactions: the deprotonation of carbonyl compounds to give eno- late anions, base-promoted elimination by the E2 and E1cb mechanisms (Figure 5.17), and the fast deprotonation step in the E1 mechanism. The useful re- action between triphenylphosphine and carbon tetrabromide, also shown in Figure 5.8, proceeds by overlap of the nonbonding orbital on phosphorus with a C—Br σ* orbital at the bromine end.
Problem
5-8 What will be the products formed in the two reactions in Figure 5.17? Assume that there is no further movement of electrons.
Frontier Molecular Orbital Overlap Between p and a Orbitals
The addition of a localized electrophile to a carbon-carbon π bond is an important reaction that is involved not only in the electrophilic addition to alkenes but also in electrophilic aromatic substitution reactions. It is initiated by the overlap of the empty a orbital of the electrophile with the filled π orbital of the alkene, as illustrated in Figure 5.18.
Figure 5.17 Initial frontier molecular orbital overlap involving an n orbital and an s* orbital
HO H
R RR
R X
Ph3P
Br Br Br Br
n σ*
n σ*
C C
C C
C
C C
π
π* C a
σ a
C C
C σ*
H
H Me
Me
H3C + H3C
CH2 C Me Me
Figure 5.18 Frontier molecu- lar orbital overlap between a and p orbitals
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In this reaction, three orbitals are affected: the two FMOs as well as the antibonding orbital corresponding to the HOMO. In this case, the electrons originally in the π orbital are used to form the new σ bond, so that the second terminus of the original π bond be- comes an atom bearing an empty nonbonding orbital.
This combination of FMOs is the pairing in the addition of carbocations to alkenes, as in the Johnson polyene cyclization,18,19 the alkylation of enol silyl ethers by alkyl halides and titanium tetrachloride,20 and, formally, the hydroboration of alkenes.21 It is also the first step of the electrophilic substitution reactions of arenes and alkenes. Although reac- tions initiated by protonation may be viewed as belonging to this class, one should also bear in mind that the free proton does not actually exist in condensed media and that protonation reactions really belong to the class initiated by σ* + π overlap.
CO2Me
H2SO4, HCO2H 20°C, 6h
CO2Me H
OH
(5.20)
OSiMe3 Cl
TiCl4, CH2Cl2, -50°C
O
60-62%
(5.21)
BH3•THF H
B (5.22)
Frontier Molecular Orbital Overlap Between π and π* Orbitals
This pairing of FMOs occurs in two major reaction classes: electrophilic addition to simple alkenes and arenes (as in the first step of electrophilic aromatic substitution) as well as in cycloaddition reactions.
Electrophilic Addition
The critical part of the HOMO-LUMO overlap is obviously the formation of the new σ orbital (and its associated σ* orbital, which has been omitted from Figure 5.19 for clarity). The electrons in the complementary π orbital of the electrophile become a non- bonding lone pair in the product, and the complementary π* orbital of the nucleophile becomes an empty nonbonding orbital in the product. From the perspective of both participating bonds, these reactions are addition reactions because both π bonds are broken and replaced by σ bonds. From the perspective of the LUMO, this is a nucleop- hilic addition reaction, and from the perspective of the HOMO, it is an electrophilic addition reaction.
18. Johnson, W.S. Acc. Chem. Res. 1968 1, 1.
19. Stadler, P.A.; Nechvatal, A.; Frey, A.J.; Eschenmoser, A. Helv. Chim. Acta 1957, 40, 1373.
20. (a) Reetz, M.T.; Chatziiosifidis, I.; Lửwe, U.; Maier, W.F. Tetrahedron Lett. 1979, 1427. (b) Reetz, M.T.;
Chatziiosifidis, I.; Hübner, F.; Heimbach, H. Org. Syn. 1984, 62, 95.
21. (a) Brown, H.C. Hydroboration (W.A. Benjamin: New York, 1962). (b) Brown, H.C. Boranes in Organic Chemistry (Cornell University Press: Ithaca, NY, 1972). (c) Brown, H.C. Organic Synthesis via Boranes (Wiley-Interscience: New York, 1975).
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This pairing of FMOs is the overlap that initiates electrophilic addition of carbonyl and iminium groups to electron-rich alkenes, as in the Mannich reaction,22 the Mukai- yama aldol reaction of enol trimethylsilyl ethers,23 and the Prins reaction24 of aldehydes with alkenes in the presence of acid. It is also the first step of the acylation of vinylsilanes25 and stannanes, and the first step of electrophilic aromatic substitution, as illustrated by the examples below.
NH CH2(OH)2, MeCO2H 150°C, 10 h
N
98%
Ph Ph
(5.23) OSiMe3
PhCHO, TiCl4 CH2Cl2, -78°C
92%
O
Ph OH
(5.24)
22. Reviews: (a) Tramontini, M. Synthesis, 1973, 703. (b) Thompson, B.B. J. Pharm. Sci. 1968, 57, 715.
(c) Arend, M.; Westermann, B.; Risch, N. Angew. Chem. Int. Ed. Engl. 1998, 37, 1044.
23. Mukaiyama, T.; Banno, K.; Narasaka, K. J. Am. Chem. Soc. 1974, 96, 7503.
24. Review: Adams, D.R.; Bhatnagar, S.P. Synthesis 1977, 661.
25. Fleming, I.; Pearce, A. J. Chem. Soc., Chem. Commun. 1975, 633.
C C
C
C C
π π*
σ a
H
H Me
Me Me
Me C
O O
C C
C
C C
σ*
C n O
O π
π*
O H H
H + HO
Figure 5.19 Frontier molecular orbital overlap between p and p* orbitals in electrophilic addition
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Pr OH
PhCHO/AlCl3
O Pr
Ph Cl 91%
ionic liquid solvent (5.25) SiMe3
MeCOCl, AlCl3 CH2Cl2, 0°C, 15 min
77%
O
(5.26)
Problem
5-9 Using the curved arrow formalism, write reasonable mechanisms for reactions 5.23, 5.24, 5.25, and 5.26.
Worked Problem
5-2 Using the curved arrow formalism, write a reasonable mechanism for reaction 5.20 and provide reasons for each step where appropriate:
CO2Me
H2SO4/HCO2H 20°C/6h
CO2Me H
OH
§Answer below
§ Answer to Worked Problem:
The reaction starts with the protonation of the terminal alkene π bond to give the tertiary carbocation, which then adds to the alkene π bond in the middle of the chain to give a new tertiary carbocation. This cation adds to the final alkene π bond in the direction to place the carbocation at the α, rather than the β position of the ester (why is this regiochemistry preferred? Think about the electron distribution in the carbonyl group).
The cation is then trapped by water to give the final alcohol.
O MeO
H O
MeO
O MeO
H O
MeO H
OH H
O MeO
OH H H
O MeO
OH
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Cycloadditions
Cycloaddition reactions are one reaction type in a class of reactions, known as pericyclic reactions, that involve π-bonded systems and proceed through cyclic transition states.
The Diels-Alder reaction, or [4 + 2] cycloaddition (Figure 5.20), is a typical cycloaddition reaction. The orbital correlation diagram for this reaction shows that there are six orbitals modified during the reaction. It is developed according to principles, now known as the conservation of orbital symmetry, first set forth by Woodward and Hoffmann, and by Fukui. We will look at the conservation of orbital symmetry and at pericyclic reactions in general, in much more detail in Chapter 6.
Frontier Molecular Orbital Overlap Between π and σ* Orbitals
This situation has characteristics of both the a + π and the π + π* cases. The similarity to the a + π case becomes evident when one considers that the typical reagent in this type of reaction (the oxonium ion has been used in Figure 5.21) is normally the immediate precur- sor to the carbocation electrophile in reactions like the Johnson polyene cyclization. Simi- larly, because the proton does not occur free in condensed medium, all protonations of alkenes actually involve the σ* orbital of the bond to hydrogen. In fact, in a formal sense, the same set of examples used in the section on may also be used here, including the hyd- roboration reaction (Example 5.22), where one may, in fact, view the initial electrophilic
O B H
HH (5.27)
ψ2
π*
diene
(nucleophile) dienophile (electrophile)
π*
σb
σa
+ Figure 5.20 Frontier molecu-
lar orbital overlap between π and π* orbitals in cycloaddition
O C
C C C
C C
π σ*
σ
a
C CH2 H3C H3C
+ H3C OH2
H3C
H2C CH3
Figure 5.21 Frontier molecu- lar orbital overlap between π and σ * orbitals
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