Synthesis and characterization of all-alkyl-substituted mono-, di-, and trioxosapphyrins

Article abstract of DOI:10.1021/jo9715736

The synthesis and characterization of the following heterosapphyrins is presented: 3,7,18,22-tetraethyl-2,8,12,13,17,23-hexamethyl-27-oxasapphyrin (5), 3,8,12,13,17,22-hexaethyl-2,7,18,23,-tetramethyl-15,29-dioxasapphyrin (6), and 3,7,18,22-tetraethyl-2,8,12,13,17,23-hexamethyl-15,27,29- trioxasapphyrin (7). These macrocycles were synthesized from the hitherto unknown precursors methyl 3,4-dimethylfuran-2-carboxylate (11) and methyl-4- ethyl-3-methylfuran-2-carboxylate (12). Single-crystals X-ray diffraction structures of the bis(hydrochloric acid) salt (5a) and the bis(trifluoroacetic acid) salt (5b) of 5 and of the bis(hydrochloric acid) salt (6a) of 6 were obtained. These structures are compared to those of the parent all-aza sapphyrin 4. In this context, we report the first solid-state structural analysis of a trifluoroacetic acid salt of sapphyrin (4b). Crystals of 5a are triclinic, space group P1 in a cell of the dimension a = 11.9686(13) A, b = 12.790(2) A, c = 16.236(2) A, α = 80.924(10)≡, β = 88.845(9)°, γ = 80.481(10)°, V = 2420.5(5) A³, F(000) = 1036, ρ = 1.38 g cm³, with Z = 2. Crystals of 5b are monoclinic, space group P2₁/c, in a cell of the dimensions a = 9.590(1) Am b = 33.911(3) Am c = 13.200(1) A, β = 94.931(6)°, V = 4276.8(6) A³, F(000) = 1904, ρ = 1.42 g cm³, with Z = 4. Crystals of 6a are triclinic, space group P1, in a cell of the dimensions a = 12.827(3) A, b = 13.116(3) A, c = 17.202(7) A, α = 82.89(2)°, β = 82.14(2)°, γ = 80.22(1)°, V = 2810(2) A³m F(000) = 1184, ρ = 1.36 g cm³, with Z = 2. Crystals of 4b are the triclinic, space group P1, in a cell of the dimensions a = 11.431(3) A, b = 11.562(2) A, c = 16.367(4) A, α = 88.07(2)°, β = 75.25(2)°, γ = 86.50(2), V = 2087.8(9) A³, F(000) = 872, ρ = 1.32, with Z = 2. The monooxasapphyrin salt 5a displays a structure very similar to that of the parent all- azasapphyrin (4a) in that one chloride anion is bound 1.936 A above and one chloride anion 1.814 A below the plane of the macrocycle. These distances are 1.774 and 1.877 A, respectively, for 4a. Almost the same behavior is found for 5b. Here, the carboxylate anions are bound 1.085 A above and 1.870 A below the plane of the macrocycle. These distances are 1.305 and 1.444 A, respectively, for 4b. Completely different behavior is observed in the case of 6a. In this instance, only one chloride anion is bound directly with a distance of 1.685 A above the plane of the macrocycle, while the other chloride anion is well removed from the dioxasapphyrin and solvated by four chloroform molecules.

Full text of DOI:10.1021/jo9715736

J . Org. Chem. 1997, 62, 9251-9260
9251
Syn th esis a n d Ch a r a cter iza tion of All-Alk yl-Su bstitu ted Mon o-,
Di-, a n d Tr ioxosa p p h yr in s
J onathan L. Sessler,* Michael C. Hoehner, Andreas Gebauer, Andrei Andrievsky, and
Vincent Lynch
Department of Chemistry and Biochemistry, University of Texas at Austin, Austin, Texas 78712
Received August 22, 1997X
The synthesis and characterization of the following heterosapphyrins is presented: 3,7,18,22-
tetraethyl-2,8,12,13,17,23-hexamethyl-27-oxasapphyrin (5), 3,8,12,13,17,22-hexaethyl-2,7,18,23-
tetramethyl-15,29-dioxasapphyrin (6), and 3,7,18,22-tetraethyl-2,8,12,13,17,23-hexamethyl-15,27,29-
trioxasapphyrin (7). These macrocycles were synthesized from the hitherto unknown precursors
methyl 3,4-dimethylfuran-2-carboxylate (11) and methyl 4-ethyl-3-methylfuran-2-carboxylate (12).
Single-crystal X-ray diffraction structures of the bis(hydrochloric acid) salt (5a ) and the bis(tri-
fluoroacetic acid) salt (5b) of 5 and of the bis(hydrochloric acid) salt (6a ) of 6 were obtained. These
structures are compared to those of the parent all-aza sapphyrin 4. In this context, we report the
first solid-state structural analysis of a trifluoroacetic acid salt of sapphyrin (4b). Crystals of 5a
are triclinic, space group P1h in a cell of the dimensions a ) 11.9686(13) Å, b ) 12.790(2) Å, c )
16.236(2) Å, R ) 80.924(10)°, â ) 88.845(9)°, γ ) 80.481(10)°, V ) 2420.5(5) Å3, F(000) ) 1036, F
) 1.38 g cm3, with Z ) 2. Crystals of 5b are monoclinic, space group P21/c, in a cell of the dimensions
a ) 9.590(1) Å, b ) 33.911(3) Å, c ) 13.200(1) Å, â ) 94.931(6)°, V ) 4276.8(6) Å3, F(000) ) 1904,
F ) 1.42 g cm3, with Z ) 4. Crystals of 6a are triclinic, space group P1h, in a cell of the dimensions
a ) 12.827(3) Å, b ) 13.116(3) Å, c ) 17.202(7) Å, R ) 82.89(2)°, â ) 82.14(2)°, γ ) 80.22(1)°, V )
2810(2) Å3, F(000) ) 1184, F ) 1.36 g cm3, with Z ) 2. Crystals of 4b are triclinic, space group P1h,
in a cell of the dimensions a ) 11.431(3) Å, b ) 11.563(2) Å, c ) 16.367(4) Å, R ) 88.07(2)°, â )
75.25(2)°, γ ) 86.50(2), V ) 2087.8(9) Å3, F(000) ) 872, F ) 1.32, with Z ) 2. The monooxasapphyrin
salt 5a displays a structure very similar to that of the parent all-azasapphyrin (4a ) in that one
chloride anion is bound 1.936 Å above and one chloride anion 1.814 Å below the plane of the
macrocycle. These distances are 1.774 and 1.877 Å, respectively, for 4a . Almost the same behavior
is found for 5b. Here, the carboxylate anions are bound 1.085 Å above and 1.870 Å below the
plane of the macrocycle. These distances are 1.305 and 1.444 Å, respectively, for 4b. Completely
different behavior is observed in the case of 6a . In this instance, only one chloride anion is bound
directly with a distance of 1.685 Å above the plane of the macrocycle, while the other chloride
anion is well removed from the dioxasapphyrin and solvated by four chloroform molecules.
Sch em e 1
In tr od u ction
In recent years, expanded porphyrins have become
increasingly popular as synthetic targets.1 This is due
both to their intrinsic beauty and because they are
perceived as being useful in a variety of applications that
range from their role as models for aromatic annulenes
to their use as radiation sensitizers and putative antiviral
drug delivery systems. One of the better studied of all
expanded porphyrins is the pentapyrrolic macrocycle
sapphyrin (e.g., 4, Scheme 1). This prototypic expanded
porphyrin was first reported by Woodward and co-
workers in 1966.2,3 However, because of difficulties
associated with its synthesis, sapphyrins remained but
little studied prior to the late 1980s. At this time,
improved syntheses of both the critical tripyrrane precur-
X Abstract published in Advance ACS Abstracts, December 1, 1997.
(1) (a) Sessler, J . L.; Weghorn, S. J . Expanded, Contracted and
Isomeric Porphyrins; Elsevier: Oxford, 1997. (b) Sessler, J . L.; Burrell,
A. K. Top. Curr. Chem. 1991, 161, 177.
(2) (a) First reported by R. B. Woodward at the Aromaticity
Conference, Sheffield, U.K., 1966. (b) Baur, V. J .; Clive, D. L. J .;
Dolphin, D.; Paine, J . B., III; Harris, J . L.; King, M. M.; Loder, H.;
Wang, S.-W. C.; Woodward, R. B. J . Am. Chem. Soc. 1983, 105, 6429.
(3) Broadhurst, M. J .; Grigg, R.; J ohnson, A. W. J . Chem. Soc.,
Perkin Trans. 1 1972, 2111.
(4) Sessler, J . L.; J ohnson, M. R.; Lynch, V. J . Org. Chem. 1987,
52, 4394.
(5) (a) Sessler, J . L.; Cyr, M. J .; Lynch, V.; McGhee, E.; Ibers, J . A.
J . Am. Chem. Soc. 1990, 112, 2810. (b) Shionoya, M.; Furuta, H.; Lynch,
V.; Harriman, A.; Sessler, J . L. J . Am. Chem. Soc. 1992, 114, 5714.
sor 14 and its bipyrrole coupling partner 3 were reported.5
This, in turn, allowed sapphyrins such as 4 to be
prepared in good yields and enabled the rich chemistry
of these systems to be explored.6 One of the more
S0022-3263(97)01573-9 CCC: $14.00 © 1997 American Chemical Society

9252 J . Org. Chem., Vol. 62, No. 26, 1997
Sessler et al.
interesting findings to emerge from these studies was the
discovery that various protonated sapphyrin derivatives
are able to bind anionic species, such as halide5 and
phosphate anions,7 both in solution and in the solid state.
While the binding of anions by protonated sapphyrin
is now established, the exact determinants of the binding
process still remain to be detailed. Inspection of the
various X-ray crystal structures now available5,7 leads to
the conclusion that either electrostatic interactions or
hydrogen-bonding contacts, or both, could be responsible
for the sapphyrin dication-to-anion contacts observed in
the solid state. In an effort to distinguish between these
two limiting binding scenarios, it was considered worth-
while to prepare sapphyrin analogues where one or more
of the pyrrolic subunits is replaced by a furan. Since
neutral furans, unlike pyrroles, cannot serve as hydrogen-
bond donors, binding and transport studies using these
furan-containing sapphyrins could reveal if a forced
reduction in hydrogen-bond-donor capacity is reflected
in reductions in anion-binding affinity in solution or
increases in anion-to-sapphyrin contact distances in the
solid state. In this paper, we report the synthesis of the
all-â-alkyl (i.e., 3,4)-substituted mono-, di-, and trioxa-
sapphyrins 5, 6, and 7 corresponding to the all-aza-
substituted sapphyrin parent 4. We also report the X-ray
structures of the bis(hydrochloride) salts of 5 and 6 (5a
and 6a ) as well as those of the bis(trifluoroacetic acid)
salts of 4 and 5 (4b and 5b). Taken together, these
structures serve to show that reducing the number of
available hydrogen-bonding sites within the macrocyclic
core leads to dramatic changes in the relevant anion-to-
sapphyrin distances but does not serve to eliminate anion
binding in the solid state.
tuted furans have been reported in the literature.10-12 All
three were thus considered in the context of trying to
prepare targets 5 and 7. However, the first one10 was
quickly ruled out due to (i) the large number of trans-
formations involved and (ii) perceived difficulties associ-
ated with scale-up. The second approach, the inverse
Diels-Alder procedure of Vogel et al. used to prepare 3,4-
diethylfuran,12 was also ruled out due to the rather harsh
conditions required and because sophisticated syntheses
of the starting materials are necessary. The third
conceivable literature approach, based on a generalized
furan synthesis of Backer et al.,11 was tried. However,
it failed to prove viable in our hands. Therefore, a new
procedure involving the thermal rearrangement of gly-
cidic ester intermediates was tested. This procedure,
which involves a generalization of an approach intro-
duced previously to prepare mono-â-alkyl furans,13 was
found to give 3,4-dialkylfurans with sufficient efficiency
that follow-up syntheses of sapphyrins could be conceived
(see Scheme 2).
Although furan-containing sapphyrins are known,3,8
systems wherein the furan subunits are substituted with
alkyl groups in the â-positions are, to our knowledge,
currently unknown. Such materials are considered
necessary if reliable comparisons “back to” the alkyl-
substituted sapphyrins are to be made. This desidera-
tum, in turn, has prompted us to develop suitable
syntheses of appropriately functionalized precursors.
Therefore, in this paper, we also present the synthesis
of the hitherto unknown 3,4-dialkyl-substituted furans
11 and 12 and show how these can be elaborated into a
range of sapphyrin-type macrocycles. The synthetic
method used to generate 11 and 12 appears to be general.
It thus opens the way to preparing a range of nonsap-
phyrin, heteroatom-containing expanded porphyrins. This
is potentially important since â-substituents both im-
prove product solubility and facilitate macrocyclization
via what has been termed a “helical effect”.9
The specific precursors we wanted for the synthesis of
5-7 were methyl 3,4-dimethylfuran-2-carboxylate, 11,
and methyl 3-ethyl-4-methylfuran-2-carboxylate, 12. These
precursors were chosen because, in terms of their â-sub-
stitution pattern, they are directly analogous to the
precursors used to prepare the decaalkyl-substituted
sapphyrins currently in hand (e.g., 4). In the event, the
â-keto acetal precursors required to prepare 11 and 12,
Resu lts a n d Discu ssion
Syn th esis of th e F u r a n P r ecu r sor s. Three general
approaches toward the synthesis of 3,4-dialkyl-substi-
(6) Bru¨ckner, C.; Sternberg, E. D.; Boyle, R. W.; Dolphin, D. Chem.
Commun. 1997, 1689. Other syntheses of sapphyrin that are not
predicated on the use of tripyrranes have been reported recently: (a)
Sessler, J . L.; Lisowski, J .; Boudreaux, K. A.; Lynch, V.; Barry, J .;
Kodadek, T. J . J . Org. Chem. 1995, 60, 5975. (b) Latos-Grazynski, L.;
Rachlewics, K. Chem. Eur. J . 1995, 1, 68. (c) Paolesse, R.; Licoccia, S.;
Spagnoli, M.; Boschi, T.; Khoury, R. G.; Smith, K. J . Org. Chem. 1997,
62, 5133.
(10) Reichstein, T.; Grussner, A. Helv. Chim. Acta 1933, 16, 28.
(11) Backer, H. J .; Stevens, W. Rec. Trav. Chim. 1940, 59, 423.
(12) Vogel, E.; Do¨rr, J .; Herrmann, A.; Lex, J .; Schmickler, H.;
Walgenbach, P.; Gesselbrecht, J . P.; Gross, J . Angew. Chem., Int. Ed.
Engl. 1993, 32, 1597.
(7) (a) Iverson, B. L.; Schreder, K.; Kral, V.; Sessler, J . L. J . Am.
Chem. Soc. 1993, 115, 11022. (b) Kral, V.; Sessler, J . L.; Furuta, H. J .
Am. Chem. Soc. 1992, 114, 8704. (c) Sessler, J . L.; Furuta, H.; Kral,
V. Supramol. Chem. 1993, 1, 209.
(8) Sessler, J . L.; Cyr, M.; Burrell, A. K. Tetrahedron 1992, 48, 9661.
(9) Sessler, J . L.; Weghorn, S. J .; Hiseada, Y.; Lynch, V. Chem. Eur.
J . 1995, 1, 56.
(13) (a) Burness, D. M. Organic Synthesis; Wiley: New York, 1963;
Collect. Vol. IV, p 649. (b) Klein, L. L. Synth. Commun. 1986, 16, 431.
(14) (a) Royals, E. E.; Brannock, K. C. J . Am. Chem. Soc. 1953, 75,
2050. (b) Royals, E. E.; Brannock, K. C. J . Am. Chem. Soc. 1954, 76,
1180. (c) Fletcher, G. L.; Hull, J . S. U.S. Patent 2,760,986, 1956.
(15) (a) Borch, R. F. Tetrahedron Lett. 1972, 36, 3761. (b) Helms,
A.; Heiler, D.; McLendon, G. J . Am. Chem. Soc. 1992, 114, 6227.

All-Alkyl-Substituted Mono-, Di-, and Trioxasapphyrins
J . Org. Chem., Vol. 62, No. 26, 1997 9253
Sch em e 2
Sch em e 3
namely 9 and 10, were synthesized using literature
procedures.14,15 These materials were then transformed
into the corresponding glycidic ester intermediates. These
latter were not isolated. Rather, the reaction mixtures
in which they were contained were subjected to warming
and distillation prior to conversion to the corresponding
furans. In this way, any unreacted â-keto acetal and enol
ether could be removed first via distillation, leaving the
crude glycidic esters to be converted to the respective
furan.
Sch em e 4
Once the desired 3,4-dialkyl-substituted furans were
in hand, the 2 and 5 positions had to be modified so as
to allow incorporation of these subunits into the sapphy-
rin skeleton. On the basis of previous experience,8 it was
considered likely that this could most easily be effected,
at least in the case of 11, if reactive acetoxymethyl groups
could be introduced at the 2 and 5 positions. To ac-
complish this, the 5 position was first subject to formyl-
ation under Vilsmeier-type conditions (to give 13; Scheme
3). Next, both the aldehyde and ester groups were
reduced to the symmetrical bis(hydroxymethyl)furan, 14.
This material was then acetylated using acetyl chloride
in the presence of pyridine. The resulting diacetoxy
furan, 15, was then reacted with 2 equiv of benzyl
3-ethyl-4-methylpyrrole-2-carboxylate to give the furan-
containing tripyrrane analogue 16.
The key precursor considered necessary for the syn-
thesis of dioxasapphyrin 6 (and the trioxa target 7) was
the dialdehyde 21. This material was synthesized by first
brominating the 5 position of 12 using Br2 in DMF
(Scheme 4).16 Then, using bis(tributyltin) in the presence
of Pd0, the resulting bromofuran, 18, was coupled to give
the bifuran diester, 19. Reduction of both esters with
lithium aluminum hydride and oxidation of the resulting
dialcohol, 20, with MnO2 then gave the desired interme-
diate target 21. This synthetic strategy was chosen after
more-standard strategies, such as those based on cou-
pling procedures such as Ullmann couplings17 and oxida-
tive dimerization,18 failed to produce any of the desired
product (i.e., 21 or its direct bifuranic precursors).
Syn th esis of th e Oxa sa p p h yr in s. With the furan-
containing precursors 16 and 21 in hand, cyclization
reactions leading to oxasapphyrins 5-7 were carried out.
In all cases, a standard2,8 3 + 2 MacDonald-type conden-
sation procedure akin to that shown in Scheme 1 was
employed. However, as detailed in the Experimental
Section, slight modifications in the solvents and condi-
tions were made as appropriate.
Use of this general procedure required conversion of
the requisite dibenzyl ester tripyrrane (i.e., 1) or oxa-
tripyrrane analogue (i.e., 16) into the corresponding
dicarboxylic acid (2 or 17, respectively). This was done
via hydrogenolysis using 10% Pd/C as the catalyst. The
resulting dicarboxcylic acids were treated as being un-
(19) The use of a solvent system different from that employed in
the case of the all-aza sapphyrin 4 resulted from an inability to effect
oxidation of the furan containing dihydrosapphyrins in ethanol.
Various oxidants, air, DDQ, and chloranil were tried, but in no case
did oxidation to the fully conjugated oxosapphyrin occur. Use of a
halogenated solvent system on the other hand, allowed these critical
oxidations to be effected readily in what is literally a one-pot procedure.
(16) Itahara, T.; Hashimoto, M.; Yumisashi, H. Synthesis 1984, 255.
(17) Diels, O.; Ilberg, K. Ber. 1916, 158.
(18) Grigg, R.; Knight, J . A.; Sargent, M. V. J . Chem. Soc. 1966,
976.

9254 J . Org. Chem., Vol. 62, No. 26, 1997
Sessler et al.
Ta ble 1. Op tica l P r op er ties of Sa p p h yr in a n d
Oxa sa p p h yr in Sa lts in CHCl3
Ta ble 2. 1H NMR Sp ectr oscop ic P r op er ties of Sa p p h yr in
a n d Oxa sa p p h yr in Bis(TF A) Sa lts in CDCl3
Soret/
nm (log ꢀ)
∆δ (ppm)
meso-H
salt
Q-bands/nm (log ꢀ)
salt
δ (ppm), NH
δ (ppm), meso-H
4b
5b
6b
7b
454 (5.49)
450 (5.54)
452 (5.65)
451 (5.26)
576 (3.76), 623 (3.88), 676 (4.00)
4b -5.11 (2H), -4.73 (1H), 11.53 (2H), 11.58 (2H)
-4.45 (2H)
0.05
609 (3.94), 625 (4.11), 667 (3.79), 689 (3.91)
610 (3.94), 637 (4.09), 671 (4.25), 703 (3.00)
593 (3.81), 646 (3.75), 717 (3.68)
5b -4.12 (2H), -2.99 (2H) 11.40 (2H), 11.65 (2H)
6b -4.08 (2H), -3.11 (1H) 11.65 (2H), 11.78 (2H)
0.2
0.13
0.28
7b -2.9 (2H)
11.29 (2H), 11.57 (2H)
stable and were thus used without purification or isola-
tion. Specifically, using a chloroform/methanol solvent
system,19 they were combined with the appropriate
diformylbifuran 21 or diformylbipyrrole 3. Aqueous
hydrochloric acid was then added in small amounts and
the solution left stirring at room temperature exposed
to air but protected from light. At the point where
starting materials could no longer be detected, 1 equiv
of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) was
added as the oxidant.20 The resulting sapphyrins were
then purified by column chromatography in the form of
their trifluoroacetic acid (TFA) salts.
Ch a r a cter iza tion a n d P r op er ties
Solu tion -Sta te Str u ctu r e. The synthesis of 4-7
provides a matched set of sapphyrin congeners with
which detailed spectroscopic comparisons can be made.
The first set of such putative comparisons involved
looking at UV/vis spectra of 4-7. Because sapphyrins
are easily protonated and because the UV/vis spectra of
sapphyrins and heterosapphyrins (when protonated) are
influenced by the identity of the counteranion,5,7,8 sap-
phyrins 4-7 were all studied in the form of their
bis(trifluoroacetic acid) salts (4b-7b). Under these
conditions, it was found that all three â-alkyl-substituted
oxasapphyrins display visible spectra in dichloromethane
that are not only similar to each other but also to that of
the parent all azasapphyrin (4b). The only observable
difference is a hypsochromic shift of the Soret bands and
a bathochromic shift of the Q-type bands in the case of
the oxasapphyrins (see Table 1). Interestingly, in the
case of the â-free systems similar but much more intense
shifts in the Soret bands are observed.8 This observation
underscores the need to use systems of like substitution
when making detailed UV/vis spectroscopic comparisons.
Proton NMR spectroscopy was also used to characterize
the new sapphyrin analogues 5-7. As is true for the
azasapphyrins (e.g., 4)5 and the â-unsubstituted oxasap-
F igu r e 1. Top and side view of 5a showing parts of the atom-
labeling scheme. Thermal ellipsoids are scaled to the 30%
probability level. Hydrogen atoms shown are drawn to an
arbitrary scale, although most have been omitted for clarity.
by including 4 in the basis set, no clear pattern can be
deduced (except that the effect, whatever its origin, is
strongest for 7). Further insight into this matter could
come with the synthesis of other â-substituted hetero-
sapphyrin derivatives.
Solid -Sta te Str u ctu r e. In addition to being charac-
terized in organic solution, two of the new oxasapphyrins
reported here were characterized via single-crystal X-ray
diffraction. In the case of the oxasapphyrin derivative
5, X-ray structures were obtained for the bis(hydrochlo-
ride) (5a , Figure 1) and bis(TFA) (5b, Figure 2) salts,
whereas in the case of 6 a structure could be obtained
only for the bis(hydrochloride) salt (6a , Figure 3).
Having structural data available for 5a and 6a allows
comparison to be made to the X-ray structure of the
already known bis(hydrochloride) complex of 4 (4a ,
Figure 4).5b Further, because of a desire to compare salt
5b “back to” the corresponding all-aza system 4b, efforts
were made to obtain solid-state structural information
for this latter bis(TFA) salt (4b). These efforts proved
successful (Figure 5), thus allowing a detailed comparison
of both the effect of heteroatom substitution on the
binding of anions by sapphyrin in the solid state and the
effect of the counteranion on the structure of sapphyrins
and heterosapphyrins as manifested in single crystals.
The three comparisons that we chose to make within
this series of complexes concerned (1) the pyrrolic nitrogen-
1
phyrins,8 the H NMR spectra of the oxasapphyrins 5-7
reveal the upfield and downfield shifts for the internal
NH protons and external (meso) ring protons character-
istic of aromatic macrocycles (see Table 2). One general
trend that is observed is that the internal NH protons
are shifted to lower field as the number of pyrroles
replaced by furans is increased. This finding most likely
reflects the known deshielding effect of the oxygen
atoms.21 Another observable change is the way in which
the relative chemical shifts of the meso proton signals
are seen to vary once oxygen is introduced into the
system. These changes most likely reflect the different
locations of the furan subunits in 5-7. However, even
(20) Although the dihydrosapphyrin intermediates will oxidize if left
in solution exposed to air (roughly 10, 24, and 48 h in the case of the
mono-, di-, and trioxasapphyrins, respectively), extensive decomposition
is detected.
(21) Streitwieser, A.; Heathcock, C. H. Introduction to Organic
Chemistry, 3rd ed.; Macmillan Publishing Company: New York, 1985;
pp 332-334.

All-Alkyl-Substituted Mono-, Di-, and Trioxasapphyrins
J . Org. Chem., Vol. 62, No. 26, 1997 9255
F igu r e 2. Top and side view of 5b showing parts of the atom-
labeling scheme. Thermal ellipsoids are scaled to the 30%
probability level. Hydrogen atoms shown are drawn to an
arbitrary scale, although most have been omitted for clarity.
F igu r e 3. Top and side view of 6a showing parts of the atom-
labeling scheme. Thermal ellipsoids are scaled to the 30%
probability level. Hydrogen atoms shown are drawn to an
arbitrary scale although most have been omitted for clarity.
to-counteranion distance, (2) the distance of the coun-
teranion from the plane of the macrocycle, and (3) the
deviation from planarity of the bipyrrolic or bifuran
subunit (bipyrrole or bifuran dihedral angle). As seen
in Figure 4 and discussed in detail previously,5b the
bis(hydrochloride salt) of 4 is almost planar. The tripyr-
rane portion of the macrocycle is extremely flat, while
the bipyrrolic portion is slightly twisted (the relevant
dihedral angle is 25.2°). The first bound chloride anion,
Cl 1, is bound by a three-hydrogen-bond interaction to
the three nitrogen atoms of the macrocycle and lies 1.77
Å above the plane of the macrocycle (defined by the five
heteroatoms). The second chloride counteranion, Cl 2,
on the other hand, is involved in hydrogen-bond interac-
tions with but two of the five nitrogen atoms and is
located 1.88 Å below this plane (cf. Table 3).
coordinated directly to the macrocycle (Figure 3). This
bound chloride anion, Cl 1, is found to lie 1.69 Å above
the plane of the macrocycle (Table 3). By contrast, the
second chloride anion is solvated by four chloroform
molecules and is well removed from the sapphyrin.
Another interesting characteristic evident in the struc-
ture of salt 6a is the rather large dihedral angle of 30.8°
present within the bifuran subunit. This bigger angle
may reflect the fact that neither of the bifuran hetero-
atoms is coordinated to the bound chloride anion. This
absence of binding “permits” the bifuran moiety to twist
and, in so doing, reduce the steric interactions that would
otherwise result from contacts between the â-substitu-
ents.
Looking at the same parameters for the oxasapphyrin
5a complex (Figure 1), one sees that the dihedral angle
of the bipyrrole subunit is 22.5°. This is a value that is
slightly smaller than that present in 4a . The relevant
chloride to nitrogen distances are shown in Table 3. Here
Cl 1 has only two hydrogen-bond interactions with the
macrocycle and is located 1.934 Å above the plane of the
macrocycle (defined as before), while Cl 2 shows three
hydrogen-bond interactions and resides 1.81 Å below this
plane.
Although the characteristics for the bis(chloride) anion
complex 5a are fairly similar to those of 4a , those of the
bis(oxasapphyrin) complex 6a are very different. In fact,
even though the diprotonated sapphyrin ligand in this
instance bears an overall 2+ charge (just as it does in
salts 4a and 5a ), only one chloride anion is found to be
The congruent pair of bis(trifluoroacetic acid) salts 4b
and 5b (Figures 5 and 2, respectively) also permits
interesting comparisons to be made. On first inspection
both complexes look very similar in that two sapphyrin
frameworks are both nearly planar with two TFA mol-
ecules being hydrogen-bonded above and below the
planes defined by these two macrocycles. However, closer
inspection reveals that the binding interactions between
the TFA anions and the macrocycle are different in 4b
and 5b. In the case of 4b one TFA anion is bound to two
nitrogen atoms while the other TFA anion is bound to
three nitrogen atoms (for relevant distances see Table
4). The distance from the plane of the macrocycle of the
TFA anion with three hydrogen-bond interactions is 1.31
Å, while the corresponding distance is 1.44 Å for the other
TFA molecule (i.e., the one with only two hydrogen-bond

9256 J . Org. Chem., Vol. 62, No. 26, 1997
Sessler et al.
F igu r e 5. Top and side view of 4b showing parts of the atom-
labeling scheme. Thermal ellipsoids are scaled to the 30%
probability level. Hydrogen atoms shown are drawn to an
arbitrary scale, although most have been omitted for clarity.
Ta ble 3. Ch lor id e to Nitr ogen Dista n ces of th e
Sa p p h yr in Com p lexes 4a , 5a , a n d 6a Given in Å3b
F igu r e 4. Top and side view of the molecular structure of
complex 4a . Thermal ellipsoids are scaled to 30% probability
level; H-atoms are drawn to an arbitrary size, although most
have been omitted for clarity. See ref 5b for further details of
this structure.
sapphyrin/ nitrogen nitrogen nitrogen nitrogen nitrogen
chloride
1
2
3
4
5
4a /Cl 1
4a /Cl 2
5a /Cl 1
5a /Cl 2
6a /Cl 1
3.212
3.198
3.189
3.128
3.186
3.316(3)
3.136(4)
interactions). For 5b, a dihedral angle of 21.1° between
the bipyrrole subunits was found, a value smaller than
those observed for 4b. In this salt, one TFA anion is
found bound to one nitrogen while the other TFA anion
is bound to three nitrogens. The relevant distances are
listed in Table 4. The distances of the triple-bound and
the single-bound TFA anion from the plane of the
macrocycle are 1.09 Å above and 1.87 Å below, respec-
tively (Table 4).
3.105(3) 3.224(3) 3.334(3)
3.176(13) 3.039(12) 3.200(12)
Ta ble 4. TF A Oxygen to Nitr ogen Dista n ces of th e
Sa p p h yr in Com p lexes 4b a n d 6b Given in Å
sapphyrin/ nitrogen nitrogen nitrogen nitrogen nitrogen
TFA oxygen
1
2
3
4
5
4b/O3
4b/O1
5b/O1b
5b/O1a
2.781(7) 2.899(7)
2.921(7) 2.913(7) 2.927(7)
2.910(4) 2.830(3)
2.847(4)
2.967(3)
While it is not surprising that the TFA anions are
bound differently in 5b than in 4b (after all, there is one
hydrogen-bond donor less in 5b), the actual mode of
binding is unexpected. A priori, one might have been
inclined to expect that the two TFA anions would share
the remaining four hydrogen-bonding sites in 5b, thus
giving rise to a binding motif wherein two hydrogen
bonds are used to stabilize the binding of each TFA anion.
While such a binding scenario pertains to a first ap-
proximation in the case of the bis(hydrochloric acid) salt
5a , it clearly does not in the case of 5b. This last set of
comparative results thus serves to highlight in a very
dramatic way how the anion-binding properties of pro-
tonated sapphyrins can depend in the solid state not just
on the choice of macrocycle but on the nature of the
anions as well. It also underscores how, at least in this
congeneric series, the anion-to-protonated macrocycle
distances relate directly to the number of hydrogen bonds
formed.
Con clu sion
In this paper, we have described the synthesis of
various â-alkyl-substituted furans and their incorpora-
tion into sapphyrin-type expanded porphyrins. This
synthesis uses relatively cheap starting materials, can
be scaled up, and gives moderate to good yields. The
resulting â-substituted oxasapphyrins provide a “matched
set” of materials with which comparisons can be made.
Solid-state structural studies of the diprotonated forms

All-Alkyl-Substituted Mono-, Di-, and Trioxasapphyrins
J . Org. Chem., Vol. 62, No. 26, 1997 9257
(Fr.) weights and percent â-keto acetal (as determined from
1H NMR analysis): Fr. 1 (11.7 g, 91%); Fr. 2 (13.1 g, 83%); Fr.
3 (6.4 g, 67%); Fr. 4 (3.2 g, 26%). Fractions 1-3 were combined
(31.1 g total; 25.7 g or 82% of the â-keto acetal 9) and used in
the next reaction without further purification. Analytical
samples were obtained by carrying out repeated fractionated
distillations: 1H NMR (300 MHz, CDCl3) δ 1.08 (d, 3H), 2.18
(s, 3H), 2.86-2.91 (m, 1H), 3.34 (s, 3H), 3.35 (s, 3H), 4.41 (d,
1H); 13C NMR (75.5 MHz, CDCl3) δ 12.3, 30.1, 49.6, 52.9, 55.4,
106.0; HRMS m/z calcd for C7H14O3 146.0943, found 146.0935.
Anal. Calcd for C7H14O3: C, 57.50; H, 9.66. Found: C, 57.25;
H, 9.62.
of 4-6, for instance, have served to reveal that the details
of anion binding in the solid state depend not only on
the choice of sapphyrin (i.e., number and nature of
heteroatom) but also on the specific anion being probed.
Current work is focused on exploring the solution-phase
substrate binding properties of these systems. While, in
contradistinction to what is true for 4,5b we have been
unable to find a spectroscopic “handle” that will allow
us to measure the anion affinities of the protonated forms
of oxasapphyrins 5-7 in solution, we have found that
monooxasapphyrin 5 will stabilize a UO22+ complex under
conditions where the pentaaza system 4 will not.22 Taken
together, these findings lead us to suggest that further
study of these and other heteroatom-containing expanded
porphyrins could prove informative.
Meth yl 3,4-Dim eth yl-2-ca r boxyfu r a n (11). Anhydrous
diethyl ether (70 mL) and 1,1,1,3,3,3-hexamethyldisilazane
(98% pure) (37.7 mL, 0.175 mol) were combined in an oven-
dried, 500 mL, three-neck RBF equipped with a magnetic stir
bar, reflux condenser, and argon inlet. A solution of 1.6 M
n-butyllithium (n-BuLi) in hexanes (110 mL, 0.175 mol) was
added via syringe at a rate sufficient to maintain a gentle
reflux. After the addition was complete, the solution was
heated at reflux for 0.5 h. Then, after the solution was cooled
to room temperature, the solvents were removed under aspira-
tor vacuum. The remaining white solid was dissolved in dry
THF (125 mL) and stirred in a dry ice/acetone bath. Methyl
bromoacetate (97% pure) (17.1 mL, 0.175 mol), dissolved in
dry THF (35 mL), was then added dropwise to this chilled,
amide-containing THF solution over 20 min. The resulting
solution was stirred for an additional 10 min in the cooling
bath. After this time, a solution of 9 (25.6 g, 0.175 mol) in
THF (35 mL) was added over 20 min with continued cooling.
The orange solution obtained as a result of this addition was
stirred in the dry ice/acetone bath with the bath and the
solution allowed to warm to approximately -10 °C over 3 h.
The solution was then stirred at room temperature for an
additional 1 h. The resulting dark brown solution was then
poured into an ice-water/diethyl ether mixture (600 mL; 1:1).
The two phases were separated from each other, and the
aqueous layer was extracted three times with 200 mL portions
of diethyl ether. The organic layers were combined and
washed once with aqueous 10% HCl and twice with a brine
solution, and the remaining solvent was then removed using
a rotary evaporator. This gave a yellow oil that was distilled
under high vacuum (0.5 mmHg), keeping the bath temperature
below 70 °C. Once all the unreacted starting materials were
removed, the still pot and the crude glycidic ester that
remained in it were heated to 180 °C. This resulted in the
production and distillation of methanol. Once the distillation
head temperature dropped below 50 °C, the RBF was removed
from the oil bath and allowed to cool. The dark oil that
remained was then distilled under high vacuum with the
fraction boiling at 49 °C/0.15 mmHg being collected. This gave
9.7 g of 11 (36% yield) in >93% purity. An analytical sample
was obtained by column chromatography using silica gel as
the solid support and 17% ethyl acetate in hexanes as the
eluent. For 11: 1H NMR (300 MHz, CDCl3) δ 1.96 (s, 3H),
2.26 (s, 3H), 3.88 (s, 3H), 7.26 (s, 1H); 13C NMR (75.5 MHz,
CDCl3) δ 7.8, 9.3, 51.3, 123.0, 131.4, 140.0, 141.9, 160.0; HRMS
m/z calcd for C8H11O3 155.0708, found 155.0697. Anal. Calcd
for C8H11O3: C, 62.33; H, 6.54. Found: C, 62.21; H, 6.50.
Meth yl 5-For m yl-3,4-dim eth ylfu r an -2-car boxylate (13).
Dry DMF (32 mL) was placed in an oven-dried RBF equipped
with an argon inlet and a magnetic stirrer. The DMF was
cooled in an ice-water bath while phosphorus oxychloride
(POCl3) (12.8 mL, 0.137 mol) was added portionwise. After
the addition was complete, the pink solution was removed from
the bath, and dichloroethane (55 mL) was added. The result-
ing solution was placed back into the ice-water bath as furan
11 (10.6 g, 0.0686 mol) dissolved in a second portion of
dichloroethane (55 mL) was added dropwise over 15 min.
After the addition, the resulting bright red solution was
allowed to come to room temperature and then set to reflux
for 5 h. After the reflux period, the solution was brought to
room temperature and then cooled in an ice water bath as a
concentrated aqueous sodium acetate solution (100 mL) was
added dropwise. This two-phase mixture was heated at reflux
for 30 min and then allowed to cool. The organic layer was
Exp er im en ta l Section
Gen er a l Meth od s. Melting points, 1H and 13C NMR
spectra, UV/vis spectra, elemental analyses, and low- and high-
resolution FAB and CI mass spectra were obtained using
instrumentation described previously.6a,8,9 Dichloromethane
was dried by distillation under nitrogen from calcium hydride.
Tetrahydrofuran (THF) was dried by distillation under nitro-
gen from sodium. Methanol was dried by distillation under
nitrogen from calcium hydride. All other solvents, acids, bases,
and reagents were obtained from commercial sources and used
as received unless indicated otherwise.
Syn th etic Exp er im en ta l P r oced u r es. 2-Meth yl-3-oxo-
bu ta n a l (8). Methyl ethyl ketone (268 mL, 3 mol), methyl
formate (182 mL, 3 mol), and dry diethyl ether (3 L) were
placed under a nitrogen atmosphere in a 5 L, three-neck round-
bottomed flask (RBF), equipped with a mechanical stirrer. The
resulting solution was then stirred while being cooled in an
ice-water bath, and sodium metal (69 g, 3 mol) was added
portionwise over 2 h. After all of the sodium had been added,
the orange solution was allowed to warm to room temperature
by stirring under a nitrogen atmosphere overnight. The
resulting yellow/orange sodium salt was filtered off, rinsed
with diethyl ether, and dried in vacuo. After drying 246.1 g
(67.3%) of the yellow sodium salt was obtained. This salt (96.4
g, 0.79 mol) was placed in an Erlenmeyer flask, and anhydrous
diethyl ether (900 mL) was added. The mixture was stirred
and cooled in an ice-water bath as dry HCl gas was bubbled
through the mixture until the solution became neutral to
acidic. The resulting white solids were filtered off and rinsed
with ether. The combined red filtrates were taken to dryness
on a rotary evaporator. This afforded a red solid that was then
dried in vacuo without heating. Once dry, the red/orange solid
was sublimed directly into a 100 mL RBF cooled with liquid
nitrogen at 0.05 mmHg and 45 °C. This gave 44.4 g (56%) of
1
8 as a hard white solid: mp 65-68 °C; H NMR (300 MHz,
CDCl3) δ 1.80 (s, 3H), 2.14 (s, 3H), 7.74 (d, 1H), 14.65 (d, 1H);
13C NMR (75.5 MHz, CDCl3) δ 13.2, 25.2, 107.8, 173.3, 197.3;
HRMS m/z calcd for C5H9O2 101.0603, found 101.0608. Anal.
Calcd for C5H8O2: C, 59.97; H, 8.06. Found: C, 60.08; H, 8.01.
4,4-Dim eth oxy-3-m eth yl-2-bu ta n on e (9). Dry HCl gas
(6 g, 0.16 mol) was dissolved in dry methanol (250 mL) in a
dry 1000 mL RBF. The keto aldehyde 8 (38 g, 0.38 mol) was
dissolved in dry methanol (250 mL) and added dropwise over
30 min to this HCl/methanol solution at room temperature.
The solution was stirred for 48 h under an argon atmosphere
and then neutralized with solid sodium methoxide as the
solution was cooled in an ice-water bath. The precipitated
salts were filtered off and rinsed with dichloromethane. The
original red filtrate and the dichloromethane washings were
combined and taken to dryness on a rotary evaporator. This
afforded a dark oil that was fractionally distilled under high
vacuum (28-32 °C, 0.05-0.5 mmHg) using a 26 cm Vigreux
column to afford four fractions (34.3 g total) of the desired
â-keto acetal mixed with the enol ether byproduct. Fraction
(22) Sessler, J . L.; Gebauer, A.; Hoehner, M. C.; Lynch, V. Submitted
to J . Am. Chem. Soc.

9258 J . Org. Chem., Vol. 62, No. 26, 1997
Sessler et al.
separated off, and the aqueous layer was extracted four times
(600 mL total) with dichloromethane. All the organic layers
were combined and washed with aqueous 10% HCl (four times;
700 mL total) and then with brine (1 × 175 mL). The resulting
brown organic solution was then dried over sodium sulfate and
placed on a rotary evaporator to remove the solvents. Hexanes
(25 mL) were added to the resulting brown oil, and the mixture
was cooled in an ice water bath while crystallization was
induced with a glass rod. The resulting dark solid was
dissolved in hot hexanes (175 mL), giving a small amount of
an immiscible oil. The hexane solution was decanted from the
(75.5 MHz, CDCl3) δ 8.2, 20.8, 56.5, 121.7, 144.8, 170.7; HRMS
m/z calcd for C12H17O5 241.1076, found 241.1074. Anal. Calcd
for C12H16O5: C, 59.99; H, 6.71. Found: C, 60.07; H, 6.73.
3,4-Dim eth yl-2,5-bis[[5-(ben zyloxyca r bon yl)-4-eth yl-3-
m eth ylp yr r ol-2-yl]m eth yl]fu r a n (16). Diacetoxy furan 15
(3.0 g, 0.125 mol) and benzyl 3-ethyl-4-methylpyrrole-2-car-
boxylate8 (6.1 g, 0.025 mol) were combined in a 500 mL RBF
and dissolved in nitromethane (145 mL). The clear yellow
solution was heated to 50 °C and p-toluenesulfonic acid
monohydrate (1.5 g, 0.0079 mol) added. The solution was
stirred at 50 °C for 4 h, at which time saturated aqueous
sodium bicarbonate (100 mL) was added. The resulting two-
phase mixture was separated and the aqueous layer extracted
(1 × 100 mL) with dichloromethane. The organic layers were
combined and washed (1 × 100 mL) with brine and dried over
sodium sulfate. Solvents were removed using a rotary evapo-
rator to afford a black/brown oil. The oil was placed under
high vacuum under which conditions the oil solidified after
approximately 5 min. Purification of the sticky solid was
accomplished by column chromatography using silica gel that
was pretreated with anhydrous ammonia as the solid support
and dichloromethane as the eluent. After one column (6 cm
× 17 cm), 3.3 g (43%) of 16 was obtained in >98% purity. This
was used in the ensuing cyclizations without further purifica-
tion. An analytical sample, however, was obtained as the
result of a second chromatographic purification made using
the above conditions: TLC reference (silica gel, 100% dichlo-
romethane eluent) Rf pyrrole ) 0.62, Rf 15 ) 0.38, Rf 16 )
oil and allowed to cool, resulting in
a powdery, yellow
precipitate that was filtered and rinsed with cold hexanes. A
second crop was obtained by removing the solvents from the
filtrate and cooling the oil that remained. The solid that
formed was dissolved in dichloromethane and passed through
a glass frit containing 17.5 g of silica gel using so-called flash
conditions. The resulting filtrate was taken to dryness using
a rotary evaporator, giving an orange oil that solidified upon
cooling. To remove the small amount of starting furan from
both the first and second crops, both crops were combined with
70 mL of pentane and heated at reflux for 10 min. The
resulting solution was allowed to cool, first to room tempera-
ture, and then in an ice-water bath. The solids obtained by
this procedure were collected by filtration and rinsed with cold
pentane to give product 13 (7.38 g, 59%) as a tan solid: mp
1
65-68 °C; H NMR (300 MHz, CDCl3) δ 2.29 (s, 3H), 2.31 (s,
3H), 3.93 (s, 3H), 9.86 (s, 1H); 13C NMR (75.5 MHz, CDCl3) δ
8.6, 9.0, 52.1, 132.2, 132.4, 142.3, 148.2, 159.5, 180.2; HRMS
m/z calcd for C9H11O4 183.0657, found 183.0660. Anal. Calcd
for C9H11O4: C, 59.34; H, 5.53. Found: C, 59.05; H, 5.59.
2,5-Bis(h yd r oxym eth yl)-3,4-d im eth ylfu r a n (14). A 1 M
solution of LiAlH4 in THF (100 mL) was placed in a dry 500
mL RBF under an argon atmosphere. This solution was then
stirred at room temperature in a water bath as 13 (6 g, 0.033
mol) dissolved in THF (70 mL) was added dropwise over 30
min. The resulting solution was allowed to stir at room
temperature for 3 h. The reaction was then cooled in an ice-
water bath and quenched via careful addition of water (100
mL). After the water addition, a dilute sodium hydroxide
solution (100 mL) was added, resulting in a white precipitate
that was filtered off and washed first with water and then with
copious amounts of dichloromethane. The aqueous layer of
the filtrate was separated off and extracted with copious
amounts of dichloromethane. All of the organic phases were
then combined and washed once with aqueous 10% HCl and
once with brine prior to being dried over sodium sulfate. After
drying, the solvents were removed using a rotary evaporator
to give an orange oil, 14 (3.9 g, 76%), that solidified upon
cooling: 1H NMR (300 MHz, CDCl3) δ 1.92 (s, 6H), 2.60 (bs,
2H), 4.50 (s, 4H); 13C NMR (75.5 MHz, CDCl3) δ 8.1, 55.3,
118.8, 148.2; HRMS m/z calcd for C8H12O3 156.0786, found
156.0781. Anal. Calcd for C8H12O3: C, 61.52; H, 7.74.
Found: C, 61.26; H, 7.69.
1
0.49; H NMR (300 MHz, CDCl3) δ 1.10 (t, 6H), 1.83 (s, 6H),
1.96 (s, 6H), 2.75 (q, 4H), 3.77 (s, 4H), 5.28 (s, 4H), 7.30-7.41
(m, 10H), 8.57 (bs, 2H); 13C NMR (75.5 MHz, CDCl3) δ 8.3,
8.5, 15.1, 18.5, 23.4, 65.4, 116.3, 116.9, 127.9, 128.4, 130.0,
134.4, 136.7, 144.6, 161.1; HRMS m/z calcd for C38H42N2O5
606.3094, found 606.3093. Anal. Calcd for C38H42N2O5‚H2O:
C, 73.05; H, 7.10; N, 4.48. Found: C, 73.07; H, 6.83; N, 4.46.
2-Met h yl-3-oxo-1,1-d im et h oxyp en t a n e (10). Sodium
methoxide (54 g, 1 mol) was weighed into an oven-dried 1 L,
three-neck RBF equipped with a mechanical stirrer, reflux
condenser, and an addition funnel. The RBF was cooled in
an ice-water bath, and methyl formate (557 g, 9.28 mol) was
added via an addition funnel over 10 min. The resulting thick
slurry was stirred at room temperature for 10 min, after which
time 3-pentanone (86 g, 1 mol) was added over 10 min. The
nonhomogeneous solution was set to reflux for 2 h. During
the reflux period, dry HCl gas (38.9 g, 1.08 mol) was dissolved
in dry methanol (226 mL, 5.59 mol) and the solution placed
in a 2 L, three-neck RBF equipped with a mechanical stirrer
and an argon inlet. After the reflux period, the methyl formate
slurry was cooled to room temperature and then added
portionwise over 20 min to the HCl/methanol solution, which
was being cooled in an ice-water bath. After the addition was
complete, the mixture was stirred at room temperature under
argon for 18 h. To neutralize the solution, sodium methoxide
(14 g, 0.26 mol) was dissolved in methanol (200 mL) and added
portionwise to the reaction until the pH of the reaction mixture
was between 6 and 7. The resulting salts were filtered and
washed with dichloromethane, and the filtrate was placed on
a rotary evaporator to remove all solvents. The remaining oil
was vacuum distilled using a 30 cm fractional distillation
column. Six fractions were taken that distilled between 30
and 36 °C/0.4-0.6 mmHg. Proton NMR spectral analysis
indicated that the first five fractions (98.4 g total) contained
between 98% and 80% pure 10. Fraction 6 (10.1 g; <20% of
the total yield) was discarded, and fractions 1-5 were com-
bined to afford 98.4 g of 10 that was >95% pure as judged by
1H NMR spectral analysis. This material was carried on in
the synthesis of 12, while analytical samples were obtained
by performing a second fractional distillation: 1H NMR (300
MHz, CDCl3) δ 1.00-1.07 (m, 6H), 2.49 (m, 2H), 2.89 (m, 1H),
3.34 (s, 6H), 4.39 (d, 1H); 13C NMR (75.5 MHz, CDCl3) δ 7.4,
12.6, 36.3, 48.7, 52.7, 55.6, 106.3; HRMS m/z calcd for C8H16O3
160.1100, found 160.1099. Anal. Calcd for C8H16O3: H, 10.07;
C, 59.96. Found: H, 10.02; C, 60.03.
2,5-Bis(a cetoxym eth yl)-3,4-d im eth ylfu r a n (15). The fu-
ran dialcohol 14 (3.0 g, 0.0192 mol) was placed in a 250 mL
RBF equipped with a magnetic stirrer. First THF (125 mL)
and then pyridine (4.3 mL, 0.0532 mol) were added. The
solution was cooled in an ice-water bath and acetyl chloride
(3.7 mL, 0.052 mol) subsequently added. The reaction flask
was removed from the ice-water bath and stirred at room
temperature for 4 h. Then a solution of aqueous concentrated
sodium bicarbonate (100 mL) was added portionwise. The
resulting two-phase solution was separated and the aqueous
layer extracted twice with dichloromethane. The combined
organic layers were washed twice with aqueous 5% HCl, once
with saturated, aqueous sodium bicarbonate and once with
brine. The organic solution was dried over sodium sulfate and
the solvent removed using a rotary evaporator to give a brown
oil, 15 (4.6 g, 99%), which solidified upon cooling. The 1H NMR
spectrum of this material showed it to be >98% pure, and it
was, therefore, used in the next reaction step without further
purification. For analysis, a purified sample was obtained via
column chromatography using silica gel as the solid support
and dichloromethane as the eluent. For 15: 1H NMR (300
MHz, CDCl3) δ 1.96 (s, 6H), 2.06 (s, 6H), 5.00 (s, 4H); 13C NMR
Meth yl 3-Eth yl-4-m eth ylfu r a n -2-ca r boxyla te (12). An-
hydrous diethyl ether (110 mL) and 1,1,1,3,3,3-hexamethyl-
disilazane (66 mL, 0.313 mol) were combined in an oven-dried,

All-Alkyl-Substituted Mono-, Di-, and Trioxasapphyrins
J . Org. Chem., Vol. 62, No. 26, 1997 9259
1 L, three-neck RBF equipped with a magnetic stir bar, reflux
condenser, and an argon inlet. A solution of 1.6 M n-
butyllithium in hexanes (195 mL, 0.313 mol) was added via
syringe at a rate sufficient to maintain a gentle reflux. After
the addition was complete, the solution was set to reflux for
0.5 h. After this time, the solvents were removed under
aspirator vacuum to give a white solid. This solid was
dissolved in dry THF (200 mL) and stirred in a dry ice/acetone
bath. Once cool, methyl bromoacetate (29.6 mL, 0.313 mol),
dissolved in dry THF (60 mL), was added over the course of
20 min. The resulting thick, yellow mixture was stirred an
additional 10 min in the cooling bath before 10 (50 g, 0.313
mol), dissolved in dry THF (60 mL), was added over a period
of 15 min with continued cooling. After the addition was
complete, the reaction was stirred in the cooling bath while
being allowed to warm to approximately -10 °C over a period
of 3 h. The reaction was then stirred at room temperature
for an additional 1 h. The resulting orange-colored solution
was poured into an ice-water/diethyl ether mixture (1000 mL;
1:1). The two-phase solution that resulted was separated and
the aqueous layer extracted three times with diethyl ether (600
mL total). The combined organic layers were washed once
with aqueous 10% HCl and twice with an aqueous brine
solution. This solution was dried over sodium sulfate, and the
solvent was removed using a rotary evaporator to give an
orange oil that was subjected to distillation under high vacuum
with the heating bath not exceeding 70 °C. This served to
remove unreacted 10 and enol ether. After this operation, the
dark oil that remained in the still pot was heated to 180 °C,
resulting in the distillation of methanol. The RBF was
removed from the heating bath after the distillation head
temperature dropped below 50 °C. The oil remaining in the
still pot was allowed to cool and subjected anew to vacuum
distillation with the fraction boiling between 45 and 50 °C/
0.025-0.05 mmHg being collected. Proton NMR spectral
analysis confirmed that this fraction (13.9 g, 28%) was product
12 that was at least 95% pure. This material was carried on
in the subsequent reactions. Analytical samples were obtained
by column chromatography using silica gel and 17% ethyl
acetate in hexanes: 1H NMR (300 MHz, CDCl3) δ 1.14 (t, 3H),
1.99 (s, 3H), 2.75 (q, 2H), 3.88 (s, 3H), 7.26 (s, 1H); 13C NMR
(75.5 MHz, CDCl3) δ 7.7, 14.0, 17.3, 51.4, 122.4, 137.4, 139.5,
142.1, 159.8; HRMS m/z calcd for C9H13O3 169.0865, found
169.0868. Anal. Calcd for C9H12O3: C, 64.27; H, 7.19.
Found: C, 64.18; H, 7.22.
bis(tributyltin) (34.3 g, 0.0591 mol) were combined in an oven-
dried 250 mL RBF equipped with an argon inlet, magnetic
stir bar, and reflux condenser. Distilled toluene (450 mL) was
added and the clear, yellowish solution stirred at room
temperature while argon was bubbled through the solution
for approximately 10 min. Tetrakis(triphenylphosphine)-
palladium (1.2 g, 1 mmol) was added, and the solution was
set to reflux while keeping it under argon atmosphere. The
solution was heated at reflux for 48 h and then allowed to cool
to room temperature. Once cool, the dark solution was filtered
through Celite. The solvent was then removed using a rotary
evaporator to give a dark solid. Hexanes were added to this
solid and then filtered to give 19 (5.35 g, 54%). A second crop
was obtained by removing the solvent from the hexanes filtrate
and placing the oil in the freezer for 48 h. The solid that
formed was filtered and rinsed with cold hexanes to give an
1
additional 0.78 g of 19: mp 157-160 °C; H NMR (300 MHz,
CDCl3) δ 1.13 (t, 6H), 2.26 (s, 6H), 2.75 (q, 4H), 3.87 (s, 6H);
13C NMR (75.5 MHz, CDCl3) δ 8.5, 14.1, 17.4, 51.5, 121.4,
138.4, 138.8, 144.2, 159.8; HRMS m/z calcd for C18H22O6
334.1416, found 334.1418. Anal. Calcd for C18H22O6: H, 6.64;
C, 64.64. Found: H, 6.69; C, 64.36.
5,5′-Bis(h yd r oxym eth yl)-4,4′d ieth yl-3,3′-d im eth yl-2,2′-
bifu r a n (20). Lithium aluminum hydride (LAH, 3.5 g, 0.0922
mol) was weighed out in an oven-dried 1000 mL RBF. Dry
THF (325 mL) was placed in an addition funnel and added
dropwise to the LAH while the reaction flask was being cooled
in an ice-water bath. Bifuran 19 (3.0 g, 9 mmol) was then
dissolved in dry THF (170 mL), placed in an addition funnel,
and added dropwise to the above LAH/THF mixture. After
the addition was complete, the reaction was allowed to stir at
room temperature for 0.5 h and then heated at reflux for 1 h.
The solution was allowed to cool to room temperature in the
air and then cooled further in an ice-water bath. The reaction
was carefully quenched with water (75 mL), and then a 1 M
aqueous NaOH solution (75 mL) was added. The white solid
that formed as the result of the sodium hydroxide addition
was filtered off and washed first with water and then copious
amounts of dichloromethane. The two-phase filtrate was
separated and the aqueous layer extracted five times with
dichloromethane. The combined organic layers were washed
one time with an aqueous brine solution and dried over sodium
sulfate. The solvent was removed using a rotary evaporator
to give a cream-colored solid that was taken up in hexanes
and filtered to give methylethylbifuran dialcohol 20 (2.3 g,
94%): mp > 270 °C dec; 1H NMR (300 MHz, CDCl3) δ 1.14 (t,
6H), 2.12 (s, 6H), 2.43 (q, 4H), 4.59 (s, 4H); 13C NMR (75.5
MHz, CDCl3) δ 9.0, 15.3, 16.7, 55.8, 118.4, 126.1, 141.6, 148.0;
HRMS m/z calcd for C16H22O4 278.1518, found 278.1525. Anal.
Calcd for C16H22O4: C, 69.04; H, 7.97. Found: C, 68.92; H,
7.93.
Meth yl 2-Br om o-4-eth yl-3-m eth ylfu r a n -2-ca r boxyla te
(18). Furan 12 (4.0 g, 0.024 mol) was placed in a dry 100 mL
RBF and dissolved in dry dimethylformamide (DMF, 10 mL).
A second portion of dry DMF (10 mL) was placed in a 25 mL
RBF and cooled in
a dry ice/acetone bath under argon.
Bromine (2.5 mL, 0.048 mol) was added dropwise to the latter
portion of cooled DMF via an addition funnel and with stirring.
As the addition progressed, the solution solidified. The
reaction flask was then allowed to warm until this solid
dissolved and a homogeneous solution was produced. This
solution was placed in an addition funnel in portions and added
dropwise with stirring to the original furan/DMF solution still
at room temperature. After all of the Br2/DMF had been added
(ca. 1 h), the reaction was allowed to stir at room temperature
for an additional 2 h. The resulting dark red solution was
extracted eight times with a total of about 400 mL of 8.5%
ethyl acetate in hexanes. The ethyl acetate/hexane solution
was reduced to an orange oil by use of a rotary evaporator.
This oil was distilled under high vacuum (ca. 0.5 mmHg). The
fractions collected consisted sequentially of (1) DMF; (2) furan,
12; and finally (3) bromofuran, 18 (4.3 g, 74%, boiling point:
85 °C/0.1 mmHg). Analytical samples were obtained by
column chromatography using silica gel as the solid support
and 17% ethyl acetate in hexanes as the eluent: 1H NMR (300
MHz, CDCl3) δ 1.13 (t, 3H), 1.95 (s, 3H), 2.77 (q, 2H), 3.87 (s,
3H); 13C NMR (75.5 MHz, CDCl3) δ 8.7, 13.9, 18.0, 51.6, 122.3,
125.3, 139.0, 140.7, 158.9; HRMS m/z calcd for C9H12O3Br:
246.9970, found 246.9960. Anal. Calcd for C9H11O3Br: C,
43.75; H, 4.49. Found: C, 43.65; H, 4.52.
4,4′-Dieth yl-5,5′-difor m yl-3,3′-dim eth yl-2,2′-bifu r an (21).
The bifuran dialcohol 20 (2.3 g, 0.0084 mol) was placed in a
500 mL RBF under a nitrogen atmosphere. Dry dichlo-
romethane (250 mL) was added and the solution stirred at
room temperature for 6 h during which time MnO2 (24 g,
0.2760 mol) was added portionwise. After the addition was
complete, the solution was set to reflux for 18 h. The resulting
dark mixture was filtered through Celite to give a clear,
orange-tinted solution. The solvent was removed using a
rotary evaporator. This produced a brown solid that was
dissolved in a minimum of hot dichloromethane. Hexanes
were added, and the resulting dark solution was placed on a
rotary evaporator. The solvents were removed until a yellow
solid started to precipitate, at which time more hexanes (ca.
50 mL) were added and the mixture placed in the freezer
overnight. The solid that formed was filtered and rinsed with
1
cold hexanes to give 21 (1.38 g, 60.4%): mp 128-130 °C; H
NMR (300 MHz, CDCl3) δ 1.22 (t, 6H), 2.35 (s, 6H), 2.79 (q,
4H), 9.76 (s, 2H); 13C NMR (75.5 MHz, CDCl3) δ 8.5, 14.6, 16.6,
123.0, 141.1, 146.1, 147.4, 177.3; HRMS m/z calcd for C16H19O4
275.1283, found 275.1286. Anal. Calcd for C16H18O4: H, 6.62;
C, 70.04. Found: H, 6.67; C, 69.77.
3,7,18,22-Te t r a e t h yl-2,8,12,13,17,23-h e xa m e t h yl-27-
oxa sa p p h yr in (5). The oxatripyrrane 16 (0.323 g, 5.3 mmol)
was placed in a 250 mL RBF along with 10% palladium on
Dim eth yl 4,4′-Dieth yl-3,3′-d im eth yl-2,2′-bifu r a n -5,5′-d i-
ca r boxyla te (19). Bromofuran 18 (14.6 g, 0.0591 mol) and

9260 J . Org. Chem., Vol. 62, No. 26, 1997
Sessler et al.
carbon (0.2 g), triethylamine (4 drops), and THF (150 mL). A
hydrogen atmosphere was introduced at atomospheric pres-
sure and the solution stirred at room temperature for 24 h
protected from light. The resulting solution was filtered
through Celite with the Celite being rinsed with THF. The
solvent was removed with the aid of a rotory evaporator to
give the oxatripyrrane dicarboxylic acid 17 as a brown film in
the RBF. Diformylbipyrrole 3 (0.145 g, 5.3 mmol) was placed
in a 2 L RBF and dissolved in methanol (100 mL). Once 3
had dissolved, chloroform (900 mL) was added to the 2 L RBF
while a second portion of chloroform (100 mL) was used to
dissolve 17. This latter solution was combined with the
chloroform/methanol/3 solution with concentrated aqueous
HCl (10 drops) then being added. The solution was stirred
open to air, protected from light for 6 h after which the 2,3-
dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (1 equiv) was
added. After this solution was stirred for 10 min, the solvents
were removed from the reaction mixture giving a dark green
film in the RBF. The crude sapphyrin was purified by column
chromatography using silica gel as the solid phase and a
dichloromethane/trifluoroacetic acid (TFA)/methanol gradient
as the mobile phase. Fractions that contained the sharp
absorption band at 450 nm were combined and crystallized
using chloroform layered with hexanes to afford the oxasap-
phyrin 5 (0.153 g, 27%) as metallic blue needles. By washing
a chloroform solution of 5b (the bis(TFA) salt) with aqueous 1
M NaOH (3 × 50 mL) and then with aqueous 10% HCl (3 ×
50 mL) the dihydrochloride salt was obtained. This salt was
also crystallized as blue metallic needles by dissolving 5a in a
small amount of chloroform that was then layered with
hexanes. 5b: 1H NMR (300 MHz, CDCl3) δ -4.12 (bs, 2H),
-2.99 (bs, 2H), 2.10 (t, 6H), 2.21 (t, 6H), 4.04 (s, 6H), 4.19 (s,
6H), 4.29 (s, 6H), 4.45 (q, 4H), 4.66 (q, 4H), 11.40 (s, 2H), 11.65
(s, 2H); 13C NMR (125 MHz, CDCl3) δ 12.7, 13.4, 15.3, 17.6,
17.9, 20.7, 21.2, 89.3, 101.2, 127.4, 130.9, 131.2, 132.3, 134.6,
136.3, 138.8, 142.6, 145.2, 150.6; HRMS m/z calcd for C38H45N4O
573.3593, found 573.3585.
chloroform and then layered with hexanes. The dioxasapphy-
rin 6 (53 mg, 17.1%) crystallized as metallic blue needles. By
washing a chloroform solution of of 6b (bis(TFA) salt) with
aqueous 1 M NaOH (3 × 50 mL) and then with aqueous 10%
HCl (3 × 50 mL), the dihydrochloride salt was obtained. This
analogue was also crystalized as metallic blue needles by
dissolving 6a in a small amount of chloroform and layering
with hexanes. For 6b: 1H NMR (300 MHz, CDCl3) δ -4.08
(bs, 2H), -3.11 (bs, 1H), 2.15 (t, 6H), 2.20-2.29 (m, 12H), 4.16
(s, 6H), 4.27 (s, 6H), 4.62-4.74 (m, 12H), 11.65 (s, 2H), 11.78
(s, 2H); 13C NMR (125 MHz, CDCl3/CD3OD) δ 12.8, 15.4, 16.8,
17.6, 18.3, 20.8, 21.0, 21.1, 94.3, 97.8, 133.1, 134.8, 137.5, 137.9,
140.0, 144.6, 145.4, 145.9, 146.2, 147.9; HRMS m/z calcd for
C40H48N3O2 602.3747, found 602.3737.
3,7,18,22-Tetr aeth yl-2,8,12,13,17,23-h exam eth yl-25,27,29-
tr ioxa sa p p h yr in (7). The trioxasapphyrin 7 was synthesized
using the same procedure used to prepare 6. The following
reagents and amounts were used: oxatripyrrane 16 (0.349 g,
0.6 mmol), 10% palladium on carbon (0.2 g), triethylamine (3
drops), THF (150 mL), and hydrogen (1 atm). Cyclization:
Diformylbifuran 21 (0.158 g, 0.6 mmol), methanol (50 mL),
chloroform (1000 mL), and concentrated aqueous concentrated
HCl (10 drops). Purification was achieved by column chro-
matography using silica gel as the solid phase and a dichlo-
romethane/TFA/methanol gradient as the mobile phase. Frac-
tions that contained the sharp absorption band at 450 nm were
combined and solvents removed giving a metallic blue film in
the RBF. This material was purified twice more using the
same conditions as above to afford the trioxasapphyrin 7 (0.167
g, 29%) as a metallic blue solid. For 7b: 1H NMR (300 MHz,
CDCl3) δ -2.9 (bs, 2H), 2.06 (t, 12H), 4.08 (s, 6H), 4.10 (s, 6H),
4.18 (s, 6H), 4.50-4.63 (m, 8H), 11.29 (s, 2H), 11.57 (s, 2H);
13C NMR (125 MHz, CDCl3) δ 12.7, 13.1, 14.9, 16.6, 17.5, 20.8,
21.0, 91.2, 99.3, 133.5, 134.1, 138.6, 139.3, 142.4, 146.2, 146.8,
147.7, 148.0, 152.2; HRMS m/z calcd for C38H44N2O3 576.3352,
found 576.3345.
3,8,12,13,17,22-Hexa eth yl-2,7,18,23-tetr a m eth yl-25,29-
d ioxa sa p p h yr in (6). The oxasapphyrin 6 was synthesized
using the same procedure used to prepare 5. The following
reagents amounts were used: Tripyrrane 2 (0.501 g, 0.8 mmol),
10% palladium on carbon (0.3 g), triethylamine (3 drops), THF
(150 mL), and hydrogen (1 atm). Cyclization: Diformylbifuran
21 (0.207 g, 0.8 mmol), methanol (100 mL), chloroform (1300
mL), and concentrated aqueous concentrated HCl (10 drops).
Purification was achieved by column chromatography using
silica gel as the solid phase and a dichloromethane/TFA/
methanol gradient as the mobile phase. Fractions that
contained the sharp absorption band at 450 nm were com-
bined, and solvents were removed. The metallic blue film that
remained in the RBF was dissolved in a minimum amount of
Ack n ow led gm en t. This work was supported by
NSF Grant Nos. CHE 9122161 and CHE 9725399 to
J .L.S.
Su p p or tin g In for m a tion Ava ila ble: Tables of crystal-
lographic data collection procedures and parameters, complete
atomic coordinates and thermal parameters, bond distances
and angles, torsion angles, and least-squares planes (99 pages).
This material is contained in libraries on microfiche, im-
mediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
J O9715736