Functionalized Deep-Cavity Cavitands

Full text of DOI:10.1021/jo9909913

9286
J . Org. Chem. 1999, 64, 9286-9288
our research program directed toward the synthesis of
F u n ction a lized Deep -Ca vity Ca vita n d s
enzyme mimics possessing preorganized catalytic ma-
chinery, we report here that this strategy can also be
employed with a range of substituted benzal bromides.
Thus, by using similar or slightly modified conditions, a
range of functionalized DCCs can be synthesized in good
yield. We believe these derivatives bode well for the
formation of a broad range of potential concave hosts
possessing catalytic machinery.
Huaping Xi, Corinne L. D. Gibb, and Bruce C. Gibb*
Department of Chemistry, University of New Orleans,
New Orleans, Louisiana 70148
Received J une 22, 1999
In the development of efficient artificial enzymes1-6
possessing preorganized catalytic machinery, a primary
consideration for chemists is the choice of scaffold used
to arrange and hold the requisite functional groups in
the necessary three-dimensional array. This scaffold,
acting as a surrogate for the bulk of the main chain of
the target enzyme, must therefore possess three impor-
tant aspects. First, the chemical architecture of the
scaffold must afford it a reasonably high degree of rigidity
while simultaneously providing the necessary scale for
the orientation of the catalytic functional groups. Second,
it should possess reasonable stability under a variety of
reaction conditions. Finally, it should be readily available;
in other words, its synthesis should be straightforward
and readily scaled up. Bearing these criteria in mind,
chemists have utilized cyclodextrins,7-9 calixarenes,1,10-12
porphyrins,13-15 cyclophanes,16 and a variety of other
molecules17 as scaffolds for “holding” the necessary
catalytic groups.
The general reaction utilized in the formation of the
deep-cavity cavitands is shown in Scheme 1. Previously,
we had demonstrated that the stereoselective bridging
of octols with benzal bromide was highly dependent on
both the solvent of the reaction and the feet (R groups)
of the octols themselves. However, in an attempt to gain
some understanding of the electronic or steric effects
induced by the addition of the various functional groups,
we chose to initially investigate the benzal bridging of
phenethyl (PE) octol 1 (R ) CH2CH2Ph) in dimethyl-
acetamide (DMA) with K2CO3 as base. As the requisite
benzal bromides were not commercially available, we
chose two routes by which they could be readily ac-
cessed.19 Thus, the bridging materials were synthesized
by either treating the corresponding aldehyde with boron
tribromide20 or performing a free radical bromination
with N-bromosuccinimide (NBS) on the respective tolyl
derivative.21 The former conditions were applied to al-
dehydes whose additional functional groups did not
possess any lone pairs that may induce deleterious side
reactions, and the latter NBS reaction was used for those
that did. As expected, the kinetics of both approaches
were found to be dependent on the substitution pattern
of the particular aromatic derivative. However, by ma-
nipulation of temperature and/or time, a range of benzal
bromides were synthesized in yields of ca. 70-100% yield
from the aldehyde and 43-72% yield from the tolyl
derivatives. One exception to these two approaches, 3,5-
dibromobenzal bromide, was obtained via a two-step
procedure starting from 1,3,5-tribromobenzene. Thus,
monoformylation via metal-halogen exchange and
quenching with dimethylformamide (DMF), followed by
halogenation of the resulting aldehyde22 with BBr3,
afforded the bridging material in 73% yield for the two
steps. Generally these bridging materials were stable and
required no special handling techniques. However, the
p-Me derivative, with its electron-donating Me group, was
noted to spontaneously hydrolyze in the presence of
atmospheric moisture and as a consequence was isolated
and manipulated only under anhydrous conditions.23,24
We recently demonstrated the synthesis of a new
family of deep-cavity cavitands (DCCs) formed by the
stereoselective bridging of resorcinarenes (octols) with
benzal bromide, a procedure that, although involving the
formation of eight new covalent bonds and four stereo-
genic centers, proceeds in up to 58% yield.18 As part of
(1) Molenveld, P.; Stikvoort, W. M. G.; Kooijman, H.; Spek, A. L.;
Engbersen, J . F. J .; Reinhoudt, D. N. J . Org. Chem. 1999, 64, 3896-
3906 and references therein.
(2) Comprehensive Supramolecular Chemistry; Marie, J .-M., Ed.;
Pergamon: New York, 1996.
(3) Kirby, A. J . Angew. Chem., Int. Ed. Engl. 1996, 35, 707-724.
(4) Kirby, A. J . Angew. Chem., Int. Ed. Engl. 1994, 33, 551-553.
(5) Reichwein, A. M.; Verboom, W.; Reinhoudt, D. N. Rec. Trav.
Chim. Pays-Bas 1994, 113, 343-349.
(6) Brady, P. A.; Sanders, J . K. M. Chem. Soc. Rev. 1997, 26, 327-
336.
(7) Breslow, R.; Dong, S. D. Chem. Rev. 1998, 98, 1997-2011.
(8) Breslow, R.; Schmuck, C. J . Am. Chem. Soc. 1996, 118, 6601-
6605.
(9) Breslow, R. Acc. Chem. Res. 1995, 28, 146-153.
(10) Blanchard, S.; Le Clainche, L.; Rager, M.-N.; Tuchagues, J .-P.;
Dupart, A. F.; Le Mest, Y.; Reinaud, O. Angew. Chem., Int. Ed. Engl.
1998, 37, 2732-2735.
(11) For calixarenes that recognize protein surfaces, see: Park, H.
S.; Lin, Q.; Hamilton, A. D. J . Am. Chem. Soc. 1999, 121, 8-13.
(12) Ross, H.; Lu¨ning, U. Tetrahedron Lett. 1997, 38, 4539-4542.
Ross, H.; Lu¨ning, U. Angew. Chem., Int. Ed. Engl. 1995, 34, 2555-
2557.
(13) Breslow, R.; Zhang, X.; Huang, Y. J . Am. Chem. Soc. 1997, 119,
4535-4536.
(19) Some of the benzal bromides reported here were synthesized
previously but not fully characterized. For the following substituted
benzal derivatives, see the corresponding references: 2-Br,34 3-NO2,20,35
4-Br,36 4-I,37 4-Me,20 and 4-CN.36 The naphthal bromide has also been
reported but not fully characterized.38
(20) Lansinger, J . M.; Ronald, R. C. Synth. Commun. 1979, 9, 341-
349.
(21) March, J . Advanced Organic Chemistry; Reactions, Mechanisms,
and Structure; Wiley-Interscience: New York, 1992; pp 694 and
references therein.
(22) Day, G. M.; Howell, O. T.; Metzler, M. R.; Woodgate, P. D. Aust.
J . Chem. 1997, 50, 425-434.
(23) To the best of our knowledge, no systematic studies to deter-
mine σ values for the hydrolysis of benzal halides has been under-
taken.
(14) Collman, J . P.; Herrmann, P. C.; Fu, L.; Eberspacher, T. A.;
Eubanks, M.; Boitrel, B.; Hayoz, P.; Zhang, X.; Brauman, J . I.; Day,
V. W. J . Am. Chem. Soc. 1997, 119, 3481-3489.
(15) Collman, J . P.; Rapta, M.; Bro¨ring, M.; Raptova, L.; Schwen-
ninger, R.; Boitrel, B.; Fu, L.; L’Her, M. J . Am. Chem. Soc. 1999, 121,
1387-1388 and references therein.
(16) Kennan, A. J .; Whitlock, H. W. J . Am. Chem. Soc. 1996, 118,
3027-3028.
(17) Coolen, H. K. A. C.; van Leeuwen, P. W. N. M.; Nolte, R. J . M.
J . Org. Chem. 1996, 61, 4739-4747 and references therein.
(18) Xi, H.; Gibb, C. L. D.; Stevens, E. D.; Gibb, B. C. Chem.
Commun. 1998, 1743-1744 (and references therein for structurally
related cavitands).
10.1021/jo9909913 CCC: $18.00 © 1999 American Chemical Society
Published on Web 11/17/1999

Notes
J . Org. Chem., Vol. 64, No. 25, 1999 9287
Sch em e 1
Ta ble 1. Yield s of F u n ction a lized Deep -Ca vity
Ca vita n d s
Although the range of DCCs listed in Table 1 allows
access to a variety of further DCC derivatives, several of
them are worthy of brief mention here. Thus, the
synthesis of the 2-, 3-, and 4-bromo derivatives (2b, 2c,
and 2h ) provides an approach to a range of isomeric
cavitands via 4-fold metal-halogen exchange reactions.27
Likewise, cavitand 2o may provide access to a parallel
series of molecules if 8-fold metal-halogen exchange
reactions prove viable. Finally, although not directly
amenable to the formation of enzyme-mimicking deriva-
tives, the ca. 14 Å deep cavities of cavitands 2j and 3
may engender them with interesting inclusion properties.
deep-cavity cavitand
yielda (%)
2a X ) Hb
56
48
2b X ) 2-Br
2c X ) 3-Br
25 (31)c
39
2d X ) 3-Me
2e X ) 3-OCH2OEt
2f X ) 3-NO2
2g X ) 3-CN
2h X ) 4-Br
25
10 (8)c
15 (23)c
43
2i X ) 4-I
43
51
55
trace
6 (9)c
0 (40)c
5 (43)c
53
2j X ) 4-Me
2k X ) 4-Ph
2l X ) NO2
2m X ) 4-CN
2n X ) 4-CO2Et
2o X ) 3-Br, 5-Br
3 2-naphthal bridged
a
Yields are for standardized bridging in DMA with K2CO3 as
base (see Experimental Section). See ref 18. c Reaction modified
b
by using homogeneous base (diazabicyclo[5.4.0]undec-7-ene, slower
addition of benzal bromide, and longer reaction time (see Sup-
porting Information).
Under the conditions outlined above, a series of new
deep-cavity cavitands were readily synthesized with the
various benzal bromides (Table 1). As was noted in the
formation of the unsubstituted DCC 2a ,18 only the desired
C4v isomer was isolated from the varying but ubiquitous
amounts of polymer.
Two types of functional groups proved antagonistic to
the bridging process: the nitro- and cyanobenzal bro-
mides. We attribute the reduced yields for the bridging
reactions of the latter to hydrolysis of the cyano groups28
and subsequent reaction with the remaining benzal
bromide. In the case of the nitro compounds, their poor
bridging ability is possibly due to the propensity of such
compounds to undergo electron-transfer processes,29 with
the usefulness of the 4-nitro derivative as a bridging
material further impeded by the relatively high acidity
of its benzal proton.30
Evident from this series of reactions is the following.
First, functional groups at the 4-position that are not
strongly electron-donating or -withdrawing (-0.14 < σ
< 0.26)25 have little influence on the reaction when
compared to the parent DCC 2a , whereas much stronger
electron-withdrawing substituents have a significantly
detrimental effect on the reaction outcome. Lower yields
were also generally obtained for those DCCs with a
functional group at the 3-position of the second row of
aromatic rings, an observation reinforced by the much
lower yield of DCC 2o. However, for these compounds
and those with strongly electron-withdrawing groups at
the 4-position, further investigations revealed that yields
could generally be improved when a combination of the
stronger (and homogeneous) base diazabicyclo[5.4.0]-
undec-7-ene (DBU), slower addition of the bridging
material, and increased reaction time were implemented
(Table 1). These improvements suggest that a significant,
although by no means singular, contributor to the
observed yields is a competing hydrolysis of the bridging
material by water generated from the K2CO3.26
Rationalization of these results is complicated by a lack
of understanding of the bridging mechanism in general;
(26) Hydrolysis of 2-Br, 3-Br, 4-Br, and 4-CO2Et benzal bromides,
in the presence of K2CO3 (d6-DMSO) showed that, after 1 day at 60
°C, 26%, 28%, 49%, and 54% of the halide had been converted to the
corresponding aldehyde.
(27) Larock, R. C. Comprehensive Organic Transformations, VCH:
New York, 1989.
(28) Exposure of 4-CN benzal bromide to approximate reaction
conditions (K2CO3, d6-DMSO, 1 day, 60 °C) resulted in hydrolysis of
75% of the original benzal bromide to the cyanobenzladehyde, the
corresponding acid derivative, and the 4-HO2C benzal bromide.
(29) Kam, T. S.; Lim, T.-M. J . Chem. Soc., Perkin Trans. 2 1993,
147-150.
(30) Nitro-substituted benzyl halides have a propensity to undergo
SET reactions when treated with base.29 Thus, in the case of 4-ni-
trobenzal bromide under the reaction conditions, both the bridging
material and its conjugate base may undergo SET processes. Further-
more, the nucleophilicity of the latter carbanion may promote further
deleterious reaction pathways and reduce the yield of DCC 2l consider-
ably. For example, in the absence of octol, 1H NMR showed that the
4-NO2 benzal bromide rapidly formed (one diastereomer of) the
corresponding stilbene p-NO2C6H4CBrCBrC6H4-p-NO2 in essentially
quantitative yield. For further details of this chemistry see ref 35.
(24) Our efforts to examine the effects of strongly electron-donating
groups para to the benzal halide were thwarted by the instability of
p-phenoxybenzal bromide. Thus although it is readily synthesized from
the corresponding aldehyde, all attempts to isolate this bridging
material met with failure.
(25) Reference 21, p 280

9288 J . Org. Chem., Vol. 64, No. 25, 1999
Notes
mmol) was dissolved in 200 mL of dry dichloromethane. To this
stirring solution was added, over a 5 min period, 49.6 mL of 1.15
M BBr3 in dichloromethane (57.1 mmol). After stirring at room
temperature for 1 day, the mixture was run through a silica plug,
and the silica was then washed with hexane. Combining the
organic solutions and removing the solvent under reduced
pressure gave the crude benzal bromide. Flash chromatography
(mobile phase, 3:1 hexane/CHCl3) and drying (overnight, 0.1
mmHg, 25 °C) gave the benzal bromide as a colorless oil in
quantitative yield: bp 102 °C, 0.7 mmHg (lit. 100-102 °C (1.0
mmHg)); 1H NMR (400 MHz) δ 7.07 (s, 1H), 7.16 (ddd, 1H, J )
8.0, 7.2, 1.6 Hz), 7.39 (m, 1H), 7.48 (dd, 1H, J ) 8.0, 1.2 Hz),
8.00 (dd, 1H, J ) 8.0 and 1.6 Hz); MS m/z (M)+ 329.
does it occur via a double SN2 mechanism or a process
whereby the second step is an SN1 mechanism on an
oxonium intermediate? Furthermore, as is observed for
a variety of solvolyses of different benzyl halides or
sulfonates,31-33 the precise mechanism of benzal bridging
is likely to be dictated by the aromatic ring’s substituents.
Unfortunately therefore, the above data offer little op-
portunity for gleaning mechanistic details of bridging
reactions in general.
In an effort to establish criteria for the optimization
of these bridging reactions, we examined the stereose-
lective bridging of phenethyl octol with 4-Br benzal
bromide under a variety of conditions. For example, a
series of reactions using varying amounts of benzal
bromide bridging material showed that the reaction yield
with only 1.1 equiv per bridging site was reduced to 31%
but that a maximum yield of ca. 50% was attained with
only 1.3 equiv of bridging material per reaction site. We
also investigated whether, as was observed for unsub-
stituted deep-cavity cavitands,18 reaction yield was de-
pendent on the solvent and the pendant group of the
octol. Briefly, by carrying out a matrix of reactions
investigating the R group (Me, Bu, and PE) crossed-
referenced with solvent [DMA, 1-methyl-2-pyrrolidinone
(NMP), and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrim-
idinone (DMPU)] for the 4-bromo DCC 2h , we observed
the same trends as previously observed18 (see Supporting
Information). Thus, DCC formation improved, and the
yields became less solvent-dependent as the size of the
pendant (R) groups increased. Finally, another series of
experiments investigating time showed that this par-
ticular bridging reaction was essentially complete after
only 1 day at room temperature and 2 days at 60 °C.
Combining these optimizations gave a yield of 54% for
the formation of 2h .
Syn th esis of 4-Cya n oben za l Br om id e36 fr om th e Cor r e-
sp on d in g Tolyl Der iva tive. 4-Cyanotoluene (1 g, 8.5 mmol ),
NBS (3.11 g, 17.5 mmol), and benzoyl peroxide (423 mg, 1.75
mmol) were dissolved in 40 mL of dry CCl4. The solution was
heated to reflux for 2 days. After this time the solvent was
removed under reduced pressure, and the crude reaction mixture
was partitioned between water and chloroform. Washing the
organic layer twice with water, drying with anhydrous magne-
sium sulfate, and removing the solvent under reduced pressure
gave the crude product. Flash chromatography (mobile phase,
of 3:1, hexane/CHCl3) and drying (overnight, 0.1 mmHg, 25 °C)
gave a 72% yield of the benzal bromide as a colorless solid: mp
1
56-58 °C; H NMR (400 MHz, acetone-d6) δ 7.27 (s, 1H), 7.88
(s, 4H); MS m/z 309.7 (M + Cl-)-. Anal. Calcd for C8H5Br2N: C,
34.94; H, 1.83. Found: C, 34.94; H, 1.85.
Syn th esis of Deep -Ca vity Ca vita n d s 2b. A solution of the
phenethyl octol 1 (R ) CH2CH2Ph; 250 mg, 0.275 mmol) in 5
mL of DMA was added (syringe pump, 4 h) to a stirred mixture
of K2CO3 (450 mg, 3.2 mmol) and 1.65 mmol of the respective
benzal bromide in 12 mL of DMA. After 2 days of stirring at
room temperature, an additional 0.55 mmol of the benzal
bromide was added, and the reaction mixture was warmed to
60 °C. This temperature was maintained for 5 days. The reaction
mixture was then cooled, and the solvent was removed under
reduced pressure. The crude reaction mixture was partitioned
between water and chloroform, the chloroform layer was sepa-
rated, and the aqueous layer was extracted twice with chloro-
form. The organic layers were then combined and dried with
anhydrous magnesium sulfate, and the solvent was removed
under reduced pressure. Flash chromatography (1:3 CHCl3/
hexane), removal of the solvent under reduced pressure, and
drying (overnight, 0.1 mmHg, 110 °C) afforded a 48% yield of
cavitand 2b: mp 295 °C; 1H NMR (400 MHz) δ 2.60 (m, 8H),
2.73 (m, 8H), 5.05 (t, 4H, J ) 8 Hz), 5.89 (s, 4H), 6.99 (s, 4H),
7.22 (m, 28H), 7.40 (td, 4H, J ) 7.6 Hz, J ) 1.2 Hz), 7.56 (doublet
of doublets (dd), 4H, J ) 8 Hz, J ) 0.8 Hz), 7.94 (dd, 4H, J ) 8
Hz, J ) 1.8 Hz); MS m/z 1608.5 (M + Cl-)-. Anal. Calcd for
C88H68O8Br4: C, 67.18; H, 4.33. Found: C, 67.33; H, 4.49.
In summary, we have demonstrated that the stereo-
selective bridging of octols with benzal bromides is a
general process that can be applied to a range of bridging
materials. Thus, by judicious choice of base, solvent, and
octol pendant group, a range of functionalized deep-cavity
cavitands can be synthesized. Efforts to introduce cata-
lytic machinery within the cavities of these deep-cavity
cavitands are now underway.
Exp er im en ta l Section
The following syntheses are representative. See the Support-
ing Information for the synthesis of the remaining bridging
materials and deep-cavity cavitands.
Ack n ow led gm en t. We are grateful to Richard B.
Cole of the New Orleans Center for Mass Spectrometry
Research for mass analysis of the deep-cavity cavitands.
This work was partially supported by the Louisiana
Board of Regents Support fund (1997-00)-RD-A-23, a
Research Innovation Award from the Research Corpo-
ration, and the donors of the Petroleum Research Fund,
administered by the American Chemical Society.
Syn th esis of 2-Br om oben za l Br om id e34 fr om th e Cor -
r esp on d in g Ald eh yd e. 2-Bromobenzaldehyde (9.6 g, 51.9
(31) Vitullo, V. P.; Grabowski, J .; Sridharan, S. Chem. Commun.
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(32) J orge, J . A. L.; Kiyan, N. Z.; Miyata, Y.; Miller, J . J . Chem.
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(33) Lee, I.; Sohn, S. C.; Oh, Y. J .; Lee, B. C. Tetrahedron 1998, 42,
4713-4718.
Su p p or tin g In for m a tion Ava ila ble: Synthesis of all
bridging materials (except 2-bromo- and 4-cyanobenzal bro-
mides, see Experimental Section) and deep-cavity cavitands
2c-o and 3, plus the 1H and 13C NMR spectra of 3-hydroxy-
benzal bromide ethoxy methyl ether and deep-cavity cavitands
2g and 2m . This material is available free of charge via the
Internet at http://pubs.acs.org.
(34) Anderson, E.; Capon, B. J . Chem. Soc., Perkin Trans. 2 1972,
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