Structure-reactivity relationships: reactions of a 5-substituted aziadamantane in a resorcin[4]arene-based cavitand

Article abstract of DOI:10.1021/ol902667a

(Figure presented) The complexatlon properties of two novel C5-substituted adamantanediazirines within the resorcin[4]arene-based cavitand 4 were investigated In DMSO-d₆, revealing that binding Is up to 1.4 kcal/mol stronger for halogenated adamantanediazirines when compared with the unsubstituted species. The thermal behavior of 5-bromo-2-aziadamantane (3) was investigated by DSC analysis as the first representative of the adamantanediazirine family In the neat solid state, as well as encapsulated within the aromatic cavity of cavitand 4. In the solid phase, the reactions of photolytically or thermolytically generated 5-bromo-2-adamantanylldene (11) can be controlled by complexation within cavitand 4.

Full text of DOI:10.1021/ol902667a

ORGANIC
LETTERS
2010
Vol. 12, No. 2
332-335
Structure-Reactivity Relationships:
Reactions of a 5-Substituted Aziadamantane
in a Resorcin[4]arene-based Cavitand
Gerald Wagner, Wolfgang Knoll, Michael M. Bobek, Lothar Brecker,
Hendrikus W. G. van Herwijnen, and Udo H. Brinker*,†,‡
Institute of Organic Chemistry, UniVersity of Vienna, Wa¨hringer Strasse 38,
A-1090 Vienna, Austria
udo.brinker@uniVie.ac.at
Received November 19, 2009
ABSTRACT
The complexation properties of two novel C5-substituted adamantanediazirines within the resorcin[4]arene-based cavitand 4 were investigated
in DMSO-d6, revealing that binding is up to 1.4 kcal/mol stronger for halogenated adamantanediazirines when compared with the unsubstituted
species. The thermal behavior of 5-bromo-2-aziadamantane (3) was investigated by DSC analysis as the first representative of the
adamantanediazirine family in the neat solid state, as well as encapsulated within the aromatic cavity of cavitand 4. In the solid phase, the
reactions of photolytically or thermolytically generated 5-bromo-2-adamantanylidene (11) can be controlled by complexation within cavitand 4.
The encapsulation of reactive intermediates inside the
nanoscopic cavity of suitable host molecules can increase
their lifetime and hence facilitate their spectroscopic char-
acterization and/or alter their reaction behavior.1 Classic
examples of reactive species like 1,3-cyclobutadiene,2 ben-
zyne,3 or phenylnitrene4 have been spectroscopically analyzed
in complexed form. We have investigated the influence of
complexation of carbenes and phenylnitrene in the cavity of
cyclodextrins5 and a resorcin[4]arene-based cavitand.6 Further-
more, the supramolecular chemistry of native adamantanylidene
and 5-hydroxy-2-adamantanylidene (20) has been studied.
Moreover, the reactions of electron-donating and electron-
withdrawing substituents at C5 have been investigated
experimentally by Brinker’s and theroretically by Tomoda’s
group to gain a deeper understanding of the observed
diastereoselectivities of such adamantanylidenes in intra- and
intermolecular reactions.7
Herein, we report the reactions of carbenes 10 and 11
generated from two hitherto unknown diazirines, i.e., 5-chloro-
2-aziadamantane (2) and 5-bromo-2-aziadamantane (3).
Carbenes 10 and 11 were generated by gas-phase pyrolysis,
* Corresponding author. Phone: +43-1-4277-52121. Fax: +43-1-4277-
52140.
(5) (a) Mieusset, J.-L.; Wagner, G.; Su, K.-J.; Steurer, M.; Pacar, M.;
Abraham, M.; Brinker, U. H. Eur. J. Org. Chem. 2009, 5907. (b) Mieusset,
J.-L.; Krois, D.; Pacar, M.; Brecker, L.; Giester, G.; Brinker, U. H. Org.
Lett. 2004, 6, 1967. (c) Krois, D.; Brecker, L.; Werner, A.; Brinker, U. H.
AdV. Synth. Catal. 2004, 346, 1367. (d) Krois, D.; Bobek, M. M.; Werner,
A.; Ka¨hlig, H.; Brinker, U. H. Org. Lett. 2000, 2, 315. (e) Brinker, U. H.;
Buchkremer, R.; Kolodziejczyk, M.; Kupfer, R.; Rosenberg, M.; Poliks,
M. D.; Orlando, M.; Gross, M. L. Angew. Chem., Int. Ed. 1993, 32, 1344.
(6) Wagner, G.; Arion, V. B.; Brecker, L.; Krantz, C.; Mieusset, J.-L.;
Brinker, U. H. Org. Lett. 2009, 11, 3056.
† Chair of Physical Organic and Structural Chemistry.
‡ Carbene Rearrangements 78. For Part 77 see reference 5a.
(1) Yoshizawa, M.; Klosterman, J. K.; Fujita, M. Angew. Chem., Int.
Ed. 2009, 48, 3418.
(2) Cram, D. J.; Tanner, M. E.; Thomas, R. Angew. Chem., Int. Ed.
1991, 30, 1024.
(3) Warmuth, R. Angew. Chem., Int. Ed. 1997, 109, 1406.
(4) Warmuth, R.; Makowiec, S. J. Am. Chem. Soc. 2007, 129, 1233.
10.1021/ol902667a  2010 American Chemical Society
Published on Web 12/17/2009

DSC (differential scanning calorimetry), and photolysis in
the solid state.
yield, according to NMR and GC/MS analysis. The diagram
(Figure 2) shows a sharp endothermic peak at 95 °C (onset:
In contrast, the binding properties of the supramolecular
complexes between cavitand 4 and adamantanediazirines 2
and 3 were investigated in the liquid phase (Figure 1).
Figure 2. DSC analysis of diazirines 2, 3, and complex 3@4.
Figure 1. C5-substituted 2-aziadamantanes 2 and 3 investigated
and resorcin[4]arene-based cavitand 4.
94 °C) corresponding to melting (m), followed by a broad
exothermic transition assigned to thermal decomposition and
reaction (onset: 118 °C). DSC analysis of 5-chloro-2-
aziadamantane (2) provides similar results and gives solely
5-chloro-2-adamantanone azine (16) in 37% yield. In that
case, the broad decomposition peak (onset: 122 °C) overlaps
with a small peak due to melting (onset: 107 °C).
Most probably, azine 16 is formed via reaction of the
thermolytically generated singlet carbene with its nitroge-
nated precursor adjacent in the crystal lattice.10
Furthermore, the modified reaction behavior of 5-bromo-
2-adamantanylidene (11), encapsulated in cavitand 4, has
been investigated in the solid state by DSC analysis and
irradiation experiments. Resorcin[4]arene-based cavitand 4
possesses a lipophilic and preorganized cavity, deep-func-
tionalized with a ring of weakly acidic benzalic C-H groups
capable of forming multiple hydrogen bonds with a large
variety of guest molecules, preferentially halogen-substituted
adamantanes.8
In contrast, vacuum pyrolysis at ca. 230-270 °C of 3
affords nearly quantitatively the diastereomeric didehy-
droadamantanes 13 and 15 (ratio: 89:11), originating from
an intramolecular 1,3 C-H insertion of carbene 11. Pyrolysis
of 5-chloro-2-aziadamantane (2) under the same conditions
gives the anticipated didehydroadamantanes 12 and 14, again
in quantitative yield in a ratio of 90:10 (Scheme 2).
The novel diazirines 2 and 3 were synthesized following
established procedures.9 Ketones 6 and 7 were treated with
hydroxylamine-O-sulfonic acid (HOSA) followed by direct
oxidation to afford the corresponding diazirines 2 and 3 in
27 and 48% yield, respectively (Scheme 1).
Scheme 1
Scheme 2
DSC analysis of 5-bromo-2-aziadamantane (3) afforded
exclusively 5-bromo-2-adamantanone azine (17) in 47%
(7) (a) Bobek, M. M.; Brinker, U. H. J. Am. Chem. Soc. 2000, 122,
7430. (b) Knoll, W.; Bobek, M. M.; Kalchhauser, H.; Rosenberg, M. G.;
Brinker, U. H. Org. Lett. 2003, 5, 2943. (c) Kaneno, D.; Tomoda, S. Org.
Lett. 2003, 5, 2947. (d) Knoll, W.; Bobek, M. M.; Giester, G.; Brinker,
U. H. Tetrahedron Lett. 2001, 42, 9161.
(8) (a) Gibb, C. L. D.; Stevens, E. D.; Gibb, B. C. J. Am. Chem. Soc.
2001, 123, 5849. (b) Laughrey, Z. R.; Gibb, C. L. D.; Senechal, T.; Gibb,
B. C. Chem.sEur. J. 2003, 9, 130.
According to calculations, the carbene bridge in several
adamantanylidenes swings back and forth between the syn
Org. Lett., Vol. 12, No. 2, 2010
333

and anti side (Figure 3a).7c Ab initio calculations of
5-hydroxy-2-adamantanylidene (20) and 5-amino-2-adaman-
Table 1. Yieldsa in % and Product Ratios in Parentheses
12 + 14
reaction
or
conditions
13 + 15
18 + 19
16 or 17 6 or 7
DSC
2
3
37
47
3@4
82
pyrolysis
2
3
excl.b (90:10)c
excl.b (89:11)c
photolysis
2
tr.d
tr.d
25
>95
>95
tr.d
tr.d
1
3
3@4e
74 (65:35)f
a Unless otherwise noted, the yields were determined by NMR analysis
of the crude product mixtures. b Exclusively. c Error: (2%. Ratios were
ascertained by direct injection of 2 and 3 into the injector of a GC at 270
°C. d “Traces”. e Conversion: 100%, determined by HPLC analysis. f Error:
(5%, determined by NMR and GC/MS analysis.
Figure 3. (a) Swinging motion of carbene bridge in adamanta-
nylidenes. (b) Signal assignment in 5-bromo-2-aziadamantane (3).
(c) Structure of 3@4 in DMSO-d6 determined by ROESY NMR
spectroscopy.
in almost quantitative yield with traces of 5-bromo-2-
adamantanone (7) and insertion products 13 and 15. Similar
results were obtained after photolysis of 5-chloro-2-aziada-
mantane (2) under the same conditions as above: azine 16
is formed almost exclusively, again with traces of ketone 6
and didehydroadamantanes 12 and 14. While for the azine
formation various mechanisms have been discussed,16 the
involvement of an intermediate carbene-diazirine ylide was
proven.17
tanylidene (21) show that the bridge carrying the divalent
carbon in its lowest-energy state is bent away from the
substituent by an average of θ ) 17.1° and 16.5°, respec-
tively (Figure 3a).11,7a,c,d The unoccupied p-orbital of the
carbene (LUMO) interacts with both the C1-C8 and the
C3-C10 bonds, which due to the electronegatively charged
heteroatoms at C-5 are more electron-rich than the opposite
C1-C9 and C3-C4 bonds. The electronegative substituents
Cl and Br induce a similar distortion of the “carbene bridge”
toward the anti side with θ ) 17.1° and 16.9°, respectively.12
The observed diastereoselectivities from the 1,3 C-H
insertions of 10 and 11 can be explained best by the
principle of least motion.13 This would make the insertions
more likely toward the anti side of the carbenes affording
preferentially symmetric products 12 and 13, respectively.
The similarity in the selectivity for adamantanylidenes 10
and 11 may be attributed to similar electronegativities and
field effects of chlorine and bromine.14
With diazirines 1, 2, and 3, cavitand 4 forms 1:1 complexes
in which exchange is slow on the NMR time scale (400
MHz) in DMSO-d6 (Table 2). The Gibbs free energy of
a
1
Table 2. H NMR Association Constants Ka and Gibbs Free
Energies of Complexation in DMSO-d6 at 298 K
complex
Ka [M-1
]
∆G0 [kcal/mol]
1@4
2@4
3@4
630
2130
6480
-3.8
-4.5
-5.2
When irradiating diazirines, three competing pathways can
take place. The corresponding carbenes may be generated
directly by extrusion of nitrogen or indirectly after rear-
rangement to the diazo compounds. Third, a rearrangement
in the excited state (RIES) may occur.15
a Error: (15%. Values were determined by Ha integration (Figure 3c).
Broadband irradiation (λ > 300 nm, 4-5 h) of diazirine 3
in the solid state at 10 °C afforded the anticipated azine 17
binding increases from unsubstituted adamantanediazirine (1)
to 5-chloro-2-aziadamantane (2), to 5-bromo-2-aziadaman-
tane (3), where complexation is 1.4 kcal/mol stronger than
for 1.
Most probably, binding of halogenated aziadamantanes is
enhanced as a result of hydrogen bond formation to the
(9) (a) Schmitz, E. Chemistry of Diazirines; Liu, M. T. H., Ed.; CRC:
Boca Raton, FL, 1987; Vol. 1, p 57. (b) Isaev, S. D.; Yurchenko, A. G.;
Stepanov, F. N.; Kolyada, G. G.; Novikov, S. S.; Karpenko, N. F. J. Org.
Chem. USSR 1973, 9, 745. (c) Schmitz, E.; Ohme, R. Chem. Ber. 1962,
95, 795. (d) Schmitz, E.; Ohme, R. Chem. Ber. 1961, 94, 2166.
(10) Sanrame, C. N.; Suhrada, C. P.; Dang, H.; Garcia-Garibay, M. A.
J. Phys. Chem. A 2003, 107, 3287.
(15) (a) Platz, M. S. AdVances in Carbene Chemistry; Brinker, U. H.,
Ed.; JAI: Stamford, CT, 1998; Vol. 2, p 133. (b) Merrer, D. C.; Moss,
R. A. AdVances in Carbene Chemistry; Brinker, U. H., Ed.; Elsevier:
Amsterdam, 2001; Vol. 3, p 53. (c) Bonneau, R.; Liu, M. T. H. AdVances
in Carbene Chemistry; Brinker, U. H., Ed.; JAI: Stamford, CT, 1998; Vol.
2, p 1.
(11) We define θ as the angle between the 1-2-3 plane (Figure 3a)
and the 1-3-6 plane.
(12) We are grateful to Professor S. Tomoda (University of Tokio) for
B3LYP/6-31+G-(d,p) calculations.
(13) Hine, J. J. Org. Chem. 1966, 31, 1236.
(14) Adcock, W.; Cotton, J.; Trout, N. A. J. Org. Chem. 1994, 59,1867
and citations therein.
(16) Shustov, G. V.; Liu, M. T. H.; Houk, K. N. Can. J. Chem. 1999,
77, 540.
334
Org. Lett., Vol. 12, No. 2, 2010

centrally positioned benzalic hydrogens (Ha), in a halogen
group down orientation. This effect continues to grow as
the halogen atom increases in size and polarizability.8
ROESY NMR spectroscopy (Figure 3c) corroborates the
supposed orientation for 3@4. NOE signals derive from H7
(Figure 3b) to Hc and from H6 and H9a/H4a to Ha and Hb.
Bromine-substituted diazirine 3 was selected for encap-
sulation within cavitand 4 in the solid state, due to the
expected strong influence of complexation on the innermo-
lecular reaction behavior of thermolytically or photolytically
generated carbene 11.
Complex 3@4 is formed in a 1:1 stoichiometry in up to
74% yield by crystallization from a saturated solution of
cavitand 4 in CH2Cl2 with a 3-fold excess of 5-bromo-2-
aziadamantane (3). Single-crystal X-ray diffraction showed
that the bromine atom of 3 is centrally located between the
benzalic Ha protons of cavitand 4.18
DSC analysis of 3@4 (Figure 2) reveals one broad
exothermic peak (onset: 131 °C) corresponding to thermal
denitrogenation and reaction. Since the onset for denitroge-
nation of neat 5-bromo-2-aziadamantane (3) already starts
at 118 °C, complexation seems to lead to an enhancement
of the thermal stability of the diazirine. NMR and GC/MS
analysis after DSC provides definite proof for the exclusive
formation of intramolecular insertion products 13 and 15 in
a combined yield of 82% (ratio: 90-95:10-5 by GC/MS
analysis).19
13 and 15 (ratio: 90-95:10-5). While 5-bromo-2-adaman-
tanone (7) was found only in traces, the large amount of
alcohols formed probably has to be attributed to the presence
of fortuituous water molecules tightly attached to the
complex, which could not be removed completely. The
predominant formation of (Z)-alcohol 18 over (E)-isomer 19
(Table 1) probably results from the distortion of the geometry
of 11. This makes the approach of the reagent more favorable
from the more accessible syn site (see Figure 3a). However,
18 and 19 can result either from a direct insertion of carbene
11 into the O-H bonds of a water molecule or from a
protonation of diazo compound 9 and subsequent loss of
nitrogen, following a carbocation mechanism.20
The unique large amount of didehydroadamantanes 13 and
15 formed during photolysis or thermolysis of 3@4 can be
attributed most probably to an ideal spatial separation of the
generated carbene from other reaction partners inside the
cavity of 4. Thus, the reaction inside cavitand 4 is largely
controlled by packing motives of the complex. It might be
anticipated that incarceration of 11 does influence the ratios
found for 13 and 15. This effect, however, is hard to pinpoint
since 15, the minor isomer isolated, is difficult to distinguish
anyway. Our results suggest only a very weak influence on
the ratios found.
In summary, the association properties of novel 5-bromo-
2-aziadamantane (3) encapsulated in cavitand 4 were inves-
tigated in solution and in the solid phase. The formation of
substantial amounts of didehydroadamantanes (13, 15) after
photolysis or thermolysis of complex 3@4 can obviously
be attributed to an optimal arrangement of carbene 11 within
the confined space of cavitand 4.
Broadband irradiation (λ > 300 nm, 5 h) of 3@4 in the
solid state at 10 °C (Scheme 3) afforded as major products
Scheme 3
Acknowledgment. We are indebted to the FWF in
Österreich (Project P12533-CHE) for financial support and
to Professor V. B. Arion (Institute of Inorganic Chemistry,
University of Vienna, Austria) for his efforts to determine
the structure of 3@4 by single-crystal X-ray diffraction. We
are grateful to Ing. H. Fartely (Department of Physical
Chemistry, University of Vienna, Austria) for granting access
to DSC devices.
the diastereomeric alcohols 18 and 19 in a combined yield
of 74% as well as 25% of the two didehydroadamantanes
Supporting Information Available: Experimental pro-
cedures and details of NMR studies. This material is available
free of charge via the Internet at http://pubs.acs.org.
(17) (a) Bonneau, R.; Hellrung, B.; Liu, M. T. H.; Wirz, J. J. Photochem.
Photobiol. A: Chem. 1998, 116, 9. (b) Bonneau, R.; Liu, M. T. H. J. Phys.
Chem. A 2000, 104, 4115.
OL902667A
(18) Due to severe disorder of diazirine 3, the quality of the X-ray data
was too low for publication. However, the position of the bromine atom of
3 inside cavitand 4 is deemed to be assured.
(20) (a) Kirmse, W. AdVances in Carbene Chemistry; Brinker, U. H.,
Ed.; Elsevier: Amsterdam, 2001; Vol. 3, p 1. (b) Pezacki, J. P.; Shukla, D.;
Lusztyk, J.; Warkentin, J. J. Am. Chem. Soc. 1999, 121, 6589.
(19) A more exact determination of the ratio was not possible since
both peaks are not completely baseline-separated and show a tailing.
Org. Lett., Vol. 12, No. 2, 2010
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