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Rationally Designing Regiodivergent Dipolar Cycloadditions: Frontier Orbitals Show How to Switch Between [5 + 3] and [4 + 2] Cycloadditions Seung-yeol Baek, Ju Young Lee, Donguk Ko, Mu-Hyun Baik, and Eun Jeong Yoo ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b00845 • Publication Date (Web): 22 May 2018 Downloaded from http://pubs.acs.org on May 22, 2018

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ACS Catalysis

Rationally Designing Regiodivergent Dipolar Cycloadditions: Frontier Orbitals Show How to Switch Between [5 + 3] and [4 + 2] Cycloadditions Seung-yeol Baek,†,‡,∥ Ju Young Lee,§,∥ Donguk Ko,§ Mu-Hyun Baik†,‡,* and Eun Jeong Yoo§,*

†

Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea

‡

Center for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science (IBS), Daejeon 34141, Republic of Korea §

Department of Applied Chemistry, Kyung Hee University, Yongin, 17104, Republic of Korea

ABSTRACT: A pyridinium zwitterion substrate is employed with two different types of transition metal catalysts to develop a regio-divergent cycloaddition. The pyridinium zwitterion is a highly reactive dipolar substrate that can undergo a dipolar cycloaddition with various reactants. It has multiple reaction-sites and the chemoselectivity is determined by the electronic demand of the catalyst-substrate complex. The reaction with nucleophilic Pd-reagents affords fused Nheterocyclic compounds via regioselective [4 + 2] cycloaddition. The origin of the site-selectivity and the mechanism of this reaction are investigated in this combined experimental and computational study. We found that the pyridinium zwitterion plays a completely different role in the palladium(0)-catalyzed [4 + 2] cycloaddition reaction compared to that of the rhodium(II)-catalyzed [5 + 3] cycloaddition, which was examined experimentally in a previous study. The frontier molecular orbitals of the pyridinium substrate and activated catalyst complex reveal that the pyridinium zwitterion can act as both nucleophile and electrophile depending on the reaction partner in a much more defined way than conventional substrates leading to the observed regio-divergent chemical reactivity.

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INTRODUCTION Cycloadditions are one of the most important classes of organic reactions for accessing elaborate cyclic 1

compounds that are key constituents of natural products, pharmaceutical agents or synthetic materials. Catalytic cycloadditions are particularly attractive due to their convenient and economical abilities to regioselectively 2

provide complex scaffolds. A general strategy for engineering regioselectivity in catalytic cycloadditions relies on the interaction between a metal catalyst and π-systems of the substrate. For example, the vinylcyclopropanes 3

(VCPs), which have been extensively studied for example by Wender, selectively act as five-carbon synthons in the presence of a rhodium(I) catalyst (Scheme 1A). Although these methods are remarkably successful, and inspired 4

many related catalytic methodologies using cyclopropylimines, allenylcyclopropanes, vinylepoxides, vinylaziridines or 3-acyloxy-1,4-enynes, the robustness of these approaches remain a challenge from fundamental perspectives. Because the energy difference of competing reaction pathways are often small in these systems, the selectivities may become unreliable and seemingly benign changes in substrate composition can lead to significant loss of selectivity. A possible solution may be to encode an intrinsic selectivity into the reaction that cannot be easily overridden. 5

Catalytic dipolar cycloadditions, widely used for the constructions of five- and six-membered heterocycles, highlight an alternative means of controlling the selectivities because they are readily governed by the electronicand steric properties of the metal-bound intermediates; they can offer a reliable way of programming selectivity, as will be demonstrated below. In general, catalytic dipolar cycloadditions rarely allow divergent cycloaddition outcomes that have entirely different skeletons from identical reactants. Interestingly, divergent cycloadditions of enoldiazo compounds where the choice of the catalyst allowed for switching the regiochemistry was reported by 6

Doyle, demonstrating the versatility of dipolar reactants. As illustrated in Scheme 1B, rhodium(II) enol carbenoids that are readily generated from enoldiazo compounds usually serve as three-carbon synthons in dipolar 7

cycloadditions to produce six-membered rings in [3 + 3] cycloadditions. They can be selectively transformed into donor-acceptor cyclopropenes, however, if electron-deficient catalysts such as Rh2(tfa)4 or Rh2(pfb)4 are employed, 8

providing cyclopropane-fused [3 + 2] cycloaddition products.

Recently, we discovered that the pyridinium zwitterion may serve as a 1,5-dipole for the construction of medium9

sized heterocycles via [5 + n] cycloadditions. One remarkable feature of pyridinium zwitterions is that the 10

aromaticity of the pyridinium core stabilizes these compounds sufficiently to allow the zwitterions to be isolated.

During exploration of the characteristics of storable pyridinium zwitterions, we realized that the reactivity of pyridinium zwitterions is quite similar to that of pyridines that are electrophilically activated by a metal or a Lewis acid. Because the activation of pyridines by metal or Lewis acid is a practical strategy for the regioselective 11

functionalization of pyridines, we envisioned the intrinsic and permanent charge polarization in the pyridinium zwitterion could lead to dipole-controlled divergent cycloadditions in a rational and predictable manner. Herein we report the first example of divergent cycloadditions of pyridinium zwitterions that are controlled by the electronic properties of the metal-bound reaction partners. To understand and generalize how the regioselectivity of dipolar cycloadditions can be controlled, we carried out a combined computational and experimental study, which revealed a novel general strategy controlling the regiochemistry by either engaging the HOMO or LUMO of the dipolar substrate as the first, regio-determining step. 2


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ACS Catalysis

Scheme 1. Overview of Regioselective Cycloadditions.

EXPERIMENTAL SECTION General procedure for the Pd(0)-catalyzed cycloaddition of pyridinium zwitterion (1) and 5-methylene-2oxo-3-phenyltetrahydro-2H-pyran-3-carboxylate (2a). To a test tube with a triangular-shaped stir bar were added pyridinium zwitterion (1, 0.1 mmol), 5-methylene-2-oxo-3-phenyltetrahydro-2H-pyran-3-carboxylate (2a, 2.0 equiv), Pd(PPh3)4 (10 mol%), PBu3 (20 mol%) and THF (2.0 mL) under N2 atmosphere. The reaction mixture was stirred at room temperature for 5 min (full consumption of comp. 1). After completion, the reaction mixture was filtered through a pad of celite and then washed with Et2O (5 mL x 3). Organic solvents were removed under reduced pressure and the residue was purified by chromatography on silica gel to give the desired product 3. Computational Details. All calculations were performed using density functional theory (DFT)

12

as

13

implemented in the Jaguar 9.1 suite of ab initio quantum chemistry programs. Geometry optimizations were 14

15

performed with the B3LYP-D3 functional using the 6-31G** basis set. Palladium was represented using the Los 16

Alamos LACVP basis set

that includes relativistic core potentials. More accurate single point energies were

computed from the optimized geometries using Dunning’s correlation-consistent triple-ζ basis set, cc-pVTZ(-f)

17

that includes a double set of polarization functions. Vibrational frequencies computed at the B3LYP-D3/6-31G** level of theory were used to derive zero point energy and vibrational entropy corrections from unscaled frequencies. 18

Solvation energies were evaluated by a self-consistent reaction field (SCRF) approach

with THF (dielectric

constant ε = 7.6) using the optimized gas phase structures. The calculations were carried out using a minimally simplified model where the isopropyl group on a Rh2(OPiv)4 catalyst is replaced to a methyl group. This slight modification is not expected to have any notable impact on the conclusions of this work.

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RESULTS AND DISCUSSION In principle, the electronic structure changes required for cycloadditions can be categorized in two different 19

classes, as illustrated in Figure 1: (i) In the closed-shell mechanism, double-bonds are cleaved heterolytically and the intermediates and transition states are charge-polarized. The new bonds are formed via classical Lewis base/acid type of reactions. (ii) Alternatively, the reaction may proceed using an open-shell mechanism where bonds are broken and reformed in a homolytic fashion involving transient radicaloid species. These electronic features can be exploited to program regio- and stereo-selectivities into the cyclization: Due to the fundamentally different nature of the electronic structure distortions, the sensitivity of the selectivity towards functional group variations is 20

expected to be profoundly different. Although systematic mechanistic studies that may provide a comprehensive theory on how to fully take advantage of these design elements do not exist yet, the governing principles are plausible and simple.

Figure 1. Heterolytic, Homolytic pathway in cycloaddition

Dipolar cycloadditions offer an attractive way of forcing the cyclization to proceed through the closed-shell pathway. Figure 2 contrasts the shapes of the HOMO/LUMO in butadiene to the pyridinium zwitterion employed in this study. In conventional substrates like butadiene, there is no intrinsic bias for directing an electrophilic or nucleophilic attack because both the HOMO and LUMO are delocalized over the same atoms in an equal fashion. The localization of these orbitals to polarize the electron density into a negative and positive ends required for the closed-shell mechanism and heterolytic bond cleavage must be induced for example by an incoming nucleophile 21

during the reaction, as illustrated in Figure 2. In the pyridinium substrate, the frontier orbitals are localized to a much higher degree and the zwitterionic charges direct electrophiles to the HOMO-centered portion of the molecule, whereas nucleophiles are likely to attack via the LUMO of the pyridinium substrate, as illustrated in Figure 2.

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Figure 2. Different electronic demand of dipolar substrate

Previously, the rhodium(II)-catalyzed [5 + 3] cycloaddition between the pyridinium zwitterion and enol 9a

diazoacetates was shown to afford the eight-membered N-heterocyclic compounds 3 (Scheme 1c).

The isolable

pyridinium zwitterion acts as a nucleophilic 1,5-dipole, constituting a five-atom synthon that reacts with the rhodium(II) enol carbenoid, which acts as an electrophile along the enol scaffold (Figure 3, Type I). Because the positive charge of the pyridinium zwitterion is localized on the pyridinium fragment with the C4 position being a particularly dominant contributor of the LUMO, we may speculate that the regiochemical outcome may be diverted away from the [5 + 3] manifold to afford a regio-divergent cycloaddition at the C4-position if a suitable nucleophilic reaction partner is utilized. For instance, a [m + 2] cycloaddition of the pyridinium zwitterion can be envisioned providing fused N-heterocycles via the nucleophilic attack of a reaction partner in a regioselective manner (Figure 3, Type II). If confirmed, such a divergent behavior would highlight the aforementioned robust programming that is built into the 1,5-dipole substrate.

R1

• N

NTs

electrophilic species

R1

R2

6

N R2

N Ts

•

R

2

6

N

6

•

R1

•

•

A. Type I: pyridinium zwitterion as five-atom synthon

•

N Ts

•

B. Type II: pyridinium zwitterion as two-carbon synthon

•

4

R1 N R2

NTs

nucleophilic species

•

•

4

5

•

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ACS Catalysis

4

5

R1 N R2

5

R1 R2

5

R1

N NTs

•4

•

N NTs R

• NTs

2

Figure 3. Regio-divergence of pyridinium zwitterion in cycloaddition

Cycloaddition with γ-methylidene-δ-valerolactone. Intrigued by the aforementioned analysis, we examined the reactivity of the pyridinium substrate with nucleophilic cyclization partners. Our study commenced with the cycloaddition of pyridinium zwitterion (1a) and palladium-bound zwitterionic species readily generated from γmethylidene-δ-valerolactone (2a), which provided potently bioactive N-heterocyclic compounds

22

(Table 1).

Interestingly, the desired [4 + 2] cycloadduct (3a), where new bonds were formed on C4- and C5-positions of o

pyridinium zwitterion (1a), was observed in the presence of 10 mol% Pd(PPh3)4 at 30 C. After surveying a wide 5


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range of organic solvents, it was revealed that the cycloaddition of pyridinium zwitterion (1a) was fully converted in THF within five minutes although the product (3a) was only obtained in 70% yield (entries 1-5). The phosphine 23

ligand was found to significantly affect the reactivity of the [4 + 2] cycloaddition of the pyridinium zwitterion (1a).

Bidentate phosphine ligands dramatically reduced the yield of cycloadducts (3a) (entry 6), and dialkylbirayl phosphine ligands were also less effective (entry 7). Surprisingly, we observed that the electron-rich tributylphosphine ligands gave the best reactivity resulting in 96% yield; the trialkyl phosphine ligand has rarely been used as a ligand in the cycloaddition of γ-methylidene-δ-valerolactone (2a) (entry 9). Curiously, constitutional isomers such as the nine-membered heterocycles were not observed.

Table 1. Optimization of Pd(0)-Catalyzed Cycloaddition of Pyridinium Zwitterion and γ-Methylidene-δ valerolactone

a

entry

solvent

ligand

time (min)

yield (%)

1

1,4-dioxane

-

60

40

2

CHCl3

-

60

30

3

Toluene

-

15

56

4

Benzene

-

5

60

5

THF

-

5

70

6

THF

Dppp

5

36

7

THF

CyJohnPhos

5

58

8

THF

P(Ph)2Me

5

65

9

THF

PBu3

5

96 (93 )

b

c

6


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ACS Catalysis a

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Reaction conditions: pyridinium zwitterion (1a, 0.1 mmol), methyl 5-methylene-2-oxo-3-phenyltetrahydro-2H-pyran-3carboxylate (2a, 2.0 equiv), Pd(PPh3)4 (10 mol%), solvent (2.0 mL) b under N2. NMR yield using 1,1,2,2-tetrachloroethane as an c internal standard. Isolated yield.

With the optimized conditions in hand, we explored the generality of this site-selective cycloaddition with various pyridinium zwitterions. As shown in Table 2, the electronic and steric variations of C2-position of the pyridinium skeleton did not affect the efficiency of the selective [4 + 2] cycloadditions. The presence of halidesubstituted zwitterion posed no problems under the palladium catalysis, delivering the corresponding products 3f and 3h in 85% and 91%, respectively. Also, cycloadditions of the pyridinium zwitterion bearing a disubstituted arylor a naphthyl moiety furnished the desired products 3i and 3h in good yields under the optimized conditions. However, the cycloadducts which were transformed from other N-heteroaromatic zwitterions, such as C3substituted pyridinium zwitterions and quinolinium zwitterions, were too unstable to be isolated although the zwitterions appear to have been converted quantitatively. Reactivity of cycloaddition with respect to the substituents on the enamide moiety of pyridinium zwitterions was also investigated (Table 3). As expected, various para- and meta substituted aryl groups can be tolerated on the C1’ of the pyridinium zwitterion, promptly furnishing the desired [4 + 2] cycloadducts (3k-3r) in excellent yields and selectivities.

Table 2. Pd(0)-Catalyzed Cycloaddition of Pyridinium Zwitterions and γ-Methylidene-δ-valerolactone

a,b

7


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a

Reaction conditions: pyridinium zwitterion (1, 0.1 mmol), methyl 5-methylene-2-oxo-3-phenyltetrahydro-2H-pyran-3carboxylate (2a, 2.0 equiv), Pd(PPh3)4 (10 mol%), PBu3 (20 b mol%), THF (2.0 mL) under N2. Isolated yield of 3.

8


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ACS Catalysis

Table 3. Regioselective [4 + 2] Cycloadditions of Pyridinium Zwitterions and γ-Methylidene-δ –valerolactone

entry

R

product 3

yield (%)

1

4-Me(C6H4)

3k

96

2

4-tBu(C6H4)

3l

91

3

4-Ph(C6H4)

3m

92

4

4-CF3(C6H4)

3n

89

5

4-Br(C6H4)

3o

93

6

4-F(C6H4)

3p

93

7

3-CH3(C6H4)

3q

94

8

3-F(C6H4)

3r

91

a

b

a

Reaction conditions: pyridinium zwitterion (1, 0.1 mmol), methyl 5-methylene-2-oxo-3-phenyltetrahydro-2H-pyran-3carboxylate (2a, 2.0 equiv), Pd(PPh3)4 (10 mol%), PBu3 (20 b mol%), THF (2.0 mL) under N2. Isolated yield

Reaction mechanism of palladium catalyzed [4+2] cycloaddition. Based on these experimental observations in support of our conceptual proposal of constructing a regiodivergent reaction, we postulated a reaction pathway summarized in Scheme 2. Since the intramolecular cyclization of the pyridinium zwitterion (1a) did not occur even 15

under high temperature conditions with the palladium catalyst present, we ruled out a possible mechanism involving an intramolecular cyclization of the pyridinium zwitterion, followed by a cycloaddition of the Pd(II)pyridinium complex. Instead, a much more plausible mechanism starts with the generation of Pd(II)-1,4zwitterionic

complex

(Int2)

by

oxidative

addition

of

γ-methylidene-δ-valerolactone

accompanied

by

decarboxylation. Then, the nucleophilic carbon of Pd-stabilized 1,4-zwitterionic complex (Int2) may attack the C4 of the pyridinium zwitterion (1a) affording the C–C coupled intermediate Int3. Next, the remaining electrophilic carbon stabilized by the Pd(II)-center may undergo reductive elimination followed by intramolecular cyclization to give the six-membered ring in Int4. Finally, a ring closure via second intramolecular cyclization of Int4 gives the desired product 3a and regenerates the Pd(0) catalyst. Figure 4 illustrates the reaction energy profile of this mechanistic scenario probed by DFT calculations.

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Scheme 2. Proposed Mechanism of Cycloaddition between Pyridinium Zwitterion and Pd(II)-1,4-zwitterionic complex

10


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ACS Catalysis

Figure 4. Energy profile of the cycloaddition between pyridinium zwitterion and the model Pd-allyl complex.

The oxidative addition of γ-methylidene-δ-valerolactone (2a) to the coordinatively unsaturated Pd(0)-complex PdL2 (L = PPh3) to afford Int1 is associated with a very low barrier of only 3.4 kcal/mol. The C–O bond cleavage and ring-opening generates an anionic carboxylate and a formally cationic dimethylenealkyl moiety, which is reduced by two electrons during the oxidative addition with the Pd(0) center and becomes therefore formally an anionic allyl ligand that is bound to Pd(II) in Int1. And our calculations indicate that this intermediate Int1 will quickly liberate CO2 traversing the transition state Int1-TS at 3.3 kcal/mol to form the resting state complex Int2. Its computed structure is illustrated in Figure 5a. The negatively charged C7 in Int2 is a competent nucleophile and may engage the pyridinium substrate readily to form a C–C bond either at the C4 or C6 position, as shown in Figure 4. As may be anticipated intuitively, the nucleophilic attack at the C4 position is much more favored with the transition state Int2-TS at 1.1 kcal/mol being 11.4 kcal/mol lower than Int2-TS’, the putative transition state leading to the C6-addition product. The computed structures of Int2-TS and Int2-TS’ shown in Figure 5b and 5c show similar C–C bond lengths about ~ 2.04 Å. Interestingly, the Pd-center is not directly involved in the C–C coupling step and this intermolecular coupling is predicted to be facile with a barrier of only ~11 kcal/mol. To complete the cyclization, the Pd-allyl functionality must engage in a reductive C–C coupling reaction, where one of the 11


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methylene moieties attacks the C5-position of the pyridine skeleton to give Int4. This step is calculated to be most difficult and is associated with a barrier of 26.0 kcal/mol, as illustrated in Figure 4. The calculated structure of Int33

2

TS is shown in Figure 5d, highlights the reduction of the metal to Pd(0) and the transition from the η - to η binding. Finally, C–N bond formation between the amido-N and the cationic C6-carbon affords the final product complex 3-[Pd], which may release the product and reenter the catalytic cycle as shown in Scheme 2.

Figure 5. Optimized structures of Int2, Int2-TS, Int2-TS’ and Int3-TS (Non-essential atoms have been omitted for clarity.) (a)

(b)

4

3

5

2

6

Ph

Pd IIL 2 MeO2C

N NTs

Ph

Ph

-1.909 eV LUMO -2.871 eV

-3.226 eV

LUMO HOMO -5.050 eV

Ph

N NTs

Ph 1

HOMO

Figure 6. (a) Conceptual MO-diagram of the interaction between the pyridinium zwitterion and the Pd(II)-allyl complex (b) Isodensity plot of the the LUMO of the pyridinium zwitterion 1. 12


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ACS Catalysis The key step controlling the regiochemical outcome is Int2 → Int3 and Figure 6 conceptualizes the orbital

interactions that drive this step. As expected for the nucleophilic attack on the pyridinium backbone, the HOMO of the nucleophile at an energy of -3.22 eV attacks the LUMO of the pyridinium at the C4 position where the amplitude of the LUMO is largest. Our calculations show that this LUMO has an orbital energy of -2.87 eV and is therefore only 0.36 eV higher in energy than the HOMO of the nucleophile, allowing for an efficient electronic coupling with a remarkably low barrier, as discussed above. This interaction pattern is expected to be generally applicable to cases where the pyridinium substrate acts as the target of a nucleophilic attack, robustly and consistently directing nucleophilic reagents to the pyridinium portion of the molecule, C4 in particular. Functionalizations using even strongly electron donating or withdrawing groups will not notably change the bias of the regiochemistry, as experimentally observed and summarized in Table 3.

[Rh(II)]2 Catalyzed [5 + 3] Cycloaddition. As discussed above, the dipolar character of the zwitterionic substrate may be exploited to completely alter the regiochemical outcome, if the anionic portion of the zwitterion can be engaged at the regio-determining step. And previously, such a reaction was observed using a Rh catalyst to engage 9

the identical zwitterionic reactant in a [5 + 3] cycloaddition, as summarized in Scheme 3. In that work the mechanism was not modeled computationally, details of what determines the regiocontrol was not clear and the reaction was not seen within the context of the proposed concept of directing the regiochemical outcome based on the frontier orbitals of the dipolar substrate. Thus, we constructed a computer model of the mechanism with the goal of contrasting it to the Pd-catalyzed [4 + 2] cycloaddition within the context of the aforementioned strategy for regiocontrol.

Scheme 3. [5 + 3]-Dipolar Cycloaddition of Pyridinium Zwitterion and Enol Carbenoid

13


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Figure 7. (a) Energy profile of the rhodium(II)-catalyzed [5 + 3] cycloaddition of pyridinium zwitterion and enol diazoacetate; (b) Optimized structures of A2; (c) Optimized structures of A2-TS (Non-essential atoms have been omitted for clarity.)

Figure 7 shows the lowest energy reaction profile of the [5 + 3] cycloaddition. The addition of the enol diazoacetate substrate to the dirhodium(II)-catalyst generates the diazo complex A1, which is energetically downhill by 6.0 kcal/mol. It gives the Rh(I)-Rh(III) complex formed by a disproportionation reaction from the initial Rh(II)-Rh(II) catalyst. The diazoacetate activation mediated by the dirhodium catalyst has been explored 24

previously in detail both experimentally and computationally. The loss of N2 via the transition state A1-TS to form A2 is associated with a barrier of 18.2 kcal/mol and A2 is proposed to be the resting state of the catalytic cycle. The computed structure is illustrated in Figure 7b. A key component of the reaction is that the diazo complex A1 liberates N2 and a formally neutral carbene is generated, which binds to the Rh(III)-center of the dirhodium catalyst to afford the Fischer-carbene complex A2. The electrophilicity of the carbene is mediated along the vinyl fragment and the initial bond-forming is directed towards the electron-rich amido nitrogen of the dipolar substrate. The C–N bond formation shifts the charge from the anionic amido-N to an originally neutral carbene-C, which becomes a formally anionic vinyl ligand bound to Rh(III), as illustrated in Figure 7. This sequence of reaction steps is distinctively different from the Pd-catalyzed reaction, where the metal-bound reaction partner was the nucleophile. The C–N coupling step yielding the intermediate A3 is associated with a barrier of 19.4 kcal/mol traversing the 14


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ACS Catalysis

transition state A2-TS, where the C3–N2 distance is found to be 2.26 Å, as illustrated in Figure 7c. In both A2 and A2-TS, the Rh–C bonds display bond lengths of only 2.00 and 2.04 Å, respectively, indicating the metal-carbenoid character of these fragments. The tethered intermediate A3 contains both the positively charged pyridinium ring and the anionic carbenoid moieties, which can undergo an intramolecular cyclization to give the 8-membered cyclic product complex A4. This final step of the cyclization is associated with the transition state A3-TS at -11.9 kcal/mol, suggesting a step barrier of only 15.5 kcal/mol. Although this C–C formation is slightly uphill, we expect it to complete readily at the experimental conditions and the final step consisting of the product release and recovery of the dirhodium catalyst is predicted to be also viable at an additional energetic cost of 8.6 kcal/mol. The frontier molecular orbitals of the Rh-catalyzed [5 + 3] cycloaddition show that the Rh(II)-enol carbenoid installs a totally different electronic demand than seen in the Pd-catalyzed [4 + 2] cycloaddition discussed above. Although the HOMO and LUMO energies of the pyridinium zwitterion are unchanged, of course, the reaction partner is now an electrophile assisted by the dirhodium-carbenoid species. So, as expected for the nucleophilic attack on the rhodium complex, the HOMO of the pyridinium substrate attacks the LUMO of the rhodium complex at the vinylogous position, as illustrated in Figure 8. The other theoretically possible HOMO/LUMO interaction involves the HOMO of the rhodium complex at -5.60 eV attacking to the LUMO of the pyridinium ring at -2.87 eV. The energy gap of this alternative interaction is 0.95 eV larger than in the correct HOMO/LUMO pair, described above.

Figure 8. (a) Conceptual MO-diagram of the interaction between the pyridinium zwitterion and the Rh(II)-enol carbenoid (b) Isodensity plot of the HOMO of the pyridinium zwitterion 1.

CONCLUSION In summary, we demonstrated that regio-divergent dipolar cycloadditions using the pyridinium zwitterion can give two different products in a highly selective fashion. In previous work, we had shown that the zwitterion can act as a 1,5-dipole to readily engage in a [5 + 3] cycloaddition, when the reaction partner was chosen to be an electrophile. By switching the reaction partner to a Pd-bound nucleophile, we were able to exploit the fact that the 15


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matching positive charge of the zwitterion is delocalized over the pyridinium skeleton and direct the initial attack to the C4-position. Subsequent ring-closing gave a [4 + 2] cycloaddition product. Conceptually, The regiochemistry of the dipolar cyclization is determined by the frontier orbitals of the reaction partners: The energy gap between the HOMO of the pyridinium zwitterion and the LUMO of the Rh(II)-enol carbenoid is much smaller than the energy difference between the HOMO of Rh(II)-enol carbenoid and LUMO of pyridinium zwitterion. Thus, the dipolar substrate will act as a nucleophile and attack the low lying LUMO of the Rh(II)-enol carbenoid. In contrast, if the energy gap between the LUMO of the pyridinium zwitterion and the HOMO of the reaction partner is small, as demonstrated in the Pd-mediated cycloaddition, then the pyridinium substrate can act as an electrophile and carry out a dipolar cycloaddition. And because the HOMO and LUMO of dipolar substrates are much more localized, these two initiation patterns lead to a well-defined, predictable regiochemical outcome. In conventional cyclization substrates with zwitterionic character the connection between regiocontrol and frontier orbitals are much less defined, because there is typically no special separation of the frontier orbitals. Combining computational and experimental efforts, we derived a conceptually intuitive and mechanistically precise understanding of how to utilize the charge delocalization of the pyridinium zwitterion to obtain structurally diverse dipolar cyclization products. Additional work to expand on this new concept to design regio-, stereo- and chemoselective dipolar cycloadditions are in progress in our laboratories.

ASSOCIATED CONTENT Supporting Information The supporting information is available free of charge on the ACS Publications website. Experimental procedures, analytical data, computational details and Cartesian coordinates of all computed structures (PDF).

AUTHOR INFORMATION Corresponding Author *[email protected], *[email protected]

Author Contributions ∥ S.B.

and J. Y. L. contributed equally to this work.

Notes The authors declare no competing financial interests.

ACKNOWLEDGMENT This research was supported by National Research Foundation of Korea (NRF) grants (NRF-2016R1A2B4015351 and NRF- 2016R1A4A1011451), funded by the Korea government. M.-H. B. acknowledges support from the Institute for Basic Science (IBS-R10-D1) in Korea. We thank Dr. Samat Tussupbayev for helpful discussions.

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