What controls regiochemistry in 1,3-dipolar cycloadditions of Muenchnones with nitrostyrenes?

Article abstract of DOI:10.1021/ol402385v

The distinct experimentally observed regiochemistries of the reactions between mesoionic muenchnones and β-nitrostyrenes or phenylacetylene are shown by DFT/BDA/ETS-NOCV analyses of the transition states to be dominated by steric and reactant reorganization factors, rather than the orbital overlap considerations predicted by Frontier Molecular Orbital (FMO) Theory.

Full text of DOI:10.1021/ol402385v

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
What Controls Regiochemistry in
1,3-Dipolar Cycloadditions of
€
Munchnones with Nitrostyrenes?
Justin M. Lopchuk, Russell P. Hughes,* and Gordon W. Gribble*
Department of Chemistry, Dartmouth College, Hanover, New Hampshire 03755,
United States
gordon.w.gribble@dartmouth.edu; Russell.P.Hughes@dartmouth.edu
Received August 20, 2013
ABSTRACT
€
The distinct experimentally observed regiochemistries of the reactions between mesoionic munchnones and β-nitrostyrenes or phenylacetylene
are shown by DFT/BDA/ETS-NOCV analyses of the transition states to be dominated by steric and reactant reorganization factors, rather than the
orbital overlap considerations predicted by Frontier Molecular Orbital (FMO) Theory.
1
Munchnones(1,3-oxazolium-5-olates) are five-membered
€
mesoionic heterocycles that undergo 1,3-dipolar cycloaddi-
tions with acetylenes and electron-deficient alkenes.2 Although
3
€
the reaction of munchnones with acetylenic dipolarophiles
has been studied for many years, more recent investigations
utilize nitroalkenes as synthetic equivalents of alkynes.4 A
striking regiochemical feature of these reactions is the lack of
correlation with FMO theory,1ꢀ5 in contrast to its utility in
predicting the outcome of many other cycloadditions.2
(1) Gribble, G. W. Mesoionic Oxazoles. In The Chemistry of Hetero-
cyclic Compounds, Oxazoles: Synthesis, Reactions, and Spectroscopy;
Taylor, E. C., Wipf, P., Eds.; John Wiley & Sons: Hoboken, NJ, 2003; Vol. 60,
Part A, p 473.
(2) Gribble, G. W. Mesoionic Ring Systems. In The Chemistry of
Heterocyclic Compounds: Synthetic Applications of 1,3-Dipolar Cycload-
dition Chemistry Toward Heterocycles and Natural Products; Padwa, A.,
Pearson, W. H., Eds.; John Wiley & Sons: Hoboken, NJ, 2002; Vol. 59, p 681.
(3) (a) Padwa, A.; Burgess, E. M.; Gingrich, H. L.; Roush, D. M.
J. Org. Chem. 1982, 47, 786. (b) Coppola, B. P.; Noe, M. C.; Schwartz,
D. J.; Abdon, R. L.; Trost, B. M. Tetrahedron 1994, 50, 93. (c) St-Cyr,
D. J.; Morin, M. S. T.; Belanger-Gariepy, F.; Arndtsen, B. A.; Krenske,
E. H.; Houk, K. N. J. Org. Chem. 2010, 75, 4261.
(4) (a) Avalos, M.; Babiano, R.; Bautista, I.; Fernandez, J. I.; Jimenez,
J. L.; Palacios, J. C.; Plumet, J.; Rebolledo, F. Carbohydr. Res. 1989, 186,
C7. (b) Nesi, R.; Giomi, D.; Turchi, S.; Tedeschi, P.; Ponticelli, F. Gazz.
Chim. Ital. 1993, 123, 633. (c) Avalos, M.; Babiano, R.; Cabanillas, A.;
Cintas, P.; Jimenez, J. L.; Palacios, J. C. J. Org. Chem. 1996, 61, 7291. (d)
Gribble, G. W.; Pelkey, E. T.; Switzer, F. L. Synlett 1998, 1061.
(5) (a) Gribble, G. W.; Pelkey, E. T.; Simon, W. M.; Trujillo, H. A.
Tetrahedron 2000, 56, 10133. (b) Lopchuk, J. M.; Gribble, G. W.
Heterocycles 2011, 82, 1617. (c) Lopchuk, J. M.; Gribble, G. W. Tetra-
hedron Lett. 2011, 52, 4106.
Figure 1. Experimentally observed products from 1,3-dipolar
€
cycloadditions of munchnones and dipolarophiles.
Although some DFT calculations have been reported to
rationalize the experimentally observed regiochemistry,3a,4c
the specific factors involved remain elusive, but are
assumed to comprise a combination of electronic, steric,
and stereoelectronic effects. Herein we report a combina-
tion of synthetic and computational studies that shed
light on the factors contributing to the regioselectivity
observed in these reactions.
During investigations5 into the reaction of nitroindoles,
€
nitrovinylindoles, and nitrovinylpyridines with munchnones,
we became interested in the general reactivity and
r
10.1021/ol402385v
XXXX American Chemical Society

regioselectivity of β-nitrostyrene derivatives as the dipo-
larophiles in these 1,3-dipolar cycloadditions (Figure 1).
The nitroalkenes (1ꢀ13, Table 1) utilized in this work
were prepared by condensation of the appropriate benzal-
dehyde derivatives with nitromethane (Henry reaction).6
Most of these reactions proceed in excellent yield (see
Supporting Information (SI)), although two strong
electron-withdrawing groups (NO2 and CF3) are notable
exceptions.
implemented in the Jaguar9 suite of programs. Full details
are provided as SI. Examination of the KohnꢀSham
HOMO/LUMO energies for each set of nitrostyrene and
€
munchnone starting materials showed a significantly bet-
€
ter energy match between the munchnone HOMO and the
nitrostyrene LUMO, rather than vice versa.11 As observed
previously using FMO theory,12 the DFT HOMO/LUMO
coefficients do not predict the correct regiochemistry for
cycloaddition. Similar observations hold for the reactions
We used a standard method5 to synthesize unsymmetrical
of both munchnones with phenylacetylene. Transition
€
states corresponding to the eight regio- and stereochemical
€
munchnones 16 and 17 from the appropriate ethyl bromo-
ester in high yield (see SI for details). The munchnones
€
€
options for nitrostyrene/munchnone cycloadditions were
located, as were those for the four regiochemical options
were not isolated, but instead generated in situ by cyclo-
dehydration with N,N0-diisopropylcarbodiimide (DIPC)
€
for phenylacetylene/munchnone cycloaddition; each was
€
(Scheme 1). Thus, a mixture of the munchnone precur-
confirmed to be the correct transition state by observation
ofa single imaginary frequencyand by subsequent intrinsic
reaction coordinate (IRC) calculations. These computa-
tions are excellent predictors for the regiochemical selec-
sors, 14 and 15, and the nitroalkenes in THF was treated
with DIPC, and the mixture was heated to reflux for
12ꢀ36 h to yield the desired substituted pyrroles as
mixtures of two isomers (Table 1). The indicated regio-
chemistry of the products was confirmed by 1D NOESY
(irradiation of the pyrrole ring proton) and the presence
(or absence) of long-range coupling between the ring
proton and the methyl group.
€
tivity for each munchnone and even correctly predict the
reversal of regiochemistry observed in entry 6. In all cases
the cycloaddition proceeds in a single step via an unsym-
metrical transition state in which one CꢀC bond is more
completely formed than the other; initial cycloaddition is
the slow step, and loss of CO2 togivethe pyrrole product(s)
is fast. For example, the lowest energy transition state
€
Scheme 1. Cyclization of Unsymmetrical Munchnones
These results demonstrate that the reactions are quite
insensitive to varying electron-donating or -withdrawing
substituents on the phenyl ring of the nitroalkene, resulting
in minimal effects on product yields and isomer distribu-
tions. However, when the steric bulk of the phenyl ring on
the nitroalkene is significantly increased (e.g., dual ortho
substitution; entries 12, 13) yields decrease dramatically but
product ratios are altered only slightly (unreacted starting
material comprises the bulk of the reaction mixture).
€
Munchnone 17 proved higher yielding in every case and
was more regioselective with all but the most sterically
hindered nitroalkenes (mesityl 12 and anthracene 13).
Competition experiments also indicate that 17 was more
€
reactive than munchnone 16 (see SI for details).
Density Functional Theory (DFT) calculations were
carried out at the B3LYP-D3/6-311G**þþ level,7,8 as
Figure 2. (Top) Lowest energy transition states for reaction of 17
˚
(TS2) and 16 (TS4) with nitrostyrene, with CꢀC distances (A).
(6) Cote, A.; Lindsay, V. N. G.; Charette, A. B. Org. Lett. 2007, 9, 85.
(7) (a) Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B 1988, 37, 785–789.
(b) Becke, A. D. J. Chem. Phys. 1993, 98, 5648–5652. (c) Becke, A. D.
J. Chem. Phys. 1993, 98, 1372–1377.
(Bottom) Principal deformation densities in the same transition
states (0.005e isosurfaces), showing electron “flow” from red to
blue between reactants.
(8) (a) Dunning, T. H.; Hay, P. J. In Modern Theoretical Chemistry,
Vol. 4: Applications of Electronic Structure Theory; Schaefer, H. F., III,
Ed.; Plenum, NY: 1977. (b) Hay, P. J.; Wadt, W. R. J. Chem. Phys. 1985, 82,
270–283. (c) Hay, P. J.; Wadt, W. R. J. Chem. Phys. 1985, 82, 299–310.
(d) Wadt, W. R.; Hay, P. J. J. Chem. Phys. 1985, 82, 284–298.
(10) (a) Glendening, E. D.; Badenhoop, J. K.; Reed, A. K.; Carpenter,
J. E.; Bohmann, J. A.; Morales, C. M.; Weinhold, F. NBO 5.0, Theoretical
Chemistry Institute, University of Wisconsin; Madison: 2001. (b) Weinhold, F.;
Landis, C. R. Valency and Bonding: A Natural Bond Orbital Donor-Acceptor
Perspective; Cambridge University Press: Cambridge, 2005.
€
(9) Jaguar, versions 7.0ꢀ7.7; Schrodinger, LLC: New York, NY,
2007ꢀ2010.
B
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€
Table 1. Results of Munchnone Cyclizations
€
€
reaction with munchnone 17
reaction with munchnone 16
ratio
(syn:anti)a
yield
(%)b
ratio
(syn:anti)a
yield
(%)b
entry
R
products
products
1
H (1)
18a:18b
19a:19b
20a:20b
21b:21b
22a:22b
23a:23b
24a:24b
25a:25b
26a:26b
27a:27b
28a:28b
29a:29b
30a:30b
18a:18b
92:8
94
80
97
52
65
58
64
70
61
86
76
12
18
83
18a:18b
19a:19b
20a:20b
21b:21b
22a:22b
23a:23b
24a:24b
25a:25b
26a:26b
27a:27b
28a:28b
29a:29b
30a:30b
18a:18b
14:86
24:76
19:81
17:83
20:80
57:43
14:86
26:74
22:78
26:74
34:66
11:89
17:83
>99:1
81
71
75
45
62
50
63
67
57
67
68
7
2
4-Cl (2)
3-F (3)
95:5
3
88:12
81:19
94:6
4
4-NMe2 (4)
4-OMe (5)
5
6
4-NO2 (6)
85:15
89:11
92:8
7
4-Me (7)
8
4-CF3 (8)
9
4-Ph (9)
91:9
10
11
12
13
14
2-NO2 (10)
2-Me (11)
95:5
89:11
62:34
75:25
1:>99
2,4,6-Me (12)
anthracen-9-yl (13)
phenylacetylene
8
32
a Product ratios were determined by NMR integration; regiochemistry was determined by NOE resonance of the pyrrole ring proton. b Yields refer to
isolated products after column chromatography.
(TS2; ΔG‡ = 13.0 kcal/mol) for reaction of 17 with
nitrostyrene to give the syn product and that for reaction
of 16 (TS4; ΔG‡ = 14.2 kcal/mol) to give the anti product
are illustrated in Figure 2. Details for all transition states
are provided as SI.
For syn-selective reaction of 17 TS2 is 2.6 kcal/mol more
favored than the lowest energy transition state leading to
the anti product, while for antiselective 16 TS4 lies 1.9 kcal/
mol lower than that favoring the syn product. This is
consistent with the observed higher selectivities seen for
(EDA/B3LYP-D3/TZ2P), based on the Extended Transi-
tion State (ETS) method,14 as implemented in the ADF
computational package.15 The ETS approach partitions
the total energy of interaction (Eint, corresponding to the
activation energy) between reacting fragments at the tran-
sition state into the energy costs to deform the reagent
fragments into their transition state geometries (Eprep) and
Pauli repulsion between fragments (EPauli) as well as the
energy stabilization resulting from attractive electrostatic
interaction (Eestat) and covalent interactions (Eorb).
€
munchnone 17 (Table 1). All transition states with the NO2
group directed toward the lactone are more significantly
disfavored. Table 2 summarizes DFT predictions and
experimental outcomes. It is noteworthy that use of the
B3LYP functional without the Grimme (D3) dispersion
correction resulted in considerably higher activation bar-
riers (see SI) for these associative reactions, emphasizing
the importance of including dispersion interactions be-
tween the two reacting fragments.13 In order to examine
further the nature of the transition states, each was
subjected to a fragment energy decomposition analysis
Table 2. Summary of Experimental Observations vs Predictive
Methods
prediction
observed
FMO
16
DFT
€
munchnone
17
16
17
17
16
phenylacetylene
anti
syn
syn
anti
syn
anti
anti
syn
anti
syn
syn
anti
β-nitrostyrene
The use of this kind of method for analysis of energy
components in transition states has led to the activationꢀ
strain16 and distortionꢀinteraction17 models. Furthermore,
(11) For example: β-Nitrostyrene (HOMO ꢀ7.323 eV; LUMO
€
ꢀ3.097 eV): Munchnone 17 (HOMO ꢀ5.032 eV; LUMO ꢀ1.866 eV).
Full details are provided in the SI.
(12) Gribble, G. W.; Trujillo, H. A., unpublished results.
(13) (a) Goerigk, L.; Grimme, S. Phys. Chem. Chem. Phys. 2011, 13,
6670–6688. (b) Grimme, S.; Antony, J.; Ehrlich, S.; Krieg, H. J. Chem.
Phys. 2010, 132, 154104.
(14) (a) Ziegler, T.; Rauk, A. Inorg. Chem. 1979, 18, 1558–1565. (b)
Ziegler, T.; Rauk, A. Inorg. Chem. 1979, 18, 1755–1759.
Org. Lett., Vol. XX, No. XX, XXXX
C

implemented in ADF closely match the values of ΔG‡
obtained using the Gaussian type 6-311G basis functions
of Jaguar, and likewise predict the lowest energy transi-
tion states TS2 and TS4. For 17, the most attractive
bonding interactions Eestat and Eorb favor TS5, leading
to the anti product, consistent with FMO predictions.
However TS5 also has both the highest Pauli repulsions
and energetic cost of distortion of the reactants, driving it
above TS2, and leading to the observed selectivity. Similar
arguments pertain for reactions of 16 with nitrostyrene
(Figure 3) and for reactions of phenylacetylene with both
€
munchnones (see SI). Similar differences between FMO
and DFT predictions in addition reactions of linear 1,3-
dipoles with alkenes and alkynes havebeen reportedbyEss
and Houk as resulting from distortion effects overwhelm-
ing FMO control.18
As noted above these cycloadditions appear to have a
strong steric component. A single ortho substituent on the
phenyl ring of the nitrostyrene (entries 10, 11) is well
tolerated; the transition state likely has a degree of flex-
ibility when forming the initial bond. However, incorpora-
tion of two ortho substituents with either sp2 or sp3
carbons (entries 13 and 12, respectively) significantly
attenuates the reactivity. Presumably initial bond forma-
tion occurs next tothe now sterically congestedmesityl and
anthracenyl rings and thus proceeds sluggishly. Inaddition
to the low yields, the otherwise minor regioisomer com-
prises a higher percentage of the product mixture. These
lower selectivities are also correctly predicted by DFT.
In summary, the 1,3-dipolar cycloaddition between
Figure 3. Energy components from energy decomposition ana-
lyses of each set of transition states for reactions of 17 and 16
with nitrostyrene.
the recently established extension of the ETS method to
the evaluation of Natural Orbitals for Chemical Valence
(NOCV)18 allowed the overall orbital contribution Eorb
to be further partitioned into component contributions.
Figure 2 also shows an electron deformation density plot
of the principal NOCV component (∼75% of the total
€
munchnones and β-nitrostyrenes provides a convenient
E
orb) illustrating how electron density is redistributed
synthesis of substituted pyrroles, in a reaction with regios-
electivity that seems to be governed by steric and reactant
reorganizational factors rather than FMO overlap.
Further synthetic and computational investigations into
the electronic and steric parameters of these types of
reactions are underway and will be reported in due course.
between fragments in the lowest energy transition states
for each system. It is clear that the major contributor
€
involves donation from munchnone to styrene, as ex-
pected from HOMO/LUMO energy considerations. A
more complete picture emerges from Figure 3, which
shows plots of the energy components for the transition
states for reactions of 17 and 16 with nitrostyrene. It is
important to note that the values of Eint derived by this
method using the Slater type TZ2P basis functions
Acknowledgment. R.P.H. acknowledges the National
Science Foundation for operating grant funds that helped
purchase some computational resources at Dartmouth. J.
M.L. acknowledges a GAANN Fellowship from the U.S.
Department of Education. G.W.G. acknowledges support
by the Donors of the Petroleum Research Fund (PRF),
administered by the American Chemical Society, and
support by Wyeth.
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Supporting Information Available. Experimental pro-
cedures, computational methods and data, and spectro-
scopic data. This material is available free of charge via
the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
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