Stereochemistry of oxachlorocarbene SNi reactions

Article abstract of DOI:10.1021/ol050185k

(Chemical Equation Presented) 3-Nortricyclyloxychlorocarbene and trans-4-methylcyclohexyloxychlorocarbene both fragment in hydrocarbon solvents with extensive loss of stereochemical integrity to the corresponding chlorides via competitive and nearly isoenergetic S_Ni-like transition states.

Full text of DOI:10.1021/ol050185k

ORGANIC
LETTERS
2005
Vol. 7, No. 7
1371-1374
Stereochemistry of Oxachlorocarbene
SNi Reactions
Robert A. Moss,*,† Xiaolin Fu,† Jingzhi Tian,† Ronald Sauers,*,† and Peter Wipf*,‡
Department of Chemistry and Chemical Biology, Rutgers, The State UniVersity of
New Jersey, New Brunswick, New Jersey 08903, and Department of Chemistry,
UniVersity of Pittsburgh, Pittsburgh, PennsylVania 15260
moss@rutchem.rutgers.edu
Received January 28, 2005
ABSTRACT
3-Nortricyclyloxychlorocarbene and trans-4-methylcyclohexyloxychlorocarbene both fragment in hydrocarbon solvents with extensive loss of
stereochemical integrity to the corresponding chlorides via competitive and nearly isoenergetic SNi-like transition states.
The contemporary mechanism for the SNi reaction1 (“sub-
stitution, nucleophilic, internal”) is formulated in terms of
ion pairs.2-4 In the iconic case of chlorosulfite decomposition,
the initial ion pairs are 1 from secondary or tertiary substrates
and 2 from primary substrates.2b,4a In either case, the
“internal” chloride nucleophile ultimately reacts with a cation
(R+ or ROSO+) to form the product RCl.
The related fragmentations of alkoxychlorocarbenes (eq
1) can also be formulated in terms of ion pairs.5 When the
cation is sufficiently stable and the solvent is polar,
ROC¨ Cl f [R+-OCCl] f RCl + CO
(1)
solvent-equilibrated [R+Cl-] ion pairs intervene,6 but as R+
becomes less stable and the solvent less polar, the stability
and lifetime of the ion pairs decrease. In a vacuum, rare gas
matrices, or pentane, calculations point to effectively “con-
certed” decompositions of ROCCl (or fragmentation that
proceeds through very short-lived ion pairs).7 One imagines
that such ROCCl f RCl transformations would feature
nearly complete frontside fragmentation and concomitant
stereochemical retention. For example, the fragmentation of
R-deuteriobenzyloxychlorocarbene to R-deuteriobenzyl chlo-
ride in acetonitrile, a reaction likely to involve a short-lived
ion pair,7a occurs with at least 60% net retention.8
The stereochemical outcomes of SNi reactions vary and
depend on both the nature of R and the solvent: secondary
or tertiary R groups and polar solvents favor retention via
front-side return of chloride, whereas primary R groups and
hydrocarbon solvents favor inverting, backside attack of
chloride.2,4 Shreiner et al. designated these mechanistic
alternatives as “SNi” and “SN2i”, respectively.4a
In remarkable contrast, however, computational studies of
the fragmentation of cyclic, secondary ROCCl reveal two
† Rutgers University.
‡ University of Pittsburgh.
(1) Cowdrey, W. A., Hughes, E. D.; Ingold, C. K.; Masterman, S.; Scott,
A. D. J. Chem. Soc. 1937, 1252.
(5) Moss, R. A. Acc. Chem. Res. 1999, 32, 969.
(6) Moss, R. A.; Zheng, F.; Fede´, J.-M.; Johnson, L. A. Sauers, R. R. J.
Am. Chem. Soc. 2004, 126, 12421.
(7) (a) Moss, R. A.; Ma, Y.; Zheng, F.; Sauers, R. R.; Bally, T.; Maltsev,
A.; Toscano, J. P.; Showalter, B. M. J. Phys. Chem. A 2002, 106, 12280.
(b) Moss, R. A.; Sauers, R. R.; Zheng, F.; Fu, X.; Bally, T.; Maltsev, A. J.
Am. Chem. Soc. 2004, 126, 8466.
(2) (a) Lewis, E. S.; Boozer, C. E. J. Am. Chem. Soc. 1952, 74, 308. (b)
Lewis, E. S.; Boozer, C. E. J. Am. Chem. Soc. 1953, 75, 3182.
(3) Wiberg, K. B.; Shryne, T. M. J. Am. Chem. Soc. 1955, 77, 2774.
(4) (a) Schreiner, P. R.; Schleyer, P. v. R.; Hill, R. K. J. Org. Chem.
1993, 58, 2822. (b) Schreiner, P. R.; Schleyer, P. v. R.; Hill, R. K. J. Org.
Chem. 1994, 59, 1849.
(8) Moss, R. A.; Kim, H.-R. Tetrahedron Lett. 1990, 31, 4715.
10.1021/ol050185k CCC: $30.25
© 2005 American Chemical Society
Published on Web 03/03/2005

Figure 1. B3LYP/6-31G(d) transition states for the fragmentation of carbene 3 to chloride 4 with retention (TS A) or inversion (TS B);
cf. ref 9.
transition states of comparable energies that, by intrinsic
reaction coordinate (IRC) methodology, lead directly to either
retained or inverted RCl by frontside or backside fragmenta-
tion. Ion pairs are not involved as energy minima along the
reaction coordinates.
nortricyclanol was converted to the corresponding isouronium
salt with cyanamide and methanesulfonic acid,9,13 and the
latter was oxidized to diazirine 6 with aqueous NaOCl.9,14
For example, in our study of the fragmentation of
3-nortricyclyloxychlorocarbene (3), we observed that 3-nortri-
cyclyl chloride (4) was the exclusive product in pentane and
that rearranged products were produced in solvents of
increasing polarity.9
Diazirine 6 was decomposed photolytically (λ > 320 nm)
or thermally at 25 °C in cyclohexane-d12, CDCl3, or CD3-
CN. In cyclohexane (as in pentane9), carbene 3 formed from
6 and fragmented to 3-nortricyclyl chloride 4, accompanied
by traces of exo-5-chloro-2-norbornene (7).15 With greater
solvent polarity, the yield of 7 rose slightly: 5-7% in CDCl3
and 4-7% in CD3CN.
Defining the stereochemistry of the 3 f 4 conversion
requires knowledge of the absolute configurations and
rotation of chloride 4, which are unknown. We computed
this information. The initial assignment of a natural product
by a linear-response HF-based calculation was made in
1998,16 and there has since been a dramatic increase in the
application of modern computational methods for [R]D
calculations of organic molecules.17 There are now many
successful cases in which an absolute configuration has been
assigned by ab initio theory.18
This led us to propose a spectrum of ion pair behavior for
these reactions, with those in pentane proceeding via a
limiting SNi process. Our suggestion was supported by
computational results that gave rise to two fragmentation
transition states of comparable energy, one leading to
retention of configuration (∆H* ) 14.2 kcal/mol), as
determined by analysis by IRC methodology, and the other
to inversion of configuration (∆H* ) 14.8 kcal/mol); see
transition states A and B, respectively, in Figure 1.9
The counterintuitive implication is that chiral carbene 3
should yield chloride 4 with extensive racemization in
pentane not because of stereochemical randomization within
an intermediate ion pair but because of competitive frontside
or backside SNi fragmentations. Here we describe experi-
mental tests of this idea in the nortricyclyl and cyclohexyl
systems.
(12) Based upon [R]20D -22.3 (c 1.0, CHCl3) for 54.7% ee (S)-5, which
extrapolates to [R]20 -40.8 in CHCl3 for the optically pure material:
D
Hirose, Y.; Anzai, M.; Saitoh, M.; Naemura, K.; Chikamatsu, H. Chem.
Lett. 1989, 1939. A value of [R]20D -40 (CHCl3) was reported by: Kirmse,
W.; Kno¨pfel, N. J. Am. Chem. Soc. 1976, 98, 4672.
(13) Moss, R. A.; Kaczmarczyk, G.; Johnson, L. A. Synth. Commun.
2000, 30, 3233.
exo-Norbornene oxide10 was converted to (S)-(-)-nortri-
cylanol, (S)-(-)-5, by reaction with the Li salt of (S,S)-bis-
(1-phenylethyl)amine in ether.11 Our sample had [R]25D -19.0
(c 5.0, CHCl3), corresponding to an ee of 46.5%.12 The
(14) Graham, W. H. J. Am. Chem. Soc. 1965, 87, 4396.
(15) Up to 14% of the dimer of carbene 3 was also formed.
(16) Kondru, R. K.; Wipf, P.; Beratan, D. N. J. Am. Chem. Soc. 1998,
120, 2204.
(17) (a)Kondru, R. K.; Wipf, P.; Beratan, D. N. Science 1998, 282, 2247.
(b) Kondru, R. K.; Chen, C. H.-T.; Curran, D. P.; Beratan, D. N.; Wipf, P.
Tetrahedron: Asymmetry 1999, 10, 4143. (c) Ribe, S.; Kondru, R. K.;
Beratan, B. N.; Wipf, P. J. Am. Chem. Soc. 2000, 122, 4608. (d) Specht,
K. M.; Nam, J.; Ho, D. M.; Berova, N.; Kondru, R. K.; Beratan, D. N.;
Wipf, P.; Pascal, R. A.; Kahne, D. J. Am. Chem. Soc. 2001, 123, 8961.
(18) For a recent review, see: Polavurapu, P. L. Chirality 2002, 14, 768.
For a recent application, see: Giorgio, E.; Maddau, L.; Spanu, E.; Evidente,
A.; Rosini, C. J. Org. Chem. 2005, 70, 7.
(9) Moss, R. A.; Ma, Y.; Sauers, R. R.; Madni, M. J. Org. Chem. 2004,
69, 3628.
(10) Walborsky, H. M.; Loncrini, D. F. J. Am. Chem. Soc. 1954, 76,
5396.
(11) Hodgson, D. M.; Lee, G. P.; Marriott, R. E.; Thompson, A. J.;
Wisedale, R.; Witherington, J. J. Chem. Soc., Perkin Trans. 1 1998, 2151.
1372
Org. Lett., Vol. 7, No. 7, 2005

Figure 2. B3LYP/6-31G(d) transition states for the fragmentation of cyclohexyloxychlorocarbene to cyclohexyl chloride with inversion or
retention. See Supporting Information for a more complete rendering with IRC intermediate structures.
The structure of chloride 4 was minimized at the DFT-
RB3LYP level with a 6-31G(d) basis set, and the optical
rotation value at the sodium D line was calculated with
RB3LYP/6-311++G(2d,p) from the Gaussian 03 suite.19 The
calculations predict [R]D -114 for (S)-(4) in solvents such
as CH2Cl2 or CHCl3. A sample of 4, chromatographically
isolated from the fragmentation of (S)-carbene 3 in C6D12,
chlorocarbene to cyclohexyl chloride: one led to axial
cyclohexyl chloride with inversion, while the second led to
the equatorial chloride with retention; cf. Figure 2.
The corresponding ∆H* values (in vacuo) were 17.9 and
17.2 kcal/mol for the inversion and retention pathways,
respectively. IRC calculations revealed no ion pair minima
between TS and product for either pathway; both fragmenta-
tions were direct SNi-like processes. (In Supporting Informa-
tion, we provide intermediate structures along the IRC to
illustrate this point.) Again, the implication of the calculations
is that the fragmentation of equatorial cyclohexyloxychlo-
rocarbene should occur (in vacuo or in hydrocarbon solvent)
with substantial loss of stereospecificity.
We reported that menthyloxychlorocarbene, with an
equatorial OCCl unit, fragments in polar solvents (e.g., 1,2-
dichloroethane, DCE) preferentially with retention to menthyl
chloride (59%) rather than with inversion to neomenthyl
chloride (16%).24 Similarly, trans-4-methylcyclohexyloxy-
chlorocarbene (9) fragments in DCE to trans-4-methylcy-
clohexyl chloride (10) with retention (59%), in preference
to cis-4-methylcyclohexyl chloride (11) with inversion
(17%).25 Now, we have also examined the fragmentations
of 9 in pentane, benzene, and MeCN.
had [R]25 -0.117 ( 0.001°.20 The levorotatory character
D
indicated that the sample was (S)-4, so that the fragmentation
of (S)-3 (derived from (S)-5) occurred with overall retention.
GC analysis of the chloride on a 30 m × 0.25 mm
Chiraldex GTA column at 50 °C gave (S)-4/(R)-4 in ratios
of 1.09:1 (hν fragmentation of 6) or 1.05:1 (thermal
fragmentation), corresponding to an ee of 4 or 2%, respec-
tively. (An example of the GC separation is included in
Supporting Information.) Given that the initial (S)-(-)-5 from
which diazirine 6 was prepared had an ee of 46.5%, we
conclude that the fragamentation of carbene 3 to chloride 4
occurred with 4-9% net retention; i.e., with extensiVe
racemization. This result accords with the competitive
frontside and backside SNi-like fragmentations of carbene 3
predicted by theory; cf. Figure 1.
In the more polar CDCl3 or CD3CN solvents, retention in
the 3 f 4 fragmentation increased to ∼13 or ∼24%,
respectively, with comparable results from either photolytic
or thermolytic generation of 3. Here, TS A or B might evolve
into ion pair 8.9,21 Return with net retention could then
account for the marginal increase in overall retention
observed in CDCl3 or CD3CN compared with cyclohexane.
trans-4-Methylcyclohexanol was converted to the isouro-
nium methanesulfonate salt,13 and the latter was oxidized14
to diazirine 12; experimental details appear in Supporting
Information. Photolyses of 12 in several solvents gave
chlorides 10 and 11, as well as 4-methylcyclohexene, by
fragmentation of carbene 9. The products were identified by
capillary GC spiking experiments with authentic samples.
A tabular survey of the three fragmentation products appears
(21) Attempts to computationally optimize TSs A and B in simulated
dichloroethane by the polarized continuum method were unsuccessful.
(22) All structures were fully optimized by analytical gradient methods
using the Gaussian 98 and Gaussian 03 suites19 and density functional (DFT)
calculations at the 6-31G(d) level, the exchange potentials of Becke,23a and
the correlation functional of Lee, Yang, and Parr.23b Activation energies
were corrected for zero-point energy differences (ZPVE) (unscaled) and
thermal effects at 298.150 K. Vibrational analyses established the nature
of all stationary points as either energy minima (no imaginary frequencies)
or first-order saddle points (one imaginary frequency).
We next considered the cyclohexyl system. As for carbene
3,9 B3LYP/6-31G(d) calculations19,22,23 located two transition
states for the fragmentation of equatorial cyclohexyloxy-
(23) (a)Becke, A. D. J. Chem. Phys. 1993, 98, 5648. (b) Lee, C.; Yang,
W.; Paar, R. G. Phys. ReV. B. 1988, 37, 785.
(19) Gaussian 03, revision B.03; Gaussian, Inc.: Pittsburgh, PA, 2003.
See Supporting Information for the full reference.
(20) The 83.5 mg sample of 4 was dissolved in 5 mL of CDCl3 and
read in a 1 dm cell.
(24) Moss, R. A.; Johnson, L. A.; Kasprzynski, M.; Sauers, R. R. J.
Org. Chem. 2003, 68, 5114.
(25) See ref 18 in: Moss, R. A.; Ma, Y.; Sauers, R. R.; Madni, M. J.
Org. Chem. 2004, 69, 3628. The repetition (Table 1) gave 57% retention.
Org. Lett., Vol. 7, No. 7, 2005
1373

stereochemical outcome of the ROCCl f RCl conversion
for carbene 9 in pentane, like that of carbene 3 in cyclo-
hexane (see above), accords with the computationally
predicted simultaneous operation of retention and inversion
SNi-like transition states (Figures 1 and 2). The observed
stereochemical randomization is a consequence of the SNi
character of these reactions and their transition states rather
than of processes occurring within ion pair intermediates that
might intervene if more stable carbocations were generated.
The observed behavior may be reasonably general for
secondary cyclic alkoxychlorocarbenes that lack additional
carbocation-stabilizing features, at least in nonpolar sol-
vents.28,29 Extensions to open-chain secondary systems are
in progress, but the computational studies are complicated
by a plethora of available conformations.30
in Table 1; a complete tabulation of all products is included
in Supporting Information.26
Table 1. Chloride Products from Carbene 9
Acknowledgment. We are grateful to the National
Science Foundation for financial support and to the National
Center for Computer Applications for an allocation of time
on the IBM P Series 690 (CHE 030060 to RRS).
10
(%)a
11
(%)a
alkene
(%)a,b
net
solvent
retentionc
pentane
benzene
DCEd
44.8 ( 0.5
58.2 ( 0.5
57.0 ( 0.8
51.5 ( 0.8
19.3 ( 0.4
18.6 ( 0.2
17.1 ( 1.4
11.6 ( 0.2
20.8 ( 0.9
15.9 ( 0.6
17.7 ( 0.8
15.3 ( 1.6
25.5
39.6
39.9
39.9
Supporting Information Available: Experimental details
for the preparation of diazirine 12; expanded version of Table
1; expanded version of Figure 2; and chiraldex GC separation
of (S)-4 and (R)-4. This material is available free of charge
via the Internet at http://pubs.acs.org.
MeCN
a Percent yield of product. See Supporting Information for a complete
survey of the products. Errors are average deviations of 3-4 experiments.
b 4-Methylcyclohexene. c %10 - %11. d 1,2-Dichloroethane.
OL050185K
(27) Distributions of 10/11 within Table 1 are insensitive to a doubling
of diazirine concentration and are therefore unlikely to reflect SN2 reactions
of Cl- and carbene 10.
We observe extensive loss of stereospecificity in all four
solvents;27 as anticipated, this is maximized in pentane. The
(28) See: Likhotvorik, I. R.; Jones, M., Jr.; Yurchenko, A. G.; Krasutsky,
P. Tetrahedron Lett. 1989, 30, 5089.
(29) We have made similar observations in the fragmentation of
7-norbornyloxychlorocarbene to 7-norbornyl chloride.
(30) For an earlier experimental study, see: Moss, R. A.; Balcerzak, P.
J. Am. Chem. Soc. 1992, 114, 9386.
(26) Small quantities of trans-4-methylcyclohexyl formate and trans-4-
methylcyclohexyl dichloromethyl ether were also formed via carbene capture
by H2O or HCl, respectively. In MeCN, 8-11% of trans-4-methyl-N-
cyclohexylacetamide was formed by carbene attack on the solvent, followed
by hydrolysis by traces of water.
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Org. Lett., Vol. 7, No. 7, 2005