Investigation of conditions giving minimal scrambling in the synthesis of trans-porphyrins from dipyrromethanes and aldehydes

Article abstract of DOI:10.1021/jo982452o

A diverse range of reaction conditions for the MacDonald-type 2 + 2 condensation of a 5-substituted dipyrromethane and an aldehyde has been studied with the goal of eliminating acid-catalyzed polypyrrolic rearrangement reactions in the synthesis of trans-porphyrins. A rapid screening method based on laser desorption mass spectrometry has enabled the degree of rearrangement to be examined as a function of the acid catalyst, reagent concentration, reagent stoichiometry, solvent, salts, and temperature. For condensations involving 5-mesityldipyrromethane, we identified reaction at 10 mM concentration in CH₂Cl₂ with 17.8 mM TFA as optimal conditions for suppression of the rearrangement reaction. A synthetic procedure based on these conditions allowed the expedient synthesis of multigram batches of eight trans-porphyrins in 48-14% yield from 5-mesityldipyrromethane, with minimal chromatography. The same conditions were also effective for the synthesis of two trans-porphyrins derived from 5-(2,6-dichlorophenyl)dipyrromethane. Application of the same conditions to condensations involving 5-phenyldipyrromethane showed extensive rearrangement. Examination of a wide range of conditions showed that slow reactions are associated with less rearrangement. Two sets of conditions were identified that gave little or no scrambling: (1) condensation at 10 mM in MeCN at 0 °C with BF₃-Et₂O catalysis in the presence Of NH₄Cl followed by DDQ oxidation and (2) condensation at 0.1 M in DMSO at 100 °C in the presence of NH₄Cl (with no added acid catalyst) with air oxidation. Although yields are typically less than 10%, the elimination of the need to perform tedious chromatography improves the methodology available for the preparation of trans-porphyrins, derived from sterically unhindered dipyrromethanes.

Full text of DOI:10.1021/jo982452o

2864
J . Org. Chem. 1999, 64, 2864-2872
In vestiga tion of Con d ition s Givin g Min im a l Scr a m blin g in th e
Syn th esis of tr a n s-P or p h yr in s fr om Dip yr r om eth a n es a n d
Ald eh yd es
Benjamin J . Littler, Yangzhen Ciringh, and J onathan S. Lindsey*
Department of Chemistry, North Carolina State University, Raleigh, North Carolina 27695-8204
Received December 16, 1998
A diverse range of reaction conditions for the MacDonald-type 2 + 2 condensation of a 5-substituted
dipyrromethane and an aldehyde has been studied with the goal of eliminating acid-catalyzed
polypyrrolic rearrangement reactions in the synthesis of trans-porphyrins. A rapid screening method
based on laser desorption mass spectrometry has enabled the degree of rearrangement to be
examined as a function of the acid catalyst, reagent concentration, reagent stoichiometry, solvent,
salts, and temperature. For condensations involving 5-mesityldipyrromethane, we identified reaction
at 10 mM concentration in CH2Cl2 with 17.8 mM TFA as optimal conditions for suppression of the
rearrangement reaction. A synthetic procedure based on these conditions allowed the expedient
synthesis of multigram batches of eight trans-porphyrins in 48-14% yield from 5-mesityldipyr-
romethane, with minimal chromatography. The same conditions were also effective for the synthesis
of two trans-porphyrins derived from 5-(2,6-dichlorophenyl)dipyrromethane. Application of the same
conditions to condensations involving 5-phenyldipyrromethane showed extensive rearrangement.
Examination of a wide range of conditions showed that slow reactions are associated with less
rearrangement. Two sets of conditions were identified that gave little or no scrambling: (1)
condensation at 10 mM in MeCN at 0 °C with BF3‚Et2O catalysis in the presence of NH4Cl followed
by DDQ oxidation and (2) condensation at 0.1 M in DMSO at 100 °C in the presence of NH4Cl
(with no added acid catalyst) with air oxidation. Although yields are typically less than 10%, the
elimination of the need to perform tedious chromatography improves the methodology available
for the preparation of trans-porphyrins, derived from sterically unhindered dipyrromethanes.
In tr od u ction
for photodynamic cancer therapy,8 bilayer lipid mem-
brane spanning arrays,9 and liquid crystals.10 Good syn-
thetic methods for preparing trans-porphyrins are es-
sential for the construction of such materials and devices.
As part of our research program in porphyrin chem-
istry, we have been developing methods for the synthesis
of versatile porphyrin building blocks bearing a wide
range of functionality.11 We recently developed a conve-
nient preparation of analytically pure multigram batches
of 5-substituted dipyrromethanes by the acid-catalyzed
condensation of an aldehyde with excess pyrrole in
solvent-free conditions.12 Condensation of a dipyrro-
methane with an aldehyde in a MacDonald-type 2 + 2
condensation,13 as illustrated in Scheme 1, has been used
to prepare a wide range of meso-substituted trans-
porphyrins.14
meso-Substituted trans-porphyrins are key structural
components found in a wide range of model systems in
biomimetic and materials chemistry. A trans-porphyrin
provides a linear substitution pattern that can be used
for the construction of porphyrin-based architectures with
a well-defined structure. Recent applications of trans-
porphyrins in model systems include charge separation
devices that mimic photosynthesis,1 enzyme models,2
materials with nonlinear optical properties,3 chiral cata-
lysts,4 chiral sensors,5 synthetic receptors for small
molecules,6 optoelectronic devices,7 potential sensitizers
(1) Wasielewski, M. R. Chem. Rev. 1992, 92, 435-461. Gust, D.;
Moore, T. A.; Moore, A. L. Acc. Chem. Res. 1993, 26, 198-205. Osuka,
A.; Marumo, S.; Mataga, N.; Taniguchi, S.; Okada, T.; Yamazaki, I.;
Nishimura, Y.; Ohno, T.; Nozaki, K. J . Am. Chem. Soc. 1996, 118, 155-
168. Collin, J .-P.; Harriman, A.; Heitz, V.; Odobel, F.; Sauvage, J .-P.
Coord. Chem. Rev. 1996, 148, 63-69. Liddell, P. A.; Kuciauskas, D.;
Sumida, J . P.; Nash, B.; Nguyen, D.; Moore, A. L.; Moore, T. A.; Gust,
D. J . Am. Chem. Soc. 1997, 119, 1400-1405.
(2) Volz, H.; Holzbecher, M. Angew. Chem., Int. Ed. Engl. 1997, 36,
1442-1445. Wagenknecht, H.-A.; Claude, C.; Woggon, W.-D. Helv.
Chim. Acta 1998, 81, 1506-1520.
(3) Yeung, M.; Ng, A. C. H.; Drew, M. G. B.; Vorpagel, E.; Breitung,
E. M.; McMahon, R. J .; Ng, D. K. P. J . Org. Chem. 1998, 63, 7143-
7150. Qureshi, F. M.; Martin, S. J .; Long, X.; Bradley, D. D. C.; Henari,
F. Z.; Blau, W. J .; Smith, E. C., Wang, C. H., Kar, A. K.; Anderson, H.
L. Chem. Phys. 1998, 231, 87-94. Blake, I. M.; Anderson, H. L.;
Beljonne, D.; Bre´das, J .-L.; Clegg, W. J . Am. Chem. Soc. 1998, 120,
10764-10765.
(7) Wagner, R. W.; Lindsey, J . S. J . Am. Chem. Soc. 1994, 116,
9759-9760. Wagner, R. W.; Lindsey, J . S.; Seth, J .; Palaniappan, V.;
Bocian, D. F. J . Am. Chem. Soc. 1996, 118, 3996-3997.
(8) Lacey, J . A.; Phillips, D.; Milgrom, L. R.; Yahioglu, G.; Rees, R.
D. Photochem. Photobiol. 1998, 67, 97-100.
(9) Nishino, N.; Wagner, R. W.; Lindsey, J . S. J . Org. Chem. 1996,
61, 7534-7544.
(10) Wang, Q. M.; Bruce, D. W. Tetrahedron Lett. 1996, 37, 7641-
7644. Wang, Q. M.; Bruce, D. W. Angew. Chem., Int. Ed. Engl. 1997,
36, 150-152.
(11) Lindsey, J . S.; Prathapan, S.; J ohnson, T. E.; Wagner, R. W.
Tetrahedron 1994, 50, 8941-8968. Wagner, R. W.; J ohnson, T. E.;
Lindsey, J . S. J . Am. Chem. Soc. 1996, 118, 11166-11180. Lindsey, J .
S. In Modular Chemistry; Michl, J ., Ed.; NATO ASI Series C:
Mathematical and Physical Sciences, Vol. 499; Kluwer Academic
Publishers: Dordrecht, 1997; pp 517-528.
(12) Littler, B. J .; Miller, M. A.; Hung, C.-H.; Wagner, R. W.; O’Shea,
D. F.; Boyle, P. D.; Lindsey, J . S. J . Org. Chem. 1999, 64, 1391-1396.
(13) Arsenault, G. P.; Bullock, E.; MacDonald, S. F. J . Am. Chem.
Soc. 1960, 82, 4384-4389.
(4) Halterman, R. L.; Mei, X. Tetrahedron Lett. 1996, 37, 6291-
6294.
(5) Furusho, Y.; Kimura, T.; Mizuno, Y.; Aida, T. J . Am. Chem. Soc.
1997, 119, 5267-5268.
(6) French, R. R.; Wirz, J .; Woggon, W.-D. Helv. Chim. Acta 1998,
81, 1521-1527.
10.1021/jo982452o CCC: $18.00 © 1999 American Chemical Society
Published on Web 03/26/1999

Minimal Scrambling in Synthesis of trans-Porphyrins
J . Org. Chem., Vol. 64, No. 8, 1999 2865
Sch em e 1
Sch em e 2
overall porphyrin yield during the course of the conden-
sation was monitored using UV-vis spectroscopy, by
removing small aliquots that were then oxidized by
DDQ.16 The porphyrin distribution in the aliquots was
then examined by time-of-flight laser desorption mass
spectrometry (LD-MS).17 The high sensitivity of mass
spectrometry enabled detection of trace amounts of
undesired porphyrin byproducts in aliquots removed from
the small-scale reactions (vide infra). The data produced
by mass spectrometry are semiquantitative; therefore we
have chosen to categorize the extent of scrambling on the
basis of the observed spectra (Figure 1):
At present, this methodology suffers from three major
limitations: (1) The condensation is performed in dilute
solution (10 mM). (2) Isolated yields of porphyrin are
modest (10-30%). (3) The product of a dipyrromethane-
aldehyde condensation is frequently not just the desired
trans-A2B2-porphyrin but a mixture of porphyrins that
can be extremely difficult to separate (especially the
trans-A2B2 and cis-A2B2 isomers). As a result, pure trans-
porphyrins have been typically available only in limited
quantities.
The exchange process frequently observed in polypyr-
rane condensations is proposed to occur by the acid-
catalyzed fragmentation of a polypyrrane 1 into pyrrolic
2 and azafulvene 3 components.15 As illustrated in
Scheme 2, recombination of 2 and 3 can form a new
polypyrrane 4 that cannot be formed by direct condensa-
tion of the dipyrromethane and aldehyde. Ultimately this
process leads to the production of a scrambled mixture
of porphyrins. The factors that promote the scrambling
process in MacDonald-type 2 + 2 condensations are
poorly understood, but suppression of scrambling is
essential for preparing large quantities of pure trans-
porphyrins. In this paper we describe a study of a wide
range of reaction conditions for the 2 + 2 condensation
that has led to refined synthetic procedures for the
preparation of trans-porphyrins.
Level 0
No scrambled products observed. Single
envelope corresponding to (M•)+ of the
expected A2B2-porphyrin.18
Level 1
Level 2
Level 3
Low levels of scrambled porphyrin.
Significant levels of scrambled porphyrin.
Peak intensities close to those anticipated from a
statistical mixture formed from the combination
of two aldehydes and pyrrole (A4 ) B4 ) 6.25%,
A3B ) AB3 ) 25%, cis- and trans-A2B2 ) 37.5%).
Skewed scrambling, such that the A2B2-porphyrin
is no longer the major component.
Level 4
1. Con den sation s with Ster ically Hin der ed Dipyr -
r om eth a n es. Previous studies have shown that 5-mesi-
tyldipyrromethane and an aldehyde can be condensed to
give pure trans-A2B2-porphyrins in 50-100 mg batches
after column chromatography.19,20 We sought to optimize
reaction conditions for the preparation of gram quantities
of sterically hindered trans-porphyrins with minimal
(16) Lindsey, J . S.; Schreiman, I. C.; Hsu, H. C.; Kearney, P. C.;
Marguerettaz, A. M. J . Org. Chem. 1987, 52, 827-836.
Resu lts a n d Discu ssion
(17) LD-MS of porphyrins gives almost exclusively the porphyrin
radical cation (M•)+ rather than the protonated species (M + H)+. See:
Srinivasan, N.; Haney, C. A.; Lindsey, J . S.; Zhang, W.; Chait, B. T. J .
Porphyrins Phthalocyanines, in press.
(18) The mass spectrum provides no distinction among cis- and
trans-A2B2-porphyrins. However, scrambling during the dipyrro-
methane-aldehyde condensation would not be expected to give
exclusively the cis-A2B2-porphyrin. Regardless, 1H NMR spectral
examination of the isolated trans-A2B2-porphyrin in each case exam-
ined showed no contaminating cis-A2B2-porphyrin.
Scr een in g Str a tegy. We adopted an empirical ap-
proach for reaction optimization, which required the
ability to rapidly screen a large number of experiments.
The reactions were performed on a small scale, and the
(14) Lindsey, J . S. In The Porphyrin Handbook; Kadish, K. M.,
Smith, K., Guilard, R., Eds.; Academic Press: Burlington, MA, 1999,
in press.
(15) Smith, K. M. In Porphyrins and Metalloporphyrins; Smith, K.
M., Ed.; Elsevier: Amsterdam, 1975; pp 29-58.
(19) Lee, C.-H.; Lindsey, J . S. Tetrahedron 1994, 50, 11427-11440.
(20) Ravikanth, M.; Strachan, J .-P.; Li, F.; Lindsey, J . S. Tetrahe-
dron 1998, 54, 7721-7734.

2866 J . Org. Chem., Vol. 64, No. 8, 1999
Littler et al.
Sch em e 3
DDQ.19,20 Figure 2 shows the spectroscopic yields for a
series of reactions run over a range of BF3‚Et2O concen-
tration (1.00-17.8 mM). LD-MS examination of the
aliquots removed at the time of maximum yield showed
Level 1 scrambling in all cases. Therefore the purity of
the final porphyrin product depends on removal of the
trace byproducts by chromatography.
F igu r e 1. Illustrative LD-MS data of scrambling levels
observed for the condensation of 5-phenyldipyrromethane and
p-tolualdehyde.
Examination of the porphyrin distribution over time
for the reaction catalyzed by 1.00 mM BF3‚Et2O showed
that scrambling increased from Level 0 to Level 1. This
observation is consistent with a study on a 2 + 2
condensation involving 5-phenyldipyrromethane where
scrambling was reduced by a short reaction time and
low BF3‚Et2O concentration.22 The data in Figure 2
show that such an approach is undesirable from a
synthetic standpoint, because this would diminish the
porphyrin yield. Also, the degree of scrambling is not
easily monitored while the reaction is in progress, so
determination of the optimal time to add the oxidant
would be difficult.
To find reaction conditions that gave no scrambling at
the time of maximum porphyrin yield, we screened
reactions for spectroscopic yield and scrambling as a
function of the acid catalyst, reaction solvent, reagent
concentration, reaction temperature, presence of catalytic
salts,23 and reagent ratio. A complete description of these
studies is included in the Supporting Information. The
key findings were as follows:
1. Reactions catalyzed by TFA gave Level 0 scrambling
for all aliquots examined regardless of the acid catalyst
concentration, reaction solvent, reagent concentration,
reaction temperature, presence of catalytic salts, or
reagent ratio.
F igu r e 2. Dependence of the spectroscopic yield on BF3‚Et2O
concentration (b 1.00, O 1.78, 2 3.16, 4 5.62, [ 10.0, and ]
17.8 mM) for the condensation of 5-mesityldipyrromethane and
p-tolualdehyde (10 mM) in CHCl3. Scrambling levels are shown
in parentheses.
chromatography. The condensation of 5-mesityldipyr-
romethane21 and p-tolualdehyde to form porphyrin 5 was
chosen as our initial model system (Scheme 3).
We reinvestigated the standard reaction conditions for
MacDonald-type 2 + 2 condensations; 5-mesityldipyr-
romethane (10 mM), p-tolualdehyde (10 mM) in CHCl3
catalyzed by BF3‚Et2O, followed by oxidation with
(21) During this study we found that use of analytically pure
dipyrromethanes, prepared as described in ref 12, was imperative to
achieve both the highest yields and the minimum scrambling.
(22) Wilson, G. S.; Anderson, H. L. Synlett 1996, 1039-1040.
(23) Li, F.; Yang, K.; Tyhonas, J . S.; MacCrum, K. A.; Lindsey, J . S.
Tetrahedron 1997, 53, 12339-12360.

Minimal Scrambling in Synthesis of trans-Porphyrins
J . Org. Chem., Vol. 64, No. 8, 1999 2867
Ta ble 1. Isola ted Yield of P or p h yr in s F or m ed by
Con d en sa tion of 5-Mesityld ip yr r om eth a n e w ith Va r iou s
Ald eh yd esa
2. CHCl3, CH2Cl2, and toluene were assessed as reac-
tion solvents. CH2Cl2 was preferred because reaction in
CHCl3 required a higher TFA concentration and conden-
sation in toluene gave lower yields. In CH2Cl2, 17.8 mM
TFA gave the highest spectroscopic yield and optimal
kinetics (40% in 30 min).
3. Identical yields and kinetics were observed for
reactions performed in CH2Cl2 freshly distilled from CaH2
and commercially supplied CH2Cl2 (Fisher, A.C.S. grade).
Drying and distillation of the solvent prior to reaction is
therefore unnecessary.
aldehyde
porphyrin yield (%) scrambling level
p-tolualdehyde
benzaldehyde
o-tolualdehyde
4-iodobezaldehyde
3-iodobenzaldehyde
p-anisaldehyde
pentafluorobenzaldehyde
n-hexanal
5
6
7
8
9
10
11
12
48
38
35
35
31
44
28
14
0
0
0
0
0
0
0
1
4. Use of a dipyrromethane and aldehyde concentration
greater than 10 mM led to an unacceptable decrease in
the porphyrin yield.
5. With TFA catalysis, cooling the reaction led to a
slower reaction rate and lower yields.
a
Reactions were performed with 5-mesityldipyrromethane (10
mM) and the aldehyde (10 mM) in CH2Cl2 with TFA (17.8 mM)
followed by oxidation with DDQ. All reactions were performed with
0.01 mol of dipyrromethane and aldehyde.
Ta ble 2. Isola ted Yield of P or p h yr in s F or m ed by
Con d en sa tion of Tw o Ald eh yd es w ith
6. For TFA catalysis, addition of simple inorganic salts
had negligible catalytic effect.
5-(2,6-Dich lor op h en yl)d ip yr r om eth a n ea
7. A 1:1 dipyrromethane:aldehyde ratio gave the high-
est yield of porphyrin.
8. The optimal conditions that emerged from this
survey are 5-mesityldipyrromethane (10 mM) and p-
tolualdehyde (10 mM) in undistilled CH2Cl2 with TFA
(17.8 mM) at room temperature, followed by oxidation
with DDQ.24
The optimum conditions were used to develop a pre-
parative procedure. The reaction was monitored spectro-
scopically, and DDQ was added when the spectroscopic
yield had stopped increasing (typically 30 min). After
stirring at room temperature for a further 1 h, the
reaction mixture was filtered through a pad of alumina
to separate porphyrin 5 from any unreacted oxidant, acid
catalyst, and polypyrrolic byproducts. No scrambled
1
byproducts were detected by LD-MS, H NMR spectros-
1
copy, or TLC, but close examination of the H NMR and
UV-vis spectra showed that a low level of chlorin
impurity was present.25 Attempts to prevent formation
of chlorin in the oxidation step by adding an excess of
DDQ (2 mol of DDQ per 1 mol of dipyrromethane),
heating under reflux in CH2Cl2, or using distilled and
degassed solvent were unsuccessful. However, reoxida-
tion with fresh DDQ in toluene at reflux26 removed the
chlorin and gave porphyrin 5 with excellent purity.
Due to the suppression of the scrambling process this
method was readily applied to gram-scale synthesis. For
example, condensation of 10 mmol of 5-mesityldipyr-
romethane and 10 mmol of p-tolualdehyde gave 1.78 g
(48% yield) of pure 5 within 6 h, requiring no chroma-
tography except for filtration through alumina after the
DDQ oxidation steps.
aldehyde
porphyrin yield (%) scrambling level
benzaldehyde
4-iodobenzaldehyde
13
14
35
26
0
0
a
Reactions performed with 5-(2,6-dichlorophenyl)dipyrromethane
(10 mM) and the aldehyde (10 mM) in CH2Cl2 with TFA (17.8 mM)
followed by oxidation with DDQ.
a general and simple gram-scale preparation of 5,15-
dimesityl-10,20-diarylporphyrins. The only modification
to the procedure was required for the reaction with
pentafluorobenzaldehyde because the porphyrin was
contaminated with non-porphyrin pigments, but these
were readily removed by triturating with hexanes. Such
pigments were also observed in the condensation with
n-hexanal and were also easily removed by trituration
with hexanes, however LD-MS showed a peak consistent
with Level 1 scrambling in this condensation. Whether
trace scrambling is a general occurrence for alkyl alde-
hydes was not pursued further in this study.
The scope of this procedure for preparing gram batches
of trans-porphyrins from 5-mesityldipyrromethane was
examined by condensation with the eight aldehydes
shown in Table 1. No scrambling was observed in the
syntheses with aryl aldehydes, so this procedure offers
We also examined whether the conditions optimized
for 5-mesityldipyrromethane could be applied to other
5-(2,6-disubstituted-aryl)dipyrromethanes. Two conden-
sations performed with 5-(2,6-dichlorophenyl)dipyr-
romethane are shown in Table 2. No scrambling was
observed, and the only differences due to the change in
the dipyrromethane were (1) an increase in the time
required for the porphyrin yield to reach a maximum
(typically 60-90 min) and (2) that a low solubility of
porphyrins 13 and 14 required that CH2Cl2 was added
to the toluene solution after reoxidation to prevent
(24) The stoichiometry of the dipyrromethane-aldehyde condensa-
tion requires 1.5 mol of DDQ per 1 mol of dipyrromethane (giving 3
mol of DDQ per 1 mol of porphyrinogen). We have found that the
oxidation can often be performed with less than the stoichiometric
amount (1 mol of DDQ per 1 mol of dipyrromethane) without a decrease
in the porphyrin yield or change in chlorin content. With 0.5 mol of
DDQ per 1 mol of dipyrromethane, the yield did decline and the amount
of chlorin increased.
(25) Crossley, M. J .; King, L. G. J . Org. Chem. 1993, 58, 4370-4375.
(26) Barnett, G. H.; Hudson, M. F.; Smith, K. M. Tetrahedron Lett.
1973, 2887-2888. Rousseau, K.; Dolphin, D. Tetrahedron Lett. 1974,
4251-4254. Barnett, G. H.; Hudson, M. F.; Smith, K. M. J . Chem. Soc.,
Perkin Trans. 1 1975, 1401-1403.

2868 J . Org. Chem., Vol. 64, No. 8, 1999
Littler et al.
Sch em e 4
scrambling, demonstrating that scrambling occurs much
more rapidly than porphyrinogen formation under the
conditions that were suitable for reactions of sterically
hindered dipyrromethanes. We therefore screened a wide
range of reaction conditions with the aim of suppressing
scrambling.
(B) Scop e of Stu d ies. Approximately 250 experi-
ments were performed in a search to suppress scrambling
in the condensation of 5-phenyldipyrromethane and
p-tolualdehyde. A complete description of all studies
performed is included in the Supporting Information,
with the results of principal synthetic and mechanistic
interest described below:
1. Montmorillonite K-10, a mesoporous clay that sup-
presses scrambling of porphyrinogens,29 gave 10-25%
yields and Level 2 scrambling in CH2Cl2. Reaction in
diethyl ether, acetonitrile, hexanes, ethyl acetate, and
THF gave slow reactions and less than 10% yields but
reduced scrambling to Level 0 or Level 1.
2. Studies with other solid Lewis acids (MgBr2‚Et2O,
FeCl3, ZnCl2, and Lewis acids supported on clays) gave
Level 2 and Level 3 scrambling with yields between 3%
and 40%. In general, fast reactions gave more scrambling
than slow reactions.
3. Model condensations performed with BF3‚Et2O and
TFA as representative homogeneous acid catalysts were
studied as a function of acid concentration, reaction
solvent (CH2Cl2, toluene, acetonitrile), and reaction tem-
perature (rt to -40 °C) and in the presence of 10 different
catalytic salts.23 Reaction in CH2Cl2 or toluene gave rapid
porphyrin formation with good to excellent yield (25-
65%) but Level 3 or Level 4 scrambling. In contrast,
reaction in acetonitrile proceeded more slowly in lower
yield, with less scrambling.30 Cooling the acetonitrile
reaction mixture with certain inorganic salts reduced
scrambling to Level 0 or Level 1, but in all cases low
scrambling was accompanied by a slow reaction rate and
a porphyrin yield less than 10%.
4. Hombrecher reported that addition of 2,6-di-tert-
butylpyridine, a non-nucleophilic base, to a particular
MacDonald-type condensation dramatically suppressed
scrambling.31 For our model system, addition of 2,6-di-
tert-butylpyridine gave Level 0 scrambling but reduced
the porphyrin yield to 3% or less under all conditions
examined.
5. Condensation in propionic acid at 70 °C gave a slow
reaction and a low yield (4% at 6 h) with Level 1
scrambling.32 Attempts to improve the yield by increasing
the reaction temperature or adding inorganic salts gave
a faster reaction rate, higher porphyrin yields, and Level
3 or 4 scrambling.
6. Heating 5-phenyldipyrromethane in neat excess
p-tolualdehyde led to porphyrin formation with Level 0
scrambling, but in less than 10% yield. Screening studies
on a thermal 2 + 2 condensation identified DMSO as a
precipitation of the porphyrin during the filtration through
alumina.
2. Con d en sa t ion s w it h Un h in d er ed Dip yr r o-
m eth a n es. Syntheses of trans-porphyrins not bearing
sterically demanding groups in the 5-position have
resulted in more extensive scrambling, and isolation of
the pure porphyrin is often difficult, even after careful
column chromatography.27 Condensation of 5-phenyl-
dipyrromethane and p-tolualdehyde was chosen as the
model system for studying a 5-aryldipyrromethane that
is not sterically hindered at the 2- and 6-positions of the
aryl group (Scheme 4). This combination provides a small
steric and electronic difference between the two compo-
nents but allows resolution of the potential porphyrin
products by LD-MS.18
(A) Use of Rea ction Con d ition s Op tim ized for
Ster ica lly Hin d er ed Dip yr r om eth a n es. The proce-
dure developed for condensation of sterically hindered
dipyrromethanes was applied to a condensation of 5-phe-
nyldipyrromethane and p-tolualdehyde (10 mM in CH2-
Cl2 containing 17.8 mM TFA for 1 h followed by DDQ
oxidation). Porphyrin products were isolated in 31% yield.
TLC showed a single porphyrin spot, and 1H NMR
spectroscopy (300 MHz) showed no signals characteristic
of scrambling, but LD-MS showed Level 3 scrambling.28
An identical condensation catalyzed by BF3‚Et2O (1.0
mM) produced Level 4 scrambling, with 5,10,15-triph-
enyl-20-(4-methylphenyl)porphyrin formed as the major
product.
The aliquot removed after 5 min (9% spectroscopic
yield) from the TFA-catalyzed reaction showed Level 3
(29) Onaka, M.; Shinoda, T.; Izumi, Y.; Nolen, E. Chem. Lett. 1993,
117-120. Onaka, M.; Shinoda, T.; Izumi, Y.; Nolen, E. Tetrahedron
Lett. 1993, 34, 2625-2628. Shinoda, T.; Onaka, M.; Izumi, Y. Chem.
Lett. 1995, 493-494. Shinoda, T.; Onaka, M.; Izumi, Y. Chem. Lett.
1995, 495-496.
(27) For examples see: (a) Wallace, D. M.; Leung, S. H.; Senge, M.
O.; Smith, K. M. J . Org. Chem. 1993, 58, 7245-7257. (b) Gaud, O.;
Granet, R.; Kaouadji, M.; Krausz, P.; Blais, J . C.; Bolbach, G. Can. J .
Chem. 1996, 74, 481-499. (c) Setsune, J .; Hashimoto, M.; Shiozawa,
K.; Hayakawa, J .; Ochi, T.; Masuda, R. Tetrahedron 1998, 54, 1407-
1424. (d) Gerasimchuk, N. N.; Mokhir, A. A.; Rodgers, K. R. Inorg.
Chem. 1998, 37, 5641-5650.
(28) This example illustrates that mass spectrometry is a more
reliable method for determination of the presence or absence of
scrambling.
(30) Acetonitrile has previously been reported as a solvent for
performing the 2 + 2 condensation of â-substituted dipyrromethanes
under mild conditions. See: Osuka, A.; Nagata, T.; Kobayashi, F.;
Maruyama, K. J . Heterocycl. Chem. 1990, 27, 1657-1659.
(31) Hombrecher, H. K.; Horter, G.; Arp, C. Tetrahedron 1992, 48,
9451-9460.
(32) For examples of MacDonald-type condensations performed in
propionic acid see refs 27a, 27c, and 27d.

Minimal Scrambling in Synthesis of trans-Porphyrins
J . Org. Chem., Vol. 64, No. 8, 1999 2869
Ta ble 3. Isola ted Yield of P or p h yr in s Obta in ed by
Con d en sa tion of Dip yr r om eth a n es a n d Ald eh yd es u n d er
Op tim ized Low -Scr a m blin g Rea ction Con d ition s
suitable reaction solvent that allowed the use of a 1:1
dipyrromethane:aldehyde ratio. At reflux in DMSO, Level
4 scrambling occurred, but lowering the reaction tem-
perature to 90 °C and performing the reaction in the
presence of NH4Cl gave Level 1 scrambling and 5% yield.
Despite the wide range of factors examined, the most
significant finding was that the scrambling process was
extremely difficult to suppress. However, a clear correla-
tion was observed over all of the diverse reaction condi-
tions examined: the slower the rate of reaction, the lower
the level of scrambling.
(C) Low -Scr a m blin g Rea ction Con d ition s. From
the screening study of the model condensation, two sets
of reaction conditions were identified that gave the
highest yield of porphyrin with Level 0 or Level 1
scrambling:
1. 5-Phenyldipyrromethane (10 mM) and p-tolualde-
hyde (10 mM) in MeCN at 0 °C, catalyzed by BF3‚Et2O
(1.0 mM) with NH4Cl (100 mmol/L) added to the reaction
mixture, although certain other inorganic chloride salts
such as NaCl behave very similarly. The reaction was
performed under an inert atmosphere, monitored by UV-
vis spectroscopy, and then DDQ was added (typically
after 4 h), with subsequent oxidation with DDQ in
toluene at reflux to remove any chlorin, followed by
column chromatography to isolate the porphyrin from
non-porphyrin materials (9% yield, Level 1).
a
Reactions performed with 10 mM dipyrromethane and alde-
hyde in MeCN at 0 °C, catalyzed by BF3‚Et2O (1.0 mM) with
NH4Cl (100 mmol/L). Reactions performed with 100 mM dipyr-
romethane and aldehyde with NH4Cl (316 mmol/L) in DMSO open
to the air at 90 °C for 24 h.
b
Sch em e 5a
2. 5-Phenyldipyrromethane (100 mM) and p-tolualde-
hyde (100 mM) with NH4Cl (316 mmol/L) in DMSO at
90 °C for 24 h. The reaction was performed without BF3‚
Et2O or TFA and is open to air to achieve oxidation of
the porphyrinogen to the porphyrin by atmospheric
oxygen. In the cases we examined, the porphyrin was
insoluble in the DMSO reaction medium and was easily
isolated by filtration, affording pure porphyrin without
detectable chlorin byproduct (5% yield, Level 1). A wide
range of salts was examined, but the catalytic effect was
found to be highly specific, with only NH4Cl leading to
porphyrin formation.
The scope of these procedures for preparing trans-
porphyrins was examined as shown in Table 3. Compari-
son of the two sets of reaction conditions demonstrates
that the principal advantage of reaction in MeCN is
higher yields, whereas reaction in DMSO benefits from
an extremely simple workup procedure. The yields of
porphyrin obtained are low in both cases, but the
scrambling process is suppressed, eliminating the need
for separation of a porphyrin mixture by chromatography.
Analytically pure 5-substituted dipyrromethanes are now
readily available in multigram quantities,12 so greater
than 100 mg of porphyrin can be easily isolated from a
reaction performed with 10 mmol of reactants with
minimal scrambling. Synthesis of 5,15-bis[4-(2-trimeth-
ylsilylethynyl)phenyl]-10,20-bis(4-iodophenyl)porphy-
rin (16) illustrates that despite the low yield these novel
methods can be very useful and are anticipated to provide
an expedient route to many trans-porphyrins.
3. Syn th etic Str a tegy in Ma cDon a ld -Typ e 2 + 2
Con d en sa tion s. The symmetry of a trans-A2B2-porphy-
rin means that it can be synthesized by two alternative
but complementary condensations. We therefore exam-
ined condensation of 5-(4-methylphenyl)dipyrromethane12
with mesitaldehyde to compare the degree of scrambling
obtained with that produced by condensation of 5-mesi-
tyldipyrromethane and p-tolualdehyde (Scheme 5).
Condensation of 5-(4-methylphenyl)dipyrromethane
and mesitaldehyde (10 mM) by 17.8 mM TFA in CHCl3
(containing 0.75% EtOH) at room temperature gave no

2870 J . Org. Chem., Vol. 64, No. 8, 1999
Littler et al.
porphyrin formation. In contrast, BF3‚Et2O catalysis
under identical conditions gave a 44% spectroscopic
porphyrin yield. Conditions suitable for condensation of
a dipyrromethane with a sterically hindered aldehyde are
therefore analogous to the condensation of pyrrole and
mesitaldehyde for the formation of tetramesitylporphy-
rin: i.e., 2,6-dimethyl-substituted benzaldehydes require
BF3‚Et2O/EtOH cocatalysis to react with pyrrolic spe-
cies.33 Reaction of 5-(4-methylphenyl)dipyrromethane and
mesitaldehyde (10 mM) in CHCl3 under BF3‚Et2O ca-
talysis produced Level 3 scrambling. In contrast, Level
1 scrambling was observed for the condensation of
5-mesityldipyrromethane and p-tolualdehyde under iden-
tical conditions. This result demonstrates that choosing
the best disconnection of the trans-porphyrin into dipyr-
romethane and aldehyde components can be crucial to
the success of the 2 + 2 strategy. In particular, a
sterically hindered aryl group should be incorporated into
the dipyrromethane rather than the aldehyde.
4. Mech a n istic Im p lica tion s. The results obtained
in this study provide insight into two important mecha-
nistic features of the acid-catalyzed condensation between
an aldehyde and a 5-substituted dipyrromethane:
1. Scrambling is very difficult to suppress but is
reduced at lower reaction temperatures. Therefore, the
nonscrambling reaction leading to trans-porphyrins must
have an activation energy that is only slightly lower than
that of the scrambling process.
trans-porphyrin in less than 10% yield, they eliminate
the need to perform lengthy chromatography. (4) In the
retrosynthetic disconnection of the porphyrin into the
dipyrromethane and aldehyde components, the sterically
hindered group should be incorporated in the dipyr-
romethane where possible.
Exp er im en ta l Section
All chemicals were obtained commercially and used as
received unless otherwise noted. Montmorillonite K-10 (Fluka)
was used as received or activated by heating to 100 °C at 0.03
Torr for 4 h.29 Solvents (A.C.S. grade) were obtained from
Fisher, except for DMSO, propionitrile, and butyronitrile
(Aldrich). All inorganic salts were ground into a fine powder
with a mortar and pestle prior to use. Pyrrole, CH2Cl2,
acetonitrile, propionitrile, butyronitrile, and toluene were
distilled from CaH2, and CHCl3 was distilled from K2CO3.
Column chromatography was performed on silica (Baker, 200-
400 mesh) or alumina (Fisher, 80-200 mesh). Reaction
sampling was performed with syringes equipped with Teflon-
tipped plungers. All reported NMR results were obtained at
300 MHz in CDCl3. UV-vis absorption spectra were recorded
in CH2Cl2/ethanol (3:1). Mass spectra of porphyrin mixtures
were obtained by laser desorption mass spectrometry (LD-MS)
without a matrix.17
Gen er a l P r oced u r e for th e In vestiga tion of Rr ea ction
Con d ition s. The progress of the reaction was monitored by
periodic removal of aliquots from the reaction mixture via
syringe, followed by oxidization with DDQ and absorption
spectroscopy. In particular, for 10.0, 31.6, and 100 mM
reactions, 25, 10, and 5 µL aliquots, respectively, were removed
from the reaction vessel and injected into 300 µL of a 10 mM
DDQ solution in toluene. Then 25 µL of this oxidized solution
was diluted in 3.0 mL of CH2Cl2/ethanol (3:1) and the visible
absorption spectrum recorded. The yield of porphyrin was
determined by the intensity of the Soret band (420 nm, ꢀ )
500 000 M-1 cm-1) measured from the apex to the base of the
red edge of the band. This eliminated the contribution of the
polypyrromethene and quinone components that exhibit a
broad absorption in the 400-500 nm region. To obtain samples
for LD-MS examination of the porphyrin distribution, the
spectroscopic aliquots were filtered through a pad of silica (6
mm diameter × 50 mm) in a standard glass Pasteur pipet.
The column was eluted with CH2Cl2 and one fraction collected
to prevent chromatographic separation of the porphyrin
mixture; the porphyrin mixture elutes close to the solvent
front, while the highly colored byproducts of the oxidation
remain bound to the top half of the pad.
5,15-Dim esityl-10,20-bis(4-m eth ylph en yl)por ph yr in (5).
Samples of 5-mesityldipyrromethane (2.64 g, 10.0 mmol) and
p-tolualdehyde (1.17 mL, 10.0 mmol) were dissolved in
CH2Cl2 (1000 mL, Fisher A.C.S grade, undistilled) in a 2 L
round-bottomed flask, and then TFA (1.37 mL, 17.8 mmol) was
added slowly over 30 s. The reaction was stirred at room
temperature with the progress of the reaction monitored by
UV-vis spectroscopy. After 30 min, DDQ (2.27 g, 10.0 mmol)24
was added, and the reaction mixture was stirred at room
temperature for a further 1 h. The complete reaction mixture
was poured onto a pad of alumina (75 mm maximum diameter
× 100 mm in a 2000 mL separatory funnel) and eluted with
CH2Cl2 until the eluting solution was pale brown (total solvent
volume ca. 1500 mL). (Note: the reaction mixture should not
be concentrated prior to filtration through the alumina pad
because the porphyrin was often difficult to fully redissolve
and/or precipitated during the filtration.) The solvent was
removed under vacuum to give a black solid which was
dissolved in toluene (200 mL) and heated under reflux for 1 h
in the presence of DDQ (2.27 g, 10.0 mmol) to oxidize any
remaining chlorin.26 After cooling to room temperature, the
entire reaction mixture was passed through a pad of alumina
(65 mm maximum diameter × 80 mm in a 500 mL separatory
funnel) and eluted with CH2Cl2 until the purple material had
completely eluted (total solvent volume ca. 600 mL). Removal
2. Complementary condensations should form the same
porphyrinogen, but in the example we studied there were
very different levels of scrambling. This demonstrates
that most scrambling must occur prior to porphyrinogen
formation.
Con clu sion s
Our detailed study into the 2 + 2 condensation between
a dipyrromethane and an aldehyde for the preparation
of pure trans-porphyrins has led to the following conclu-
sions. (1) A rapid screening method based on spectro-
scopic yield detection and LD-MS allows a wide range of
reaction conditions to be rapidly surveyed. Although we
have not studied other systems, we anticipate that this
screening method will be applicable to optimizing other
oligopyrromethane-based syntheses where scrambling is
a possibility: for example, 3 + 1 approaches to porphy-
rins,34 synthesis of heteroatom-substituted porphyrins,35
and preparation of expanded porphyrin analogues.36 (2)
For condensations involving sterically hindered dipyr-
romethanes we have identified reaction conditions that
cause no scrambling and have developed a preparative
procedure that gives pure trans-porphyrins in multigram
batches. (3) Scrambling in MacDonald-type condensa-
tions with sterically unhindered dipyrromethanes is very
difficult to suppress. Two sets of conditions were identi-
fied that reduced scrambling to the limit of detection by
LD-MS. Although both sets of conditions gave the pure
(33) Lindsey, J . S.; Wagner, R. W. J . Org. Chem. 1989, 54, 828-
836.
(34) Lash, T. D. J . Porphyrins Phthalocyanines 1997, 1, 29-44.
(35) Heo, P.-Y.; Shin, K.; Lee, C.-H. Tetrahedron Lett. 1996, 37, 197-
200. Cho, W.-S.; Lee, C.-H. Bull. Korean Chem. Soc. 1998, 19, 314-
319. Srinivasan, A.; Sridevi, B.; Reddy, V. R. R.; Narayanan, J .;
Chandrashekar, T. K. Tetrahedron Lett. 1997, 38, 4149-4152.
(36) Bru¨ckner, C.; Sternberg, E. D.; Boyle, R. W.; Dolphin, D. J .
Chem. Soc., Chem. Commun. 1997, 1689-1690. Lash, T. D.; Richter,
D. T. J . Am. Chem. Soc. 1998, 120, 9965-9966.

Minimal Scrambling in Synthesis of trans-Porphyrins
J . Org. Chem., Vol. 64, No. 8, 1999 2871
of the solvent under vacuum gave a purple solid (1.73 g,
48%): 1H NMR δ -2.61 (br s, 2 H), 1.84 (s, 12 H), 2.62 (s, 6
H), 2.68 (s, 6 H), 7.27 (s, 4 H), 7.53 (d, J ) 8.0 Hz, 4 H), 8.09
(d, J ) 8.0 Hz, 4 H), 8.67 (d, J ) 4.8 Hz, 4 H), 8.81 (d, J ) 4.8
Hz, 4 H); λabs 418, 514, 550, 590, 645 nm; C52H46N4 calcd mass
726.4, obsd 726.2 (LD-MS); calcd exact mass 726.3722, obsd
726.3722 (FAB-MS).
5,15-Dim esityl-10,20-d ip h en ylp or p h yr in (6). Condensa-
tion of 5-mesityldipyrromethane (2.64 g, 10.0 mmol) and
benzaldehyde (1.02 mL, 10.0 mmol) in CH2Cl2 (1000 mL) with
TFA (1.37 mL, 17.8 mmol) following the procedure described
for 5 gave a purple solid (1.34 g, 38%): 1H NMR δ -2.62 (br
s, 2 H), 1.84 (s, 12 H), 2.63 (s, 6 H), 7.28 (s, 4 H), 7.70-7.79
(m, 6 H), 8.20-8.24 (m, 4 H), 8.68 (d, J ) 4.8 Hz, 4 H), 8.78
(d, J ) 4.8 Hz, 4 H); λabs 417, 514, 548, 589, 645 nm; C50H42N4
calcd mass 698.4, obsd 698.0 (LD-MS); calcd exact mass
698.3409, obsd 698.3414 (FAB-MS).
5,15-Bis(2,6-d ich lor op h en yl)-10,20-d ip h en ylp or p h y-
r in (13). Utilizing the procedure developed for condensations
performed with 5-mesitydipyrromethane, 5-(2,6-dichlorophe-
nyl)dipyrromethane (2.91 g, 10.0 mmol) and benzaldehyde
(1.02 g, 10.0 mmol) were condensed in CH2Cl2 (1000 mL) with
TFA (1.37 mL, 17.8 mmol) following the procedure described
for 5 with only one modification. To prevent precipitation of
the porphyrin during filtration through the second alumina
pad, CH2Cl2 (500 mL) was added to the solution of porphyrin
in toluene after heating at reflux for 1 h and cooling to room
temperature. After filtration through the alumina pad, re-
moval of the solvent under vacuum gave a purple solid (1.32
g, 35%): 1H NMR δ -2.63 (br s, 2 H), 7.68-7.82 (m, 12 H),
8.23 (m, 4 H), 8.66 (d, J ) 4.9 Hz, 4 H), 8.87 (d, J ) 4.9 Hz, 4
H); λabs 417, 513, 546, 589, 646 nm; C44H26Cl4N4 calcd mass
750.1, obsd 751.0 (LD-MS); calcd exact mass 750.0912, obsd
750.0926 (FAB-MS).
5,15-Dim esityl-10,20-bis(2-m eth ylph en yl)por ph yr in (7).
Condensation of 5-mesityldipyrromethane (2.64 g, 10.0 mmol)
and o-tolualdehyde (1.16 mL, 10.0 mmol) in CH2Cl2 (1000 mL)
with TFA (1.37 mL, 17.8 mmol) following the procedure
described for 5 gave a purple solid (1.27 g, 35%) as a 1:1
mixture of two atropisomers: 1H NMR δ -2.58 (br s, 2 H),
1.82 (s, 3 H), 1.85 (s, 6 H), 1.88 (s, 3 H), 2.03 (s, 3 H), 2.07 (s,
3 H), 2.62 (s, 6 H), 7.27 (s, 4 H), 7.49-7.61 (m, 4 H), 7.67 (m,
2 H), 7.98 (d, J ) 7.3 Hz, 1 H), 8.04 (d, J ) 7.3 Hz, 1 H), 8.64
(m, 8 H); λabs 417, 513, 545, 589, 645 nm; C52H46N4 calcd mass
726.4, obsd 726.2 (LD-MS); calcd exact mass 726.3722, obsd
726.3721 (FAB-MS).
5,15-Dim esit yl-10,20-b is(4-iod op h en yl)p or p h yr in (8).
Condensation of 5-mesityldipyrromethane (2.64 g, 10.0 mmol)
and 4-iodobenzaldehyde (2.32 g, 10.0 mmol) in CH2Cl2 (1000
mL) with TFA (1.37 mL, 17.8 mmol) following the procedure
described for 5 gave a purple solid (1.67 g, 35%). Spectroscopic
data were identical to those previously reported.19
5,15-Dim esit yl-10,20-b is(3-iod op h en yl)p or p h yr in (9).
Condensation of 5-mesityldipyrromethane (2.64 g, 10.0 mmol)
and 3-iodobenzaldehyde (2.32 g, 10.0 mmol) in CH2Cl2 (1000
mL) with TFA (1.37 mL, 17.8 mmol) following the procedure
described for 5 gave a purple solid (1.46 g, 31%). Spectroscopic
data were identical to those previously reported.20
5,15-Dim e sit yl-10,20-b is(4-m e t h oxyp h e n yl)p or p h y-
r in (10). Condensation of 5-mesityldipyrromethane (2.64 g,
10.0 mmol) and p-anisaldehyde (1.36 g, 10.0 mmol) in CH2Cl2
(1000 mL) with TFA (1.37 mL, 17.8 mmol) following the
procedure described for 5 gave a purple solid (1.66 g, 44%):
1H NMR δ -2.60 (br s, 2 H), 1.84 (s, 12 H), 2.62 (s, 6 H), 4.08
(s, 6 H), 7.23-7.28 (m, 8 H), 8.12 (m, 4 H), 8.67 (d, J ) 4.8 Hz,
4 H), 8.81 (d, J ) 4.8 Hz, 4 H); λabs 420, 516, 552, 592, 647
nm; C52H46N4O2 calcd mass 758.4, obsd 758.1 (LD-MS); calcd
exact mass 758.3621, obsd 758.3639 (FAB-MS).
5,15-Bis(2,6-d ich lor op h en yl)-10,20-bis(4-iod op h en yl)-
p or p h yr in (14). Condensation of 5-(2,6-dichorophenyl)dipyr-
romethane (2.23 g, 7.67 mmol) and 4-iodobenzaldehyde (1.78
g, 7.67 mmol) in CH2Cl2 (770 mL) with TFA (1.06 mL, 13.7
mmol, 17.8 mM) following the procedure described for 13 gave
a purple solid (1.01 g, 26%): 1H NMR δ -2.68 (br s, 2 H), 7.72
(m, 2 H), 7.81 (m, 4 H), 7.96 (d, J ) 8.2 Hz, 4 H), 8.09 (d, J )
8.2 Hz, 4 H), 8.68 (d, J ) 4.8 Hz, 4 H), 8.84 (d, J ) 4.8 Hz, 4
H); λabs 418, 514, 550, 587 nm; C44H24Cl4I2N4 calcd mass 1001.9,
obsd 999.6 (LD-MS); calcd exact mass 1001.8845, obsd
1001.8861 (FAB-MS).
5,15-Bis(4-m e t h ylp h e n yl)-10,20-d ip h e n ylp or p h yr in
(15).27a DMSO Meth od . In a two-neck round-bottomed flask
equipped with an air condenser and a digital thermocouple,
samples of 5-phenyldipyrromethane (2.22 g, 10.0 mmol) and
p-tolualdehyde (1.18 mL, 10.0 mmol) were dissolved in DMSO
(100 mL) containing NH4Cl (1.69 g, 31.6 mmol). The mixture
was heated at 90 °C open to air for 24 h and then allowed to
cool slowly to room temperature over 3 h. Filtration of the
crude reaction mixture under suction gave a dark solid.
Washing with diethyl ether gave a purple solid (142 mg, 5%).
TLC analysis and 1H NMR spectroscopy showed no clear
evidence of scrambling, but Level 1 scrambling was observed
via the LD-MS assay: 1H NMR δ -2.78 (br s, 2 H), 2.70 (s, 6
H), 7.55 (d, J ) 7.8 Hz, 4 H), 7.71-7.81 (m, 6 H), 8.10 (d, J )
7.8 Hz, 4 H), 8.21 (m, 4 H), 8.85 (m, 8 H); C46H34N4 calcd mass
642.3, obsd 642.2 (M•+, 100%) and 657.2 [5,10,15-tris(4-
methylphenyl)-20-phenylporphyrin, 6%] (LD-MS).
MeCN Meth od . A 2000 mL round-bottomed flask, equipped
with a magnetic stirrer bar, was flushed with Ar. Then MeCN
(1000 mL, Fisher A.C.S. grade, undistilled) was added and
degassed with a stream of Ar for 10 min. Freshly ground
NH4Cl (5.35 g, 100 mmol) was added, and the flask placed in
an ice bath and cooled under Ar. Samples of 5-phenyldipyr-
romethane (2.22 g, 10.0 mmol) and p-tolualdehyde (1.18 mL,
10 mmol) were added, followed by BF3‚Et2O (126 µL, 1.00
mmol), and the mixture was stirred at 0 °C under Ar. The
progress of the reaction was monitored by UV-vis spectros-
copy, and after 4.5 h DDQ (2.27 g, 10.0 mmol) was added. The
ice bath was removed, and the mixture was stirred at room
temperature for 1 h and then filtered through a pad of alumina
eluted with CH2Cl2. The solvent was removed to give a dark
solid that was dissolved in toluene (250 mL); then DDQ was
added (2.27 g, 10.0 mmol) and the mixture heated at reflux
for 1 h. The mixture was allowed to cool to room temperature
and then filtered through a pad of alumina eluted with
CH2Cl2. Removal of the solvent gave a mixture of a purple solid
and a black solid (357 mg). Trituration of the crude product
with hexanes followed by filtration gave a purple solid (303
mg, 9%). TLC analysis and 1H NMR spectroscopy showed no
clear evidence of scrambling, but Level 1 scrambling was
observed via the LD-MS assay: C46H34N4 calcd mass 642.3,
obsd 642.2 (M•+, 100%), 656.2 [5,10,15-tris(4-methylphenyl)-
20-phenylporphyrin, 7%], 628.1 [5,10,15-triphenyl-20-(4-me-
thylphenyl)porphyrin, 1%] (LD-MS).
5,15-Dim esit yl-10,20-b is(p en t a flu or op h en yl)p or p h y-
r in (11). Condensation of 5-mesityldipyrromethane (2.64 g,
10.0 mmol) and pentafluorobenzaldehyde (1.96 g, 10.0 mmol)
in CH2Cl2 (1000 mL) with TFA (1.37 mL, 17.8 mmol) following
the procedure described for 5 gave a dark solid (2.30 g).
Trituration with hexanes removed undesired pigments and
gave a purple solid (1.22 g, 28%): 1H NMR δ -2.68 (br s, 2
H), 1.84 (s, 12 H), 2.64 (s, 6 H), 7.30 (s, 4 H), 8.76 (m, 8 H);
λ
abs 414, 510, 542, 586, 642 nm; C50H32F10N4 calcd mass 878.2,
obsd 878.4 (LD-MS); calcd exact mass 878.2467, obsd 878.2490
(FAB-MS).
5,15-Dim esityl-10,20-bis(n -p en tyl)p or p h yr in (12). Con-
densation of 5-mesityldipyrromethane (2.64 g, 10.0 mmol) and
n-hexanal (1.00 g, 10.0 mmol) in CH2Cl2 (1000 mL) with TFA
(1.37 mL, 17.8 mmol) following the procedure described for 5
gave a dark solid (0.66 g). Trituration with hexanes removed
undesired pigments and gave a purple solid (0.49 g, 14%): 1H
NMR δ -2.49 (br s, 2 H), 0.97 (t, J ) 7.3 Hz, 6 H), 1.55 (m, 4
H), 1.79 (m, 4 H), 1.83 (s, 12 H), 2.52 (m, 4 H), 2.65 (s, 6 H),
4.91 (m, 4 H), 7.29 (s, 4 H), 8.70 (d, J ) 4.8 Hz, 4 H), 9.35 (d,
J ) 4.8 Hz, 4 H); λabs 417, 517, 551, 595, 652 nm; C48H54N4
calcd mass 686.4, obsd 686.2 (M+, 100%), 629.1 [(M• - C4H9)+,
55%], 734.2 [5,10,15-trimesityl-20-(n-pentyl)porphyrin, 3%]
(LD-MS); calcd exact mass 686.4348, obsd 686.4346 (FAB-MS).
5,15-Bis[4-(2-tr im eth ylsilyleth yn yl)p h en yl]-10,20-bis-
(4-iod op h en yl)p or p h yr in (16). A mixture of 5-(4-iodophe-
nyl)dipyrromethane (1.78 g, 5.12 mmol), 4-(2-trimethylsilyl-

2872 J . Org. Chem., Vol. 64, No. 8, 1999
Littler et al.
1
ethynyl)benzaldehyde (1.04 g, 5.12 mmol), and NH4Cl (0.87
g, 16.2 mmol) in DMSO (51.2 mL) was heated at 90 °C for 24
h following the procedure described for 15 to give a purple solid
(146 mg, 5%): 1H NMR δ -2.87 (br s, 2 H), 0.38 (s, 18 H),
7.87 (d, J ) 8.1 Hz, 4 H), 7.93 (d, J ) 8.2 Hz, 4 H), 8.09 (d, J
) 8.2 Hz, 4 H), 8.14 (d, J ) 8.1 Hz, 4 H), 8.83 (m, 8 H); λabs
421, 517, 552, 591, 646 nm; C54H44I2N4Si2 calcd mass 1058.1,
obsd 1059.1 (LD-MS); calcd exact mass 1058.1194, obsd
1058.1199 (FAB-MS).
5,15-Bis[4-(2-tr im eth ylsilyleth yn yl)p h en yl]-10,20-bis-
(4-iod op h en yl)p or p h yr in (16). A mixture of 5-(4-iodophe-
nyl)dipyrromethane (1.78 g, 5.12 mmol), 4-(2-trimethylsilyl-
ethynyl)benzaldehyde (1.04 g, 5.12 mmol), and NH4Cl (2.74
g, 51.2 mmol) in ice-cold MeCN (512 mL) under Ar was treated
with BF3‚Et2O (64.5 µL, 0.512 mmol, 1 mM) following the
procedure described for 15. The reaction mixture was stirred
for 3.5 h; then DDQ (2.00 g, 8.81 mmol) was added and stirring
was continued at room temperature for 1 h. The reaction
mixture was filtered through an alumina pad eluted with
CH2Cl2 (ca. 2000 mL, due to low solubility of the porphyrin).
The solvent was removed to give a dark solid that was
dissolved in toluene (300 mL), DDQ (2.00 g) was added, and
the mixture heated at reflux for 1 h. The mixture was cooled
to room temperature and filtered through an alumina pad
eluted with CH2Cl2. Removal of the solvent gave a dark solid
that TLC and H NMR analysis showed to be a mixture of the
desired porphyrin and undefined pigments. Flash column
chromatography (silica, CH2Cl2) gave a purple solid (222 mg,
8%) despite low solubility of the porphyrin in CH2Cl2 leading
to very slow elution of the desired compound. Spectral proper-
ties were identical to those of the sample prepared above.
Ack n ow led gm en t. This work was funded by NIH
(GM36238). Mass spectra were obtained at the Mass
Spectrometry Laboratory for Biotechnology. Partial
funding for the Facility was obtained from the North
Carolina Biotechnology Center and the National Science
Foundation.
Su p p or tin g In for m a tion Ava ila ble: A full description
of the screening studies performed on the reaction of 5-mesi-
tyldipyrromethane and p-tolualdehyde and the reaction of
5-phenyldipyrromethane and p-tolualdehyde; 1H NMR spectra
of porphyrins 5-16; LD-MS spectra of porphyrins 5, 12, 15,
16. This material is available free of charge via the Internet
at http://pubs.acs.org.
J O982452O