Structural evidence that alkoxy substituents adopt electronically preferred pseudoaxial orientations in six-membered ring dioxocarbenium ions

Article abstract of DOI:10.1021/ja050830i

Nucleophilic substitution reactions of monosubstituted tetrahydropyran acetals give opposite selectivities when a remote alkyl or alkoxy substituent is present at C-4. Coupled with earlier computational reports on the intermediates of glycosylation reacti

Full text of DOI:10.1021/ja050830i

Published on Web 03/26/2005
Structural Evidence that Alkoxy Substituents Adopt Electronically Preferred
Pseudoaxial Orientations in Six-Membered Ring Dioxocarbenium Ions
Stephen Chamberland, Joseph W. Ziller, and K. A. Woerpel*
Department of Chemistry, UniVersity of California, IrVine, California 92697-2025
Received February 8, 2005; E-mail: kwoerpel@uci.edu
An electronegative substituent can exert considerable influence
over reactivity in tetrahydropyrans. For example, remote hydroxyl
substituents accelerate glycoside hydrolysis when they are axial.1
In addition, we reported a dramatic contrast in selectivity for
nucleophilic substitution reactions of tetrahydropyran acetals with
remote alkyl or alkoxy substituents.2 These counterintuitive results
inspired us to enhance our understanding of how the spatial
orientation and electronic nature of an alkoxy substituent influence
the structure of an oxocarbenium ion intermediate.3
The conformations of the intermediates in these reactions can
only be surmised based on product analysis, but computational
efforts offer insight into their structure. From their theoretical
Figure 1. Crystal structures of dioxocarbenium ions 5 and 9.
investigations on the likely intermediates involved in glycosylation
reactions, Bowen and Miljkovic´ concluded that an electronegative
C-4 substituent in tetrahydropyrylium ion 2 adopts a pseudoaxial
orientation (eq 1).4 This arrangement best promotes effective
dioxocarbenium ion salts 5 and 6 intended to resemble the
intermediates leading to highly selective C-glycosylation reactions2
of acetals.9,10 In this Communication, we provide structural evidence
that a C-4 alkoxy substituent assumes a pseudoaxial orientation in
dioxocarbenium ion 5, illustrating the conformational preference
we believe led to high selectivity in our previous work with related
oxocarbenium ions.2
through-space electrostatic stabilization of the carbocation.5 Elec-
tronically neutral alkyl substituents cannot stabilize these cationic
intermediates, so the conformational preferences parallel those of
uncharged systems. Although the theoretical studies support and
explain the selectivities we documented,2 no experimental proof
of the structures of these intermediates exists. Consequently, the
selectivities we observed may reflect the relative reactivities of the
conformers in solution and not their comparative ground-state
energies.
To address this problem directly, we sought evidence of the
conformational preferences of these intermediates in the ground
state. Establishing the ground-state preference among low-energy
conformers by observing a highly reactive oxocarbenium ion
intermediate would be difficult because its lifetime under conditions
normally used in organic synthesis is extremely short (∼10-12 s).6
Because dioxocarbenium ions are more stable than oxocarbenium
ion intermediates, investigation of these ions might provide
information about their short-lived counterparts provided that they
are structurally similar.7
The lowest-energy structure for 5 predicted by theory is the major
conformation in solution and in the solid state. Spectroscopic
analysis (1H NMR, 500 MHz, CD2Cl2) of 5 reveals a sextet11 (δ
4.28 ppm, J ) 2.0 Hz) corresponding to the C-4 methine proton.
This multiplicity can only exist when the C-4 substituent is
pseudoaxial. These coupling constants can also be compared to
coupling constants reported for the C-4 methine protons of the
structurally reminiscent and conformationally rigid lactone rings
in decalones 7 and 8.12 Even more powerful than the spectroscopic
data is the X-ray crystal structure which unambiguously proves the
pseudoaxial orientation of the C-4 alkoxy substituent in tetrahy-
dropyrylium ion 5 (Figure 1).
Establishing the structural homology between ephemeral oxo-
carbenium ions and isolable dioxocarbenium ions was paramount.
A computational examination (MP2/6-31G*)8 of C-4 alkyl- and
C-4 alkoxy-substituted dioxocarbenium ions 3 and 4 revealed that
they exhibit conformational preferences similar to those of cations
reported by Bowen and Miljkovic´ (eq 2).4 Accordingly, we prepared
A similar strategy of crystallographic analysis for C-4 methyl-
substituted cation 6 was unsuccessful. On the other hand, the
pseudoequatorial orientation of the C-4 methyl substituent in a
derivative (9) resulting from nucleophilic attack of 6 by its δ-lactone
precursor was confirmed by X-ray crystallography (Figure 1).13 In
addition, cation 6 was compared to a similar dioxocarbenium ion
salt, 10-SbCl6. Childs first reported the preparation of 10 and used
9
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10.1021/ja050830i CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
X-ray crystallography to establish that the C-5 methyl substituent
was pseudoequatorial.14 We also prepared this salt9 and compared
coupling constant data obtained for the pseudoaxial C-5 methine
In conclusion, we have proven that a C-4 alkoxy substituent
adopts a pseudoaxial orientation in the ground-state structure of
dioxocarbenium ion 5 in solution and in the solid state. This result
supports our earlier hypothesis that conformer 2 is the ground-
state structure of the intermediate leading to highly trans-selective
reactions of C-4 alkoxy-substituted tetrahydropyran acetates.2,4 The
origin of this preference likely derives from through-space elec-
trostatic effects as evidenced by computational, spectroscopic, and
crystallographic data.
Acknowledgment. This research was supported by the National
Institutes of Health, National Institute of General Medical Sciences
(GM-61066). K.A.W. thanks Johnson & Johnson and Merck
Research Laboratories for awards to support research. Dr. John
Greaves and Dr. John Mudd are acknowledged for mass spectro-
metric data.
1
proton of 10 to the C-4 methine proton of 6 using high-field H
NMR spectroscopy (500 MHz, CD2Cl2). Two large coupling
constants corresponding to the two vicinal diaxial relationships
involving Hb were present in the solution conformer of 6. These
coupling constants suggest that the methyl substituent is pseu-
doequatorial, in direct contrast to the preferred pseudoaxial orienta-
tion of the C-4 alkoxy substituent in cation 5.
Supporting Information Available: Experimental procedures,
characterization data for new compounds, spectral data for selected
compounds (PDF), and X-ray diffraction data (CIF). This material is
available free of charge via the Internet at http://pubs.acs.org.
We believe that the orientation of the C-4 alkoxy substituent in
5 is a result of electrostatic effects,4 not anchimeric assistance.15
Even though it provides the same selectivity hypothesized to arise
from through-space cation stabilization, the attraction between the
C-4 substituent and C-1 in 5 does not necessitate the formation of
a covalent bond. Anchimeric assistance would afford bridged
bicyclic cation 11. Examination of the X-ray structure of 5 reveals
that 3.301 Å separates C-1 and O-3. Within a structure such as 11,
the median carbon-oxygen bond length in the trivalent oxonium
ion comprising C-1, C-4, C-8, and O-3 should be approximately
1.5 Å.16 In addition, oxonium ion 11 is not an energy minimum
according to computational methods.8 In combination with the
X-ray, spectroscopic, and computational data we present for
dioxocarbenium ion 5, the selectivity trend we observed within a
series of nucleophilic substitution reactions of C-4 halogen-
substituted acetates (trans selectivity decreases down the series F
> Br > Cl > I)2a is most consistent with conformational stability
derived from through-space electrostatic interactions present in the
intermediate, oxocarbenium ion 2.4
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