Synthesis of 24 bacteriochlorin isotopologues, each containing a symmetrical pair of 13C or 15N atoms in the inner core of the macrocycle

Article abstract of DOI:10.1021/jo402488n

Synthetic bacteriochlorins containing site-specific isotopic substitution enable spectroscopic interrogation to delineate physicochemical features relevant to bacteriochlorophylls in photosynthesis but have been little explored. A de novo synthesis has been employed to prepare bacteriochlorins wherein each macrocycle contains a pair of ¹³C or ¹⁵N atoms yet lacks substituents other than a geminal dimethyl group in each pyrroline ring. Preparation of a dihydrodipyrrin-acetal with single-isotopic substitution gives rise to a bacteriochlorin that contains two isotopic substitutions symmetrically disposed by a 180 rotation about the normal to the plane of the macrocycle. Eight such isotopically substituted bacteriochlorins were prepared from commercially available reactants (bacteriochlorin sites): (¹³C)paraformaldehyde (1, 11); (¹³C)formamide (4, 14); triethyl (¹³C)orthoformate (5, 15); K¹³CN (6, 16); ¹³CH₃NO₂ (9, 19); N,N-dimethyl( ¹³C)formamide (10, 20); (¹⁵N)pyrrole (21, 23); CH ₃¹⁵NO₂ (22, 24). Some loss of ¹⁵N upon TiCl₃-mediated McMurry-type ring closure of a nitro( ¹⁵N)hexanone is attributed to a parallel sequence of three reactions (Nef, exchange with natural-abundance NH₄OAc buffer, and Paal-Knorr ring closure) leading to the dihydrodipyrrin-acetal. Zinc and copper chelates of each bacteriochlorin also were prepared. Together, the 24 bacteriochlorin isotopologues should provide valuable benchmarks for understanding ground- and excited-state molecular physics of the macrocycles related to photosynthetic function of bacteriochlorophylls.

Full text of DOI:10.1021/jo402488n

Article
pubs.acs.org/joc
Synthesis of 24 Bacteriochlorin Isotopologues, Each Containing a
13
15
Symmetrical Pair of C or N Atoms in the Inner Core of the
Macrocycle
Chih-Yuan Chen,† David F. Bocian,*,‡ and Jonathan S. Lindsey*,†
†Department of Chemistry, North Carolina State University, Raleigh, North Carolina 27695-8204, United States
‡Department of Chemistry, University of California, Riverside, California 92521-0403, United States
S
* Supporting Information
ABSTRACT: Synthetic bacteriochlorins containing site-specific
isotopic substitution enable spectroscopic interrogation to delineate
physicochemical features relevant to bacteriochlorophylls in photo-
synthesis but have been little explored. A de novo synthesis has been
employed to prepare bacteriochlorins wherein each macrocycle
contains a pair of 13C or 15N atoms yet lacks substituents other than
a geminal dimethyl group in each pyrroline ring. Preparation of a
dihydrodipyrrin−acetal with single-isotopic substitution gives rise to
a bacteriochlorin that contains two isotopic substitutions symmetri-
cally disposed by a 180° rotation about the normal to the plane of
the macrocycle. Eight such isotopically substituted bacteriochlorins were prepared from commercially available reactants
(bacteriochlorin sites): (13C)paraformaldehyde (1, 11); (13C)formamide (4, 14); triethyl (13C)orthoformate (5, 15); K13CN (6,
16); 13CH3NO2 (9, 19); N,N-dimethyl(13C)formamide (10, 20); (15N)pyrrole (21, 23); CH315NO2 (22, 24). Some loss of 15N
upon TiCl3-mediated McMurry-type ring closure of a nitro(15N)hexanone is attributed to a parallel sequence of three reactions
(Nef, exchange with natural-abundance NH4OAc buffer, and Paal−Knorr ring closure) leading to the dihydrodipyrrin−acetal.
Zinc and copper chelates of each bacteriochlorin also were prepared. Together, the 24 bacteriochlorin isotopologues should
provide valuable benchmarks for understanding ground- and excited-state molecular physics of the macrocycles related to
photosynthetic function of bacteriochlorophylls.
of the complexities of the photosynthetic protein assemblies,
has been a topic of longstanding interest. Spectroscopic studies
have been paramount and include traditional optical methods
(absorption and fluorescence) as well as other techniques such
as electron paramagnetic resonance (EPR) and resonance
Raman (RR) spectroscopy.2−8 EPR spectroscopy provides a
fundamental understanding of the spin-density distribution in
the radical species, whereas RR spectroscopy affords
information on the vibrational characteristics of the molecule,
which may be utilized in normal-coordinate analysis. Regard-
less, spectroscopic interrogation of bacteriochlorophylls is
limited in two ways: (1) naturally occurring bacteriochlor-
ophylls are somewhat labile and can undergo dehydrogenation
to yield the corresponding chlorins;9 (2) the nearly full
complement of peripheral substituents around the bacterio-
chlorin chromophore causes highly rich and congested spectra.
Two simplifying methods have been resorted to, including use
of porphyrins as surrogates of bacteriochlorophylls and
preparation of synthetic bacteriochlorins that bear stable
isotopes at designated sites.
INTRODUCTION
■
Bacteriochlorophylls and their free base analogues (bacterio-
pheophytins) are the chief chromophores that enable energy
transduction in photosynthetic bacteria (Chart 1).1 Con-
sequently, the characterization of the fundamental physico-
chemical properties of the isolated chromophores, independent
Chart 1. Natural Bacterial Photosynthetic Pigments
Received: November 9, 2013
Published: January 14, 2014
© 2014 American Chemical Society
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Porphyrins have long been exploited as biomimetic
analogues of bacteriochlorophylls, owing to their ready
accessibility and versatile synthetic malleability. Nonetheless,
use of the porphyrin surrogates ignores the essential structural
differences among the respective classes of tetrapyrroles;
indeed, the different reduction levels of porphyrins versus
bacteriochlorins (tetrahydroporphyrins) causes profound
changes in physicochemical properties, which are particularly
manifested in the spectral properties. To our knowledge, only
two synthetic bacteriochlorin core structures and their
isotopologues have been prepared for spectroscopic purposes;
these include meso-tetraphenylbacteriochlorin and octaethyl-
bacteriochlorin species. The meso-tetraphenylbacteriochlorin
(TPBC) scaffold has proved more versatile, with reported
isotopologues including the all-15N (shown in Chart 2), all-
Scheme 1. Representative Isotopologue of
Bacteriochlorophyll
a
20
,
Chart 2. Representative Structures of Synthetic Isotopically
Substituted Bacteriochlorins
a
The red ● denotes 13C.
Methods for the synthesis of bacterichlorins have advanced
significantly over the past two decades,21 encompassing
semisynthesis (beginning with naturally occurring macro-
cycles),9,22,23 derivatization of intact synthetic porphyrins or
chlorins,24−28 and de novo syntheses.29−33 Only the last
method enables site-specific control over isotopic placement in
the macrocycle framework. The de novo routes also
incorporate a geminal dialkyl group in each pyrroline ring
that stabilizes the tetrahydroporphyrin chromophore toward
adventitious dehydrogenation. The route we developed relies
on the acid-catalyzed self-condensation of a dihydrodipyrrin−
acetal.31 The synthetic bacteriochlorin has nominal C2h
symmetry (assuming a planar macrocycle and the appropriate
conformations of the geminal dimethyl groups) and, save for
the geminal dimethyl group in each pyrroline ring, would
exhibit D2h symmetry characteristic of the bacteriochlorin π
framework. This synthetic route is concise, has been exploited
to prepare a wide variety of substituted bacteriochlorins,34 and
accommodates numerous metal chelates.35 These advances
open the door to the use of the de novo synthetic route to
prepare bacteriochlorins that bear site-specific isotopic
substitution.
The sparsely substituted natural abundance bacteriochlorin
H2BC-NA (Chart 3), which contains no substituents other
than the geminal dimethyl groups, was first prepared by
debromination of the corresponding 3,13-dibromobacterio-
chlorin36 and more recently by condensation of the
unsubstituted dihydrodipyrrin−acetal.34 The simple substitu-
tion pattern makes H2BC-NA a valuable benchmark compound
for fundamental spectroscopic studies.36 Herein, we expanded
the benchmark compound to include zinc and copper chelates
(ZnBC-NA and CuBC-NA) with specific isotope substitution.
The nature of the self-condensation of the dihydrodipyrrin−
meso-13C, all-phenyl-d20, and β-d8 species. Fajer et al.10
examined the cation radicals of zinc and free base TPBC
isotopologues by EPR spectroscopy. Bocian et al.11 performed a
normal coordinate analysis of Cu-TPBC isotopologues based
on RR spectroscopic studies. Spiro et al.12−14 employed the
nickel(II) chelate of an isotopically substituted octaethylbacter-
iochlorin (Ni-OEBC) as well as M-TPBC isotopologues for
vibrational spectroscopic studies.
The synthetic routes to M-TPBC and Ni-OEBC relied on
hydrogenation of meso-tetraphenylporphyrin15 and transforma-
tion of octaethylporphyrin,16 respectively. Such approaches are
satisfactory for situations wherein the isotopic substitution
pattern in the porphyrin gives rise to a distinct and
unambiguous pattern in the bacteriochlorin (e.g., M-TPBC-
all-15N in Chart 2). On the other hand, transformation of a
porphyrin that bears a single isotopic atom can result in a
mixture of up to four isotopomeric bacteriochlorins. A
complementary route toward isotopically substituted bacterio-
chlorophylls relies on biosynthetic transformations;17 however,
even with the availability of rather advanced precursors (such as
δ-aminolevulinic acid or porphobilinogen) that bear site-
specific isotopic substitution,18,19 the resulting macrocycles
bear isotopic atoms at numerous sites (Scheme 1). Such
bacteriochlorophylls have numerous valuable applications20 but
are not generally well suited for studies aimed at developing
spin-density maps or vibrational force fields because of the
spectral complexity arising from multiple isotopic atoms. In this
regard, no bacteriochlorins that contain only one or two
isotopic atoms have yet been reported.
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a
Chart 3. Isotopically Substituted Synthetic Bacteriochlorins
a
The red ● denotes 13C.
Scheme 2. Retrosynthesis of Isotopically Substituted Bacteriochlorins
acetal leads to the introduction of isotopes in a pairwise
manner. Our focus to date concerns the atoms that constitute
RESULTS AND DISCUSSION
■
Throughout the paper we employ IUPAC nomenclature and
terminology for isotopic chemistry.38,39 Hereafter, we employ
X-NA for the natural abundance compound, the use of braces,
{X}, to refer to a set of isotopologues of X-NA, and X to
indicate a general structure regardless of any isotopic
substitution.
the inner core of the bacteriochlorin, namely the 12 carbon and
4 nitrogen atoms. The inner core encompasses the entire π
system excepting only the 4 β-pyrrolic carbons. Given pairwise
isotopic substitution, there are 8 resulting bacteriochlorins that
are “double-stamped” with isotopic atoms (for usage of this
term in a different context in tetrapyrrole chemistry, see Tsay et
al.37). Zinc chelates of bacteriochlorins yield stable anion and
cation radicals and therefore are suited for EPR spectroscopic
analysis. Copper bacteriochlorins afford no detectable fluo-
rescence, which otherwise causes interference in RR spectros-
copy. Accordingly, we have synthesized 8 free base bacterio-
chlorins with pairwise introduction of 13C or 15N atoms about
the inner resonance frame, as well as the corresponding zinc
and copper chelates. The structures of the synthetic
bacteriochlorinsa pair of isotopomers with 15N substitution
and 6 isotopomers with 13C substitutionare shown in Chart
3. Here, we report the synthesis; studies of the physicochemical
properties (vibrational analysis and spin density mapping) of
the 24 bacteriochlorins will be reported elsewhere.
Retrosynthetic Analysis. The retrosynthesis of isotopically
substituted metallobacteriochlorins is outlined in Scheme 2.
The desired zinc and copper chelates are obtained by
metalation of H2BC,35 which are created upon acid-catalyzed
condensation of the dihydrodipyrrin−acetal 1.34 The dihy-
drodipyrrin−acetal is synthesized through a McMurry-type
reductive cyclization of the nitrohexanone−pyrrole 2, which in
turn is derived from the nitroethylpyrrole 3 and the α,β-
unsaturated ketone−acetal 4.34 The nitroethylpyrrole 3 is
synthesized from nitromethane and pyrrole-2-carboxaldehyde
(5), for which multiple routes are available. The α,β-
unsaturated ketone−acetal 4 is obtained upon reaction of
Grignard reagent 6 with dimethoxyacetonitrile (7), which in
turn is prepared from trimethyl orthoformate (8) and
TMSCN.40
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Synthesis. The synthesis of dihydrodipyrrin−acetal 1-NA
has been reported twice34,41 during the development of routes
to bacteriochlorin H2BC-NA. The compound 2-(2-nitroethyl)-
pyrrole (3-NA) has served as a versatile intermediate in the
synthesis of chlorins42−44 and bacteriochlorins.34 The synthesis
of 3-NA has been reported five times at different scales, in
different degrees of purity, and with various extents of
characterization, given that in some cases the product was
used directly in subsequent reactions.34,41−44 The prior
syntheses were refined over the course of the work described
herein to handle small quantities of expensive isotopically
substituted reactants.
Pyrrole-2-carboxaldehydes. Four isotopologues of 5-NA
were synthesized: 5-15N, 5-13Cformyl, 5-13C2, and 5-13C5. Pyrrole-
2-carboxaldehyde 5-15N was synthesized via Vilsmeier−Haack
formylation45 of (15N)pyrrole with N,N-dimethylformamide.
The synthesis of 5-13Cformyl is known46 and was carried out by
the same reaction of pyrrole with N,N-dimethyl(13C)formamide
(Scheme 3). The percentages shown in this (98%, 82%) and
sodium p-toluenesulfinate.60 Swapping paraformaldehyde for
the 13C-substituted reagent will make an α-13C-substituted
TosMIC (TosMIC-13Cα). The same strategy has been
exploited to make an α-14C-labeled TosMIC.61 Similarly,
utilizing (13C)formamide in the reaction will make Tos-
MIC-13CNC. Thus, the corresponding 13C-substituted paraform-
aldehyde and formamide were mixed under basic conditions
(K2CO3)62 for 2 h at room temperature prior to reaction with
sodium p-toluenesulfinate in acetic acid.60 This premixing
procedure helped reduce the required amounts of 13C-
substituted reagents. Subsequent dehydration with POCl3
gave TosMIC-13Cα (from (13C)paraformaldehyde, 61%) and
TosMIC-13CNC (from (13C)formamide, 43%). The structures
of TosMIC-13Cα and TosMIC-13CNC are shown in Scheme 4.
The isotopically substituted TosMIC compounds were
employed in a standard van Leusen reaction63 with phenyl
vinyl sulfone (Scheme 4). Formation of the resulting pyrrole
was found to be regioselective: initial Michael addition of the
deprotonated TosMIC-13Cα or TosMIC-13CNC to phenyl vinyl
sulfone followed by cyclization gave 3-benzenesulfonylpyrrole
9-13C5 or 9-13C2, respectively. Vilsmeier−Haack formylation of
the known pyrrole 9-NA63 required prolonged reflux34 and
occurred at the α-position distal to the sulfonyl substituent to
yield 10-NA. A single-crystal X-ray structure of natural
abundance 10-NA provided proof of regioselective formylation
(see Figure S1 in the Supporting Information). Thus,
Vilsmeier−Haack formylation of 9-13C5 or 9-13C2 gave
10-13C2 or 10-13C5, respectively (note the change in
nomenclature upon this transformation). Pyrrolecarboxalde-
hyde 10-NA and each isotopologue thereof ({10}) were doubly
protected by sequential treatment with Boc-anhydride64 and
ethylene glycol65 to give the N-Boc acetal 11-NA and {11}.
The protected pyrroles were subjected to reductive desulfonyl-
ation by deactivated Raney nickel66 to afford the protected
pyrrole-2-carboxaldehyde 12-NA and {12}. Freshly made or
shelf-stored Raney nickel67,68 generally gave yields of <20%.
Other reducing agents, including AIBN,69 NaHg,70,71 and
Na2S2O4,72 did not yield the desired product. Subsequent
deprotection by AcOH/H2O and NaOMe73 gave the desired
pyrrole-2-carboxaldehydes 5-13C2 and 5-13C5 with site-specific
α-13C substitution.
Scheme 3. Synthesis of Isotopically Substituted Pyrrole-2-
a
carboxaldehyde
a
The red ● denotes 13C.
subsequent diagrams indicate isolated yields rather than
isotopic purities; the latter issue is discussed in Chemical
Characterization (vide infra).
The syntheses of α-13C-substituted formyl-pyrroles 5-13C2
and 5-13C5 are seemingly straightforward yet challenging in
practice. The difficulty stems from limited accessibility to
sparsely substituted pyrroles with independent control over the
2- vs 5-positions of the 13C atom and the site of formylation.
Indeed, prior syntheses via Knorr,47−51 Paal−Knorr,52,53
Hantzsch,54 and other55−57 routes typically have afforded
α-13C-substituted pyrroles that bear multiple substituents (e.g.,
alkyl, carboalkoxy); such substituents are not readily removed.
In cases where all substituents could be removed, independent
control over the 2- vs 5-sites of the formyl group and the α-13C
atom is not available.49,53 One workaround entails synthesis of a
pyrrole bearing an α-carbon protective group and the desired
13C atom at the same (α) or distinct (α, α′) positions. In this
regard, 2-(methylthio)(2-13C)pyrrole was synthesized and
found to undergo electrophilic aromatic substitution at the 5-
position.58 The methylthio group was subsequently removed by
treatment with Raney nickel. While this approach offered
potential, we turned to a route that relies on the use of 13C-
substituted p-toluenesulfonylmethyl isocyanide (TosMIC)59 to
construct the 13C-substituted pyrroles.
Alternative attempts to synthesize 5-13C2 and 5-13C5 entailed
the use of TosMIC and ethyl acrylate followed by formylation
to give the known 4-ethoxycarbonyl-2-formylpyrrole34 and
isomeric 3-ethoxycarbonyl-2-formylpyrrole. In an exploratory
study with natural abundance reactants, the isomers were
separated but attempts at thermal decarboxylation,74 iodode-
carboxylation,75 or catalytic decarboxylation76 did not yield the
desired product.
α,β-Unsaturated Ketone−Acetals. Two isotopologues of
the α,β-unsaturated ketone−acetal 4-NA were required.
Reaction of K13CN and bis(trimethylsilyl) sulfate afforded
TMS13CN.77 By an established route,40 reaction of TMS13CN
with trimethyl orthoformate and catalytic BF3·OEt2 gave 1,1-
dimethoxyacetonitrile 7-13CCN. Treatment of the latter with
Grignard reagent 6 followed by hydrolysis gave ketone−acetal
4-13C2 in 19% overall yield (Scheme 5, left sequence).
Introduction of the 13C atom at position 1 requires use of
trimethyl (13C)orthoformate, which to our knowledge was not
commercially available. Accordingly, the commercially available
triethyl (13C)orthoformate (8Et-13C1) was used instead. The
reaction sequence proceeded uneventfully, with conversion of
8Et-13C1 to 1,1-diethoxy (1-13C)acetonitrile (7Et-13C1), which
The two isotopomers can be synthesized by the same route
via isotopologues of TosMIC. TosMIC is typically synthesized
from three components: paraformaldehyde, formamide, and
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Scheme 4. Syntheses of α-13C-Substituted Pyrrole-2-
carboxaldehydes
Scheme 5. Synthesis of Isotopically Substituted α,β-
Unsaturated Ketone−Acetals
a
a
a
The red ● denotes 13C.
Scheme 6. Synthesis of Various Isotopically Substituted
Nitroethylpyrroles
a
The red ● and the blue ■ denote 13C.
upon reaction with Grignard reagent 6 followed by hydrolysis
gave 4Et-13C1 in 38% overall yield (Scheme 5, right sequence).
Nitroethylpyrroles. Four isotopologues {5} were trans-
formed to the corresponding nitroethylpyrrole {3} via
nitroaldol (Henry) condensation with CH3NO2 and subse-
quent borohydride reduction (Scheme 6). Compounds 3-13C2
(a known compound)78 and 3-15Nnitro were obtained by
reaction of 5-NA with 13CH3NO2 and CH315NO2, respectively.
Drawing on prior syntheses of 3-NA,34,43 we employed two
procedures that differ chiefly in reaction time and workup
procedure. Procedure A employed a 2.5 h Henry reaction with
partial purification of the nitrovinylpyrrole prior to LiBH4
reduction (35−42% yields), whereas a longer reaction time
(12 h) and direct addition of NaBH4 to the nitrovinylpyrrole
constituted procedure B (66, 69% yields).
Dihydrodipyrrin−Acetals. Each nitroethylpyrrole isotopo-
logue {3} was respectively reacted with α,β-unsaturated ketone
4-NA via Michael addition41 to give the corresponding
nitrohexanone−pyrrole {2} (Scheme 7). Conversely, 4-13C2,
4Et-13C1, or known compound40 4Et-NA under the same
conditions with 3-NA afforded nitrohexanone−pyrrole 2-13C2,
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ranging from 29% to 66% for conversion of pyrrole-2-
carboxaldehyde isotopologues {5} to {2}. (Note the change
in nomenclature along the series 3 → 2 → 1.)
Scheme 7. Synthesis of Isotopically Substituted
Bacteriochlorins
a
Each of the eight resulting isotopologues {2} as well as
2Et-13C1 and 2Et-NA underwent McMurry-type cyclization to
give the corresponding dihydrodipyrrin−acetal isotopologues
{1}, 1Et-13Cac, and 1Et-NA, respectively. The cyclization
employs TiCl3 in buffered aqueous/THF solution; such a
mixture was first described by McMurry for the synthesis of Δ1-
pyrrolines,79 was adopted by Battersby for the synthesis of the
1-methyldihydrodipyrrins in the preparation of the natural
chlorin Bonellin,80 and was further modified by us for synthesis
of hydrodipyrrins in routes to chlorins42,81 and bacteriochlor-
ins.31,34,82 The amount of buffer required depends on the
nature of the TiCl3 source (powder, 3% HCl solution, or 28%
HCl solution),82 as described in the Supporting Information.
We employed 6 equiv of TiCl3 (20 wt % in 3% HCl solution)
and 100−150 equiv of NH4OAc per nitrohexanone−pyrrole 2.
Bacteriochlorins. Bacteriochlorin formation is achieved by
self-condensation of a dihydrodipyrrin−acetal under acidic
conditions. The condensation of two dihydrodipyrrin−acetal
molecules liberates three molecules of methanol and affords the
monomethoxybacteriochlorin.40 We have carried out extensive
studies of acid catalysis and identified mild conditions that
afford the monomethoxybacteriochlorin in reasonable yields
(∼40% or greater). On the other hand, the reaction in the
presence of a strong acid typically affords the bacteriochlorin
lacking any methoxy substituent in addition to the mono-
methoxybacteriochlorin, with lower total yields of macrocycles.
Indeed, the only prior condensation of 1-NA employed
Bi(OTf)3 in CH2Cl2 and afforded the free base bacteriochlorin
lacking the methoxy group (H2BC-NA, 11%) and the
monomethoxybacteriochlorin (9%).34 Here, we employed
catalysis by BF3·OEt2 in CH3CN at room temperature31 to
afford {H2BC} and H2BC-NA (from 1-NA). In each case, the
free base bacteriochlorin was readily obtained as an intense
green band by a single chromatography procedure. Yields
ranged from 7 to 16%, with little methoxybacteriochlorin
detected for the lower-yielding reactions and only small
quantities detected for the higher-yielding reactions. Regardless,
the desired bacteriochlorin (lacking the methoxy substituent)
was readily isolated. The scale of reaction typically afforded
20−70 mg of each free base bacteriochlorin. In the case of
macrocycle formation from diethyl acetal 1Et-NA (or
1Et-13Cac), the reaction also gave the respective ethoxy-
substituted bacteriochlorin EtOBC-NA shown in Chart 4 (or
Chart 4. Structure of EtOBC-NA
a
See Chart 3 for individual bacteriochlorin structures.
2Et-13C1, or 2Et-NA, respectively. Compound 4Et-NA was
carried through the entire reaction sequence leading to
bacteriochlorins as a prelude to the use of the isotopologue
4Et-13C1. The prior synthesis of nitrohexanone−pyrrole 2-NA
was achieved in 25% overall yield (upon three steps of nitro-
aldol condensation, reduction, and Michael addition) from
pyrrole-2-carboxaldehyde.34 The procedural improvements
herein (see the Supporting Information) gave overall yields
EtOBC-13C5,15, not isolated but provisionally assigned). The
yields of H2BC-NA and H2BC-13C5,15 from 1Et-NA and
1Et-13Cac are significantly lower (3−5%) than those from the
corresponding dimethyl acetal {1} (7−16%).
Bacteriochlorins are metalated with substantially greater
difficulty than are chlorins or porphyrins.35 The metalation of
bacteriochlorins is facilitated by the presence of electron-
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withdrawing substituents. In the absence of any such
substituents, metalation has recently been achieved by
treatment of the bacteriochlorin with NaH or LDA followed
by the metal salt.35 Here, each free base macrocycle was treated
with NaH (or LDA) in THF containing Cu(OAc)2 or
Zn(OTf)2 to give the desired copper or zinc chelate. The
metallobacteriochlorins were typically isolated in pure form
without chromatography (Scheme 7). The metalation was
readily observed by the bathochromic shift of the long-
wavelength absorption (Qy) band. The intensity (ε ≈ 120000
Table 1. NMR Chemical Shifts (δ) of {H2BC} and {ZnBC}
{H2BC}
a
a
b
1
position
1H NMR
13C NMR
{ZnBC} H NMR
β Positions
121.84
121.73
51.4
2, 12
3, 13
7, 17
8, 18
8.77
8.73
4.47
8.65
8.61
4.46
c
c
1.97
46.0
1.98
α Positions
136.2
M
−1 cm−1) and sharpness (full width at half-maximum (fwhm)
1, 11
4, 14
6, 16
9, 19
d
d
d
d
d
d
d
d
135.3
= 12 nm) of the Qy band of the free base bacteriochlorin and
the shift from 713 to 723 nm (zinc chelate, fwhm = 14 nm) or
728 nm (copper chelate, fwhm = 19 nm) provided a very clear
and reliable indicator of the completion of the metalation
process.
Chemical Characterization. {1}−{5}, {9}−{12}, {H2BC}
(as well as EtOBC-NA), {ZnBC}, and {CuBC} were all
characterized by electrospray ionization mass spectroscopy
(ESI-MS). Each isotopically substituted compound showed the
correct molecular ion peak (except for 5-15N and {TosMIC}).
ESI-MS was also used to assess the integrity of isotopic
incorporation at the designated sites of the bacteriochlorin
isotopologues (vide infra).
157.6
169.6
Meso Positions
98.7
5, 15
8.83
8.73
8.60
8.64
10, 20
96.5
NH Positions
d
21, 23
−2.38
d
a
b
c
In CDCl3 at 298 K. In THF-d8 at 298 K. Chemical shifts of the
geminal dimethyl protons. Not available.
d
(M+) and the protonated molecule (M + H)+ upon ESI-MS
analysis. On the other hand, the zinc and copper chelates of
bacteriochlorins typically exhibit solely the molecular ion (M+).
Consequently, interpretation of the isotopic incorporation by
ESI-MS is quite complicated for the free base bacteriochlorins
but can be achieved for the zinc and copper chelates {ZnBC}
and {CuBC}. Such comparisons are posited on the
assumptions of (1) equal ionization efficiencies of isotopo-
logues and (2) peak intensities as a reliable measure of relative
ion abundance.83 The following presentation concerns data for
the zinc chelates; the same findings were arrived at upon
examination of the data for the copper chelates.
The zinc chelate of a tetrapyrrole macrocycle generally shows
a characteristic isotope pattern upon ESI-MS analysis due to
the natural abundance of five stable isotopes of zinc (64Zn
(48.9%), 66Zn (27.8%), 67Zn (4.1%), 68Zn (18.6%), and 70Zn
(0.6%)).84 For ZnBC-NA, the molecular formula is
C24H24N4Zn. The pattern due to the zinc isotopes is
superposed on that from the stable isotopes of 1H (2H
0.015%), 12C (13C 1.11%), and 14N (15N 0.37%) of the
tetrapyrrole ligand.84 For the ligand alone, the expected
distribution of natural abundance ions is as follows:85 (A +
0), 75.9%; (A + 1), 21.1%; (A + 2), 2.8%; (A + 3), 0.2%.
Hence, the ESI-MS spectrum of a zinc bacteriochlorin is
expected to exhibit multiple lines, with the monoisotopic (A +
0) entity constituting the base peak.
The observed ESI mass spectrum of ZnBC-NA is shown in
Figure 1A. The accurate monoisotopic mass for ZnBC-NA was
found at 432.128 m/z. The observed spectrum for
ZnBC-13C1,11 (Figure 1B) shows a peak distribution essentially
identical with that of ZnBC-NA except for the expected shift to
higher mass by 2 Da. In addition to the intense peak at 434.123
m/z, a tiny peak at 433.134 m/z corresponds to the
monoisotopic mass of the bacteriochlorin substituted with
only a single 13C atom. No peak was observed for the
monoisotopic species of the bacteriochlorin lacking any 13C
atoms. The spectrum of ZnBC-13C1,11 is representative of those
cases where the synthesis was performed without loss of
isotopic integrity from that of the isotopically substituted
reactant (>99% 13C, >98% 15N). Such examples also include
{1}−{5}, {9}−{12}, and {H2BC} were also all characterized
1
by H NMR and 13C NMR spectroscopy. Each isotopically
substituted compound showed the expected splitting pattern
upon 1H NMR spectroscopy and an enhanced signal upon 13C
NMR spectroscopy. All isotopologues {ZnBC} (as well as
EtOBC-NA) were characterized by 1H NMR spectroscopy and
absorption spectroscopy. The isotopologues {CuBC} were not
characterized by NMR spectroscopy, given the paramagnetism
of the copper chelate. The availability of the macrocycles with
site-specific 13C substitution enables unambiguous determi-
nation of the NMR assignments for the bacteriochlorin
skeleton. In bacteriochlorins the meso protons and β-pyrrole
protons resonate in a very narrow region (∼8.73−8.83 ppm for
1
H2BC-NA; 8.60−8.65 ppm for ZnBC-NA). While H NMR
assignments can be made without isotopic substitution, the 13
C
NMR assignments are far more challenging, given the large
number of quaternary carbons. The 1H and 13C NMR chemical
shifts for each site of 13C substitution in the isotopologues
1
{H2BC} are given in Table 1. The H NMR assignments also
are provided for {ZnBC}.
The 15N-substituted compounds ({1}−{3} and {H2BC})
were characterized by 15N NMR spectroscopy. The 15N
chemical shifts (ppm, in THF-d8 at 298 K referenced to
external nitromethane) are characteristic for the distinct types
of nitrogen-containing groups: 15N-pyrrole (3-15Npyrrol, −228;
2-15Npyrrol, −228; 1-15N11, −229; H2BC-15N21,23, −249); 15N-
nitroalkyl (3-15Nnitro, 6; 2-15Nnitro, 10); 15N-pyrroline (1-15N10,
−58; H2BC-15N22,24, −82). The in-depth NMR analyses of
each isotopologue {H2BC} will be reported elsewhere.
The bacteriochlorins {H2BC} (as well as EtOBC-NA),
{ZnBC}, and {CuBC} were characterized by absorption
spectroscopy, where each compound gave the characteristic
bacteriochlorin features of strong bands in the near-UV region
and a strong band in the near-infrared spectral region.8 The
copper bacteriochlorins gave λabs 728 nm and also were
examined by fluorescence spectroscopy to confirm the absence
of fluorescence.
Integrity of Isotopic Incorporation. Free base bacterio-
chlorins typically afford peaks due to both the molecular ion
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15N atom, respectively. The relative abundance of bacterio-
chlorins bearing 0, 1, or 2 15N atoms at the designated sites was
1.98, 24.29, or 73.73%, respectively. The overall isotopic
enrichment at the designated sites for the sample of
ZnBC-15N22,24 thus was found to be 86%. The precursor
2-15Nnitro was found to contain only 1−2% of isotopically
unsubstituted species; hence, the isotopic loss must stem from
the reductive cyclization of 2-15Nnitro to 1-15N10 by exchange
upon exposure to the large quantity of NH4OAc used as buffer.
The low quality of the mass spectrum of 1-15N10 precluded an
assessment of any isotopic loss at this step. A proposal for the
origin of the isotopic loss upon formation of 1-15N10 is shown
in Scheme 8. Treatment of 2-15Nnitro with NaOMe affords the
15N-substituted nitronate anion I, which upon addition to the
aqueous NH4OAc buffer can undergo a Nef reaction to give the
natural abundance 2,5-diketone (II) with loss of an 15N species
(e.g., hyponitrous acid or hydroxylamine). Subsequent reaction
with natural abundance NH3 from the buffer at either ketone
gives an imine or enamine (e.g., III), which undergoes a Paal−
Knorr86 reaction with the second carbonyl group to form the
pyrroline ring of 1-NA. (Alternatively, direct attack of NH3 may
occur on the carbon of the nitronate I to displace an 15N
species without the intermediacy of the 5-carbonyl group in II.)
The isotopically enriched sample hence consists of an
admixture of 1-15N10 and 1-NA. While the TiCl3-mediated
Nef reaction is known,87 the occurrence of the sequential Nef
reaction, amination with NH4OAc buffer, and Paal−Knorr
reaction in parallel with the McMurry-type ring closure for this
transformation was unknown prior to the isotopic studies
reported herein.
CONCLUSIONS
■
A de novo synthesis of stable bacteriochlorins has been
exploited to incorporate pairs of 13C or 15N atoms in a site-
specific manner. The concise nature of the synthesis enabled
straightforward conversion of isotopically substituted small-
molecule reactants (N,N-dimethyl(13C)formamide, (13C)-
paraformaldehyde, (13C)formamide, 13CH3NO2, K13CN, trieth-
yl (13C)orthoformate, (15N)pyrrole, and CH315NO2) to a set of
eight free base bacteriochlorins; subsequent metalation afforded
the zinc and copper chelates. Each bacteriochlorin is stable by
virtue of a geminal dimethyl group in each pyrroline ring. A
synthetic route to 2- or 5-13C-substituted pyrrole-2-carbox-
aldehydes proceeded via the intermediacy of isotopically
substituted TosMIC. The partial isotopic loss in two syntheses
is proposed to stem from exchange processes with natural
abundance species in the reaction medium. The zinc and
copper chelates of the bacteriochlorin isotopologues will be
examined by EPR and RR spectroscopy, respectively, to provide
spin density and vibrational information germane to the
function of the bacteriochlorin macrocycles in photosynthetic-
like energy-transduction processes.
Figure 1. ESI-mass spectra of ZnBC-NA and three isotopologues.
ZnBC-13C5,15, ZnBC-13C6,16, ZnBC-13C9,19, ZnBC-13C10,20, and
ZnBC-15N21,23
.
On the other hand, the spectrum of ZnBC-13C4,14 (Figure
1C) shows the presence of a diagnostic ion peak at 433.134 or
432.130 m/z due to the monoisotopic mass of a bacteriochlorin
bearing one or no 13C atom, respectively. The relative
abundance of bacteriochlorins bearing 0, 1, or 2 13C atoms at
the designated sites was 1.64, 23.26, or 75.10%, respectively.
The overall isotopic enrichment at the designated sites for the
sample of ZnBC-13C4,14 thus was 87% (see the Supporting
Information for the method of calculation). The isotopic loss
was also found in the earliest precursor 9-13C2, which contains
13% of isotopically unsubstituted species. No further isotopic
loss was found for the transformation of 9-13C2 to the
corresponding dihydrodipyrrin−acetal 1-13C9. The isotopic loss
apparently resulted upon formation of TosMIC-13CNC in the
presence of formic acid as solvent, where formyl exchange
between formic acid and (13C)formamide may have occurred.
The spectrum of ZnBC-15N22,24 (Figure 1D) also shows a
peak at 433.125 or 432.127 m/z corresponding to the
monoisotopic mass of a bacteriochlorin that bears one or no
EXPERIMENTAL SECTION
■
1
General Methods. H NMR (400 MHz) spectra and 13C NMR
spectra (100 MHz) were collected at room temperature in CDCl3
unless noted otherwise. 15N NMR spectroscopy (41 MHz) was
performed at room temperature. The 15N chemical shifts are reported
relative to that of nitromethane (δ 0.0) as an indirect reference using
pyrrole as a direct reference. An NMR microtube containing 8.0 M
(15N)pyrrole in THF-d8 (70 μL) was placed in an NMR tube
containing the samples in THF-d8 (500 μL). The resonance of the
pyrrole nitrogen was set to −230.1 ppm relative to nitromethane (δ
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Scheme 8. Proposed Route for the Loss of 15N upon Reductive Cyclization
0.0 ppm). The description of signals includes the following: dt, doublet
of triplets; dm, doublet of multiplets. All dipole−dipole coupling
constants were reported as positive values (note that JNH and JCN
values of (15N)pyrrole have been studied and reported as negative,88,89
yet such detailed studies were not performed herein). Electrospray
ionization mass spectrometry (ESI-MS) data are reported for the
molecular ion or adduct ion. Absorption spectra were collected in
toluene at room temperature.
7.01−7.02 (m, 1H), 7.18 (br s, 1H), 9.52 (d, J = 176 Hz, 1H), 10.28
(br s, 1H); 13C NMR δ 111.3 (d, J = 4.6 Hz), 121.8 (d, J = 8.4 Hz),
126.6 (d, J = 3.1 Hz), 132.8 (d, J = 65.6 Hz), 179.4 (13C); ESI-MS
obsd 95.0331, calcd 95.0332 [(M − H)−, M = C413CH5NO].
Pyrrole-2-carboxaldehydes {5} via TosMIC. p-Toluenesulfonyl-
(13C)methyl Isocyanide (TosMIC-13Cα). Following a modified
procedure,60,62 (13C)paraformaldehyde (5.00 g, 161 mmol), forma-
mide (22.5 g, 500 mmol), and K2CO3 (2.30 g, 16.7 mmol) were placed
in a 250 mL round-bottom flask. Water (∼5 mL) was added to
dissolve the solid materials on the wall of the flask. The mixture was
stirred at room temperature for 2 h, whereupon formic acid (52.5 g,
1.14 mol) and sodium p-toluenesulfinate hydrate (62.5 g, 233 mmol)
were added in an alternating portionwise fashion. The mixture was
heated at 90 °C for another 2 h before being poured into an ice−salt
bath (400 g of ice and 40 g of salt). The mixture was extracted with
CH2Cl2. The organic phase was washed with saturated aqueous
NaHCO3 solution until neutral, dried (Na2SO4), and concentrated to
a white solid. The crude solid was placed in a 1 L round-bottom flask,
to which freshly distilled THF (60 mL), anhydrous ether (24 mL), and
triethylamine (56 mL) were then added. The suspension was cooled to
−5 °C in an ice−salt bath. Then, a solution of POCl3 (25 g, 160
mmol) in freshly distilled THF (25 mL) was added dropwise by an
addition funnel at a rate such that the temperature was maintained
between −5 and 0 °C. The mixture was stirred for 30 min at 0 °C,
then poured into 1.5 L of ice−water with continuous stirring. The
mixture was stirred for another 30 min. The resulting brown
precipitate was collected by suction filtration and washed with cold
water (100 mL). The collected wet product was dissolved in CH2Cl2,
dried (Na2SO4), and concentrated to a brown solid (19.3 g, 61%),
which was used directly in the next step without further purification:
1H NMR δ 2.50 (s, 3H), 4.59 (d, J = 156 Hz, 2H), 7.46 (d, J = 8.1 Hz,
The 15N-substituted compounds ((15N)pyrrole, CH315NO2) ex-
hibited >98% 15N purity. The 13C-substituted compounds (N,N-
dimethyl(13C)formamide, (13C)paraformaldehyde, (13C)formamide,
13CH3NO2, K13CN, and triethyl (13C)orthoformate) exhibited 99%
13C purity. NaH (dry, 95%), LDA (2.0 M solution in heptanes/THF/
ethylbenzene), and Raney nickel were used as obtained commercially.
Silica gel (40 μm average particle size) was used for column
chromatography. All solvents were reagent grade and were used as
received unless noted otherwise. THF was freshly distilled from
sodium/benzophenone ketyl. Anhydrous CH3CN and HPLC-grade
CH3CN were used as received.
Noncommercial Compounds. Compounds 1-NA,34 3-NA,34 4-
NA,40 4Et-NA,40 9-NA,63 ZnBC-NA,35 and CuBC-NA35 were
prepared as described in the literature.
Pyrrole-2-carboxaldehydes {5}. (15N)Pyrrole-2-carboxaldehyde
(5-15N). Following a standard procedure,45 N,N-dimethylformamide
(1.61 g, 22.0 mmol) in an ice bath was slowly treated with POCl3
(3.38 g, 22.0 mmol). The ice bath was removed, and the mixture was
stirred for 5 min. The ice bath was replaced, and anhydrous 1,2-
dichloroethane (6.8 mL) was added, followed by a solution of
(15N)pyrrole (1.25 g, 18.4 mmol) in 1,2-dichloroethane (6.8 mL) over
30 min. The mixture was refluxed for 15 min and then cooled to room
temperature. A saturated aqueous NaOAc solution (6.9 g of NaOAc in
15 mL of deionized water) was added, and the mixture was refluxed for
15 min. The mixture was cooled to room temperature and then was
diluted with diethyl ether. The mixture was washed with saturated
aqueous NaHCO3 solution. The organic layer was dried (Na2SO4) and
concentrated to yield a brown solid (1.73 g, 98%): mp 38−40 °C; 1H
NMR δ 6.34−6.37 (m, 1H), 7.01−7.04 (m, 1H), 7.18−7.20 (m, 1H),
9.51 (d, J = 2.6 Hz, 1H), 10.65 (dd, J = 98.4 Hz, J = 24.0 Hz, 1H); 13C
NMR δ 111.3 (d, J = 3.1 Hz), 122.0, 127.1 (dd, J = 14.1 Hz, J = 5.0
Hz), 132.7 (d, J = 14.5 Hz), 179.5; the sample failed to show the
correct m/z peak in ESI-MS.
2H), 7.90 (d, J = 8.1 Hz, 2H); 13C NMR δ 21.8, 61.1 (13C), 129.4,
130.3, 146.9.
p-Toluenesulfonylmethyl (13C)Isocyanide (TosMIC-13CNC). The
above procedure with paraformaldehyde (3.66 g, 122 mmol),
(13C)formamide (5.00 g, 109 mmol), K2CO3 (1.52 g, 11.0 mmol),
formic acid (28.1 g, 611 mmol), and sodium p-toluenesulfinate hydrate
(31.5 g, 122 mmol) afforded the title compound as a brown solid (9.20
g, 43%), which was used directly in the next step without further
purification: 1H NMR δ 2.50 (s, 3H), 4.58−4.59 (m, 2H), 7.46 (d, J =
8.4 Hz, 2H), 7.90 (d, J = 8.4 Hz, 2H); 13C NMR δ 21.8, 129.4, 130.4,
131.9, 146.9, 166.0 (13C).
Pyrrole-2-(13C)carboxaldehyde (5-13Cformyl). The above procedure
with N,N-dimethyl(13C)formamide (1.00 g, 13.5 mmol) afforded the
title compound (previously reported with limited data)46 as a brown
3-Benzenesulfonyl(5-13C)pyrrole (9-13C5). Following a standard
procedure,63 phenyl vinyl sulfone (16.5 g, 98.5 mmol) and
TosMIC-13Cα (19.3 g, 98.5 mmol) in THF/DMSO (450 mL, 2/1)
1
solid (1.07 g, 82%): mp 37−39 °C; H NMR δ 6.36−6.37 (m, 1H),
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were added via a cannula to a suspension of NaH (7.9 g, 60% in oil
suspension, 0.20 mol) in 150 mL of THF. The reaction mixture was
stirred at room temperature for 5 h. Water was added slowly, and the
mixture was extracted with ethyl acetate. The organic extract was dried
(Na2SO4) and concentrated. Column chromatography (silica,
hexanes/ethyl acetate (2/3)) afforded a pale yellow solid (6.07 g,
(d, J = 1.83 Hz, 1H), 7.94−7.97 (m, 2 H); 13C NMR δ 27.8, 65.0, 86.6,
97.6, 110.3, 125.9, 126.65, 127.18, 129.2, 133.0, 134.7, 142.0, 147.4;
ESI-MS obsd 402.0990, calcd 402.0987 [(M + Na)+, M =
C18H21NO6S].
tert-Butyl 4-Benzenesulfonyl-2-(1,3-dioxolan-2-yl)(2-13C)pyrrole-
1-carboxylate (11-13C2). The above procedure with 10-13C2 (5.33 g,
22.6 mmol) afforded the title compound as a yellow solid (6.60 g,
77%): mp 142−144 °C; 1H NMR δ 1.61 (s, 9H), 3.97−4.01 (m, 4H),
6.35 (d, J = 2.2 Hz, 1H), 6.62−6.64 (m, 1H), 7.49−7.60 (m, 3H), 7.84
(dd, J = 5.3 Hz, J = 2.0 Hz, 1H), 7.94−7.97 (m, 2 H); 13C NMR δ
27.8, 65.0, 86.6, 97.6 (d, J = 65.6 Hz), 110.3 (d, J = 71.7 Hz), 125.9 (d,
J = 6.1 Hz), 127.2, 129.2, 133.0, 134.7 (13C), 142.0; ESI-MS obsd
403.1022, calcd 403.1016 [(M + Na)+, M = C1713CH21NO6S].
tert-Butyl 4-Benzenesulfonyl-2-(1,3-dioxolan-2-yl)(5-13C)pyrrole-
1-carboxylate (11-13C5). The above procedure with 10-13C5 (4.20 g,
17.8 mmol) afforded the title compound as a yellow solid (4.73 g,
70%): mp 129−133 °C; 1H NMR δ 1.61 (s, 9H), 3.97−4.01 (m, 4H),
6.35 (s, 1H), 6.62−6.64 (m, 1H), 7.49−7.60 (m, 3H), 7.83 (dd, J =
98.6 Hz, J = 1.8 Hz, 1H), 7.94−7.97 (m, 2 H); 13C NMR δ 27.8, 65.0,
86.6, 97.5, 110.3, 125.9 (13C), 127.2, 129.2, 133.0, 142.0; ESI-MS obsd
403.1013, calcd 403.1016 [(M + Na)+, M = C1713CH21NO6S].
tert-Butyl 2-(1,3-Dioxolan-2-yl)pyrrole-1-carboxylate (12-NA).
Raney nickel (∼100 g, slurry in H2O) was washed with deionized
water (3 × 300 mL) and acetone (3 × 300 mL) before being poured
into a three-necked, 1 L flask equipped with a mechanical stirrer and a
condenser. A total of 150 mL of acetone was used to facilitate the
transfer of Raney nickel into the flask. The Raney nickel−acetone
mixture was deactivated at 50 °C with stirring for 2 h before the
addition of a solution of 11-NA (2.28 g, 6.00 mmol) in acetone (50
mL). The mixture was stirred at 50 °C for a further 18 h. The reaction
mixture was filtered through a pad of Celite. The filter cake was
washed with acetone. The filtrate was concentrated and chromato-
graphed (silica, hexanes/ethyl acetate (3/1)) to yield a colorless liquid
(648 mg, 44%): 1H NMR δ 1.60 (s, 9H), 3.97−4.06 (m, 4H), 6.13 (t, J
= 3.3 Hz, 1H), 6.41−6.43 (m, 1H), 6.45 (s, 1H), 7.24 (dd, J = 3.3 Hz,
J = 1.8 Hz, 1H); 13C NMR δ 27.9, 64.8, 84.2, 98.4, 109.9, 112.5, 122.6,
132.0; ESI-MS obsd 262.1043, calcd 262.1050 [(M + Na)+, M =
C12H17NO4].
1
30%): mp 137−140 °C; H NMR δ 6.51−6.54 (m, 1H), 6.79−6.81
(dm, J = 189 Hz, 1H), 7.41−7.43 (m, 1H), 7.46−7.55 (m, 3H), 7.93−
7.96 (m, 2H), 8.73 (br s, 1H); 13C NMR δ 108.6 (d, J = 67.9 Hz),
120.1 (13C), 126.8, 129.0, 132.5; ESI-MS obsd 209.0470, calcd
209.0466 [(M + H)+, M = C913CH9NO2S].
3-Benzenesulfonyl(2-13C)pyrrole (9-13C2). The above procedure
with TosMIC-13CNC (8.61 g, 43.9 mmol) afforded the title compound
1
as a brown solid (3.82 g, 42%): mp 145−147 °C; H NMR δ 6.51−
6.54 (m, 1H), 6.78−6.82 (m, 1H), 7.41−7.43 (dm, J = 193 Hz, 1H),
7.46−7.55 (m, 3H), 7.93−7.96 (m, 2H), 8.73 (br s, 1H); 13C NMR δ
108.6 (d, J = 3.8 Hz), 120.2 (d, J = 4.6 Hz), 122.4 (13C), 125.4, 126.8,
129.0, 132.5; ESI-MS obsd 209.0457, calcd 209.0466 [(M + H)+, M =
C913CH9NO2S].
4-Benzenesulfonyl-2-formylpyrrole (10-NA). Following a standard
procedure,34 a solution of 9-NA (8.56 g, 41.4 mmol) in DMF (190
mL) was treated with POCl3 (6.0 mL, 64 mmol). The resulting
mixture was stirred at 80 °C for 40 h, cooled to room temperature,
treated with a mixture of saturated aqueous sodium acetate and
CH2Cl2 (400 mL, 1/1), and then stirred for 1 h. The aqueous phase
was separated and extracted with CH2Cl2. The combined organic
extract was washed with saturated brine, dried (Na2SO4), and
concentrated. Column chromatography (silica, CH2Cl2/ethyl acetate
1
(3/2)) afforded a yellow solid (8.58 g, 88%): mp 152−155 °C; H
NMR δ 7.25 (d, J = 1.5 Hz, 1H), 7.50−7.61 (m, 3H), 7.66 (br s, 1H),
7.95−7.98 (m, 2H), 9.55 (d, J = 1.1 Hz, 1H), 10.1 (br s, 1H); 13C
NMR δ 118.9, 127.0, 127.84, 128.29, 129.3, 133.2, 133.5, 142.3, 179.8;
ESI-MS obsd 236.0380, calcd 236.0381 [(M + H)+, M = C11H9NO3S].
4-Benzenesulfonyl-2-formyl(2-13C)pyrrole (10-13C2). The above
procedure with 9-13C5 (6.07 g, 29.3 mmol) afforded the title
compound as a yellow solid (5.33 g, 77%): mp 157−159 °C; 1H
NMR δ 7.25 (br s, 1H), 7.51−7.61 (m, 3H), 7.67 (d, J = 7.0 Hz, 1H),
7.95−7.98 (m, 2H), 9.54 (d, J = 30.4 Hz, 1H), 10.2 (br s, 1H); 13C
NMR δ 118.9 (d, J = 65.6 Hz), 127.0, 127.8 (d, J = 5.3 Hz), 128.3,
129.3, 133.2 (d, J = 3.8 Hz), 133.5 (13C), 142.3, 179.8 (d, J = 63.3 Hz);
ESI-MS obsd 237.0413, calcd 237.0409 [(M + H)+, M =
C1013CH9NO3S].
tert-Butyl 2-(1,3-Dioxolan-2-yl)(2-13C)pyrrole-1-carboxylate
(12-13C2). Following the above procedure, Raney nickel (∼150 g
slurry in H2O) was deactivated in acetone (450 mL) for 3.5 h before
11-13C2 (6.60 g, 17.4 mmol) in acetone (50 mL) was added. The
mixture was stirred and heated at 50 °C for a further 20 h.
Chromatography yielded the title compound as a colorless liquid (1.81
g, 43%). Further elution also recovered starting material 11-13C2 (1.65
g, 25%), which was combined with another batch and converted to the
4-Benzenesulfonyl-2-formyl(5-13C)pyrrole (10-13C5). The above
procedure with 9-13C2 (5.84 g, 28.1 mmol) afforded the title
compound as a yellow solid (5.17 g, 78%): mp 151−155 °C; 1H
NMR δ 7.25−7.28 (m, 1H), 7.51−7.62 (m, 3H), 7.67−7.68 (dm, J =
194 Hz, 1H), 7.95−7.98 (m, 2H), 9.54 (s, 1H), 10.2 (br s, 1H); 13C
NMR δ 119.0, 127.0, 127.95 (13C), 129.3, 133.2, 142.3, 179.8 (d, J =
2.3 Hz); ESI-MS obsd 259.0230, calcd 259.0229 [(M + Na)+, M =
C1013CH9NO3S].
tert-Butyl 4-Benzenesulfonyl-2-(1,3-dioxolan-2-yl)pyrrole-1-car-
boxylate (11-NA). Following standard procedures,64,65 a solution of
10-NA (8.58 g, 36.5 mmol) in THF (230 mL) was slowly treated with
NaH (1.75 g, 43.8 mmol, 60% in oil suspension) at room temperature
under argon. After 1 h, Boc anhydride (8.30 g, 40.0 mmol) was added.
The mixture was stirred for 24 h at room temperature, then quenched
by the addition of saturated aqueous NH4Cl, and then extracted with
ethyl acetate. The organic extract was concentrated to a dark red oil.
The crude solid material was dissolved in benzene (730 mL) and then
treated with ethylene glycol (50.8 mL, 91.1 mmol) and p-TsOH·H2O
(0.83 g, 44 mmol). The reaction mixture was refluxed using a Dean−
Stark apparatus for 1.5 h. After the mixture was cooled to room
temperature, saturated aqueous NaHCO3 (400 mL) was added, and
the mixture was extracted with CH2Cl2. The organic layer was washed
with saturated brine, dried (Na2SO4), and concentrated. Recrystalliza-
tion from hot 2-propanol afforded a brown solid (7.86 g, 57%). The
mother liquor was chromatographed (silica, CH2Cl2/ethyl acetate (4/
1)) to obtain an additional 2.30 g of pale yellow product for a total of
10.16 g (73%): mp 135−137 °C; 1H NMR δ 1.61 (s, 9H), 3.97−4.01
(m, 4H), 6.35 (s, 1H), 6.63−6.64 (m, 1H), 7.49−7.60 (m, 3H), 7.84
1
title compound (average overall yield of 56%): H NMR δ 1.60 (s,
9H), 3.97−4.07 (m, 4H), 6.13 (dt, J = 6.6 Hz, J = 3.3 Hz, 1H), 6.41−
6.44 (m, 1H), 6.45 (s, 1H), 7.23−7.26 (m, 1H); 13C NMR δ 27.9,
64.8, 98.4 (d, J = 66.4 Hz), 109.9, 112.5 (d, J = 71.0 Hz), 122.7, 132.0
(13C); ESI-MS obsd 263.1085, calcd 263.1083 [(M + Na)+, M =
C1113CH17NO4].
tert-Butyl 2-(1,3-Dioxolan-2-yl)(5-13C)pyrrole-1-carboxylate
(12-13C5). The above procedure with 11-13C5 (4.15 g, 10.9 mmol)
afforded the title compound as a yellow solid (1.78 g, 68%): 1H NMR
δ 1.60 (s, 9H), 3.97−4.07 (m, 4H), 6.12 (dt, J = 8.7 Hz, J = 3.3 Hz,
1H), 6.40−6.44 (m, 1H), 6.45 (s, 1H), 7.24−7.25 (dm, J = 192.0 Hz,
1H); 13C NMR δ 27.9, 64.8, 98.4, 112.5, 122.6 (13C) ; ESI-MS obsd
263.1077, calcd 263.1083 [(M + Na)+, M = C1113CH17NO4].
(2-13C)Pyrrole-2-carboxaldehyde (5-13C2). Following a standard
procedure,73 12-13C2 (2.45 g, 10.2 mmol) in a 50 mL flask was treated
with AcOH/H2O (24 mL, 1/1). The reaction mixture was stirred at
room temperature for 2 h. The reaction mixture was quenched by the
slow addition of saturated aqueous NaHCO3 and then extracted with
CH2Cl2. The organic extract was dried (Na2SO4) and concentrated.
The residue was dissolved in freshly distilled THF (40 mL) and
treated with NaOMe (1.95 g, 36.1 mmol) in MeOH (6 mL). The
reaction mixture was stirred for 15 min and then treated with water
and diethyl ether. The organic extract was dried (Na2SO4) and
concentrated to yield a brown solid (760 mg, 78%): mp 35−37 °C; 1H
1010
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Article
NMR δ 6.34−6.38 (m, 1H), 6.97−7.01 (m, 1H), 7.12−7.14 (m, 1H),
9.31 (br s, 1H), 9.53 (d, J = 29.0 Hz, 1H); 13C NMR δ 111.3 (d, J =
2.3 Hz), 120.1, 132.9 (13C), 179.2 (d, J = 65.6 Hz); ESI-MS obsd
97.0483, calcd 97.0478 [(M + H)+, M = C413CH5NO].
6.17 (m, 1H), 6.70−6.73 (m, 1H), 8.17 (br s, 1H); 13C NMR δ 25.4
(d, J = 52.6 Hz), 75.3, 106.9 (d, J = 68.7 Hz), 108.8 (d, J = 2.3 Hz),
117.8 (d, J = 7.6 Hz), 126.0; ESI-MS obsd 142.0693, calcd 142.0692
[(M + H)+, M = C513CH8N2O2].
(5-13C)Pyrrole-2-carboxaldehyde (5-13C5). The above procedure
with 12-13C5 (3.45 g, 14.4 mmol) afforded the title compound as a
brown solid (1.13 g, 82%): mp 33−37 °C; 1H NMR δ 6.35−6.38 (m,
1H), 6.98−7.02 (m, 1H), 7.15 (d, J = 186 Hz, 1H), 9.52 (s, 1H), 9.85
(br s, 1H); 13C NMR δ 111.3 (d, J = 62.6 Hz), 126.4 (13C), 179.3;
ESI-MS obsd 97.0481, calcd 97.0478 [(M + H)+, M = C413CH5NO].
Nitroethylpyrroles {3}. 2-(2-Nitroethyl)(15N)pyrrole (3-15Npyrrol).
Following a standard procedure34 with slight modification (procedure
A), a mixture of 5-15N (1.73 g, 18.0 mmol), potassium acetate (1.40 g,
14.3 mmol), and methylamine hydrochloride (0.97 g, 14 mmol) in
absolute ethanol (6.3 mL) was treated with nitromethane (2.5 mL, 47
mmol) with stirring. The mixture was stirred for 2.5 h, whereupon
water was added. The mixture was extracted with CH2Cl2. The organic
layer was dried (Na2SO4) and concentrated to yield a dark yellow
solid. The crude solid material was dissolved in freshly distilled THF
(81 mL), and the solution was cooled to −10 °C. The solution was
treated with LiBH4 (0.48 g, 90%, 22 mmol) all at once with vigorous
stirring. The reaction mixture was stirred for 25 min at −10 °C,
whereupon the reaction mixture was quenched by slow addition of a
cold saturated aqueous NH4Cl solution. The mixture was extracted
with ethyl acetate, and the organic layer was washed with brine, dried
(Na2SO4), and concentrated. Column chromatography (silica,
hexanes/ethyl acetate (3/1)) afforded an orange oil (1.07 g, 42%):
1H NMR δ 3.31 (td, J = 6.8 Hz, J = 2.2 Hz, 2H), 4.60 (t, J = 6.8 Hz,
2H), 6.00−6.02 (m, 1H), 6.13−6.16 (m, 1H), 6.70−6.72 (m, 1H),
8.17 (dq, J = 95.3 Hz, J = 2.6 Hz, 1H); 13C NMR δ 25.5, 75.4, 106.9
(d, J = 5.3 Hz), 108.8 (d, J = 3.1 Hz), 117.8 (d, J = 13.0 Hz), 126.0;
15N NMR δ −228.1; ESI-MS obsd 140.0479, calcd 140.0483 [(M −
H)−, M = C6H8N15NO2].
2-(2-Nitroethyl)(5-13C)pyrrole (3-13Cγ). Procedure B with 5-13C5
(1.60 g, 16.7 mmol) afforded the title compound as an orange oil (1.62
g, 69%): 1H NMR δ 3.31 (t, J = 6.8 Hz, 2H), 4.60 (t, J = 6.8 Hz, 2H),
6.00−6.03 (m, 1H), 6.13−6.17 (m, 1H), 6.71−6.72 (dm, J = 185 Hz,
1H), 8.17 (br s, 1H); 13C NMR δ 25.4, 75.3, 106.9, 108.8 (d, J = 66.4
Hz), 117.8 (13C), 126.0; ESI-MS obsd 142.0694, calcd 142.0692 [(M
+ H)+, M = C513CH8N2O2].
α,β-Unsaturated Ketone−Acetals {4}. 1,1-Dimethoxy-4-meth-
yl-3-(2-13C)penten-2-one (4-13C2). Following a standard procedure,77
a round-bottom flask equipped with a 10 cm Vigreux column and a
short-path condenser was charged with bis(trimethylsilyl) sulfate (11.5
g, 47.2 mmol) and K13CN (4.30 g, 65.2 mmol). The reaction mixture
was heated and distilled at 200 °C. The distillate was collected (40−60
1
°C at top of column) as a colorless liquid and found (by H NMR
spectroscopy) to contain TMS13CN (∼2.48 g, ∼38%) and silyl-
containing species. The crude distillate was used without further
1
purification: H NMR δ 0.37 (d, J = 2.9 Hz). Following a standard
procedure,40 the crude distillate (containing ∼2.48 g of TMS13CN,
24.8 mmol) was combined with trimethyl orthoformate (5.39 mL, 49.2
mmol) and treated dropwise with BF3·OEt2 (0.50 mL, 4.0 mmol)
under argon at room temperature. The reaction mixture was stirred for
3 h at room temperature, whereupon saturated aqueous NaHCO3 was
added. The aqueous phase was extracted with diethyl ether. The
organic phase was washed with saturated brine, dried (Na2SO4), and
concentrated. The residue was treated dropwise with 6 (123 mL, 61.5
mmol, 0.5 M in THF) under argon at 0 °C, followed by stirring for 2 h
at room temperature. The reaction mixture was treated with saturated
aqueous NH4Cl (500 mL) and vigorously stirred for 3 h. The aqueous
phase was extracted with diethyl ether. The organic phase was washed
with saturated brine, dried (Na2SO4), and concentrated. The resulting
mixture was chromatographed (silica, hexanes/ethyl acetate (3/1)) to
afford a pale yellow liquid (2.02 g, 19% from K13CN): 1H NMR δ 1.96
(s, 3H), 2.21 (s, 3H), 3.42 (s, 6H), 4.49 (s, 1H), 6.36−6.38 (m, 1H);
13C NMR δ 21.3 (d, J = 1.5 Hz), 28.1 (d, J = 6.1 Hz), 54.5 (d, J = 2.3
Hz), 104.5 (d, J = 53.4 Hz), 119.0 (d, J = 56.5 Hz), 160.2, 194.1 (13C);
ESI-MS obsd 182.0866, calcd 182.0869 [(M + Na)+, M =
C713CH14O3].
2-[2-(15N)Nitroethyl]pyrrole (3-15Nnitro). Procedure A with 5-NA
(1.74 g, 18.3 mmol) and CH315NO2 (1.00 g, 16.1 mmol) afforded the
title compound as an orange oil (863 mg, 38%): 1H NMR δ 3.31 (td, J
= 6.7 Hz, J = 3.5 Hz, 2H), 4.60 (td, J = 6.7 Hz, J = 2.3 Hz, 2H), 6.00−
6.02 (m, 1H), 6.13−6.16 (m, 1H), 6.70−6.72 (m, 1H), 8.17 (br s,
1H); 13C NMR δ 25.5 (13C), 75.3 (d, J = 7.6 Hz), 106.9, 108.8, 117.8,
126.0; 15N NMR δ 5.9; ESI-MS obsd 142.0630, calcd 142.0629 [(M +
H)+, M = C6H8N15NO2].
1,1-Diethoxy-4-methyl-3-(1-13C)penten-2-one (4Et-13C1). Follow-
ing a standard procedure,40 a mixture of TMSCN (1.25 mL, 1.70
mmol) and triethyl (13C)orthoformate (1.50 g, 10.5 mmol) in a round-
bottom flask was treated dropwise with BF3·OEt2 (0.2 mL, 0.1 mmol)
under argon at room temperature. The reaction mixture was stirred for
3 h at room temperature, whereupon a solution of saturated aqueous
NaHCO3 was added. The aqueous phase was extracted with diethyl
ether. The organic phase was washed with saturated brine, dried
(Na2SO4), and concentrated. The residue was treated dropwise under
argon with 6 (32 mL, 16 mmol, 0.5 M in THF) at 0 °C, followed by
stirring for 2 h at room temperature. The reaction mixture was treated
with saturated aqueous NH4Cl (150 mL) and vigorously stirred for 3
h. The aqueous phase was extracted with diethyl ether. The organic
phase was washed with saturated brine, dried (Na2SO4), and
concentrated. The resulting mixture was chromatographed (silica,
hexanes/ethyl acetate (3/1)) to afford a pale yellow liquid (742 mg,
2-[2-Nitro(1-13C)ethyl]pyrrole (3-13C1). Procedure A with 5-13Cformyl
(1.01 g, 10.5 mmol) afforded the title compound as an orange oil (513
mg, 35%): 1H NMR δ 3.31 (dt, J = 131 Hz, J = 6.7 Hz, 2H), 4.60 (td, J
= 6.7 Hz, J = 3.3 Hz, 2H), 6.01 (br s, 1H), 6.13−6.16 (m, 1H), 6.71
(br s, 1H), 8.17 (br s, 1H); 13C NMR δ 25.4, 75.3 (d, J = 35.9 Hz),
106.9 (d, J = 3.8 Hz), 108.8 (d, J = 3.1 Hz), 117.8, 126.0 (d, J = 52.6
Hz); ESI-MS obsd 142.0690, calcd 142.0692 [(M + H)+, M =
C513CH8N2O2].
2-[2-Nitro(2-13C)ethyl]pyrrole (3-13C2).78 Procedure A with 5-NA
(2.72 g, 28.6 mmol) and 13CH3NO2 (1.77 g, 28.5 mmol) afforded the
title compound as an orange oil (1.41 g, 35%): 1H NMR δ 3.31 (td, J =
6.7 Hz, J = 4.9 Hz, 2H), 4.60 (dt, J = 147 Hz, J = 6.7 Hz, 2H), 6.01 (br
s, 1H), 6.13−6.16 (m, 1H), 6.71−6.72 (m, 1H), 8.17 (br s, 1H); 13C
NMR δ 75.3 (13C); ESI-MS obsd 140.0551, calcd 140.0547 [(M −
H)−, M = C513CH8N2O2].
2-(2-Nitroethyl)(2-13C)pyrrole (3-13Cα). Following a standard
procedure (procedure B),43 5-13C2 (1.76 g, 18.3 mmol) was dissolved
in methanol (55 mL) and treated with nitromethane (2.96 mL, 55.2
mmol), sodium acetate (1.66 g, 20.0 mmol), and methylamine
hydrochloride (1.66 g, 20.0 mmol). Stirring at room temperature for
12 h afforded a yellow-brown mixture. DMF (37 mL) and methanol
(31 mL) were added to the reaction mixture. NaBH4 (2.43 g, 63.9
mmol) was added portionwise. The reaction mixture was stirred at
room temperature for 1 h, neutralized with acetic acid (∼3 mL), and
concentrated. The mixture was dissolved in CH2Cl2 and washed with
water. The organic layer was dried (Na2SO4), concentrated, and
chromatographed (silica, hexanes/ethyl acetate (3/1)) to give an
1
38%): H NMR δ 1.25 (t, J = 7.1 Hz, 6H), 1.95 (d, J = 1.1 Hz, 3H),
2.20 (d, J = 1.1 Hz, 3H), 3.54−3.74 (m, 4H), 4.58 (d, J = 161 Hz 1H),
6.40−6.41 (m, 1H); 13C NMR δ 15.1 (d, J = 3.1 Hz), 21.2, 28.1, 62.9,
103.1 (13C), 119.0 (d, J = 13.7 Hz), 159.8, 194.7 (d, J = 54.2 Hz); ESI-
MS obsd 210.1176, calcd 210.1182 [(M + Na)+, M = C913CH18O3].
Nitrohexanone−Pyrroles 2. 1,1-Dimethoxy-4,4-dimethyl-5-
nitro-6-[2-(1-15N)pyrrolyl]-2-hexanone (2-15Npyrrol). Following a
standard procedure41 with slight modification, a mixture of 3-15Npyrrol
(1.04 g, 7.38 mmol) and 4-NA (2.33 g, 14.8 mmol) was treated with
DBU (3.3 mL, 22 mmol). Ethyl acetate (∼2 mL) was added as
required to completely dissolve the reaction mixture. The reaction
mixture was stirred at room temperature for 16 h, diluted with ethyl
acetate, and washed with saturated aqueous NH4Cl solution and brine.
1
orange oil (1.70 g, 66%): H NMR δ 3.32 (td, J = 6.6 Hz, J = 6.6 Hz,
2H), 4.60 (dt, J = 6.6 Hz, J = 4.4 Hz, 2H), 5.99−6.03 (m, 1H), 6.12−
1011
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The organic layer was dried (Na2SO4) and concentrated. The resulting
mixture was chromatographed (silica, hexanes/ethyl acetate (3/1)) to
afford a brown solid (1.95 mg, 88%): mp 65−68 °C; 1H NMR δ 1.14
108.9 (d, J = 2.3 Hz), 117.7 (d, J = 7.6 Hz), 126.0 (13C), 203.6; ESI-
MS obsd 300.1634, calcd 300.1635 [(M + H)+, M = C1313CH22N2O5].
1,1-Dimethoxy-4,4-dimethyl-5-nitro-6-[2-(5-13C)pyrrolyl]-2-hexa-
none (2-13Cγ). The above procedure with 3-13Cγ (1.60 g, 11.3 mmol)
afforded the title compound as a brown solid (3.20 g, 95%): mp 70−
74 °C; 1H NMR δ 1.14 (s, 3H), 1.23 (s, 3H), 2.55, 2.77 (AB, 2J = 18.5
2
(s, 3H), 1.23 (s, 3H), 2.55, 2.77 (AB, J = 18.5 Hz, 2H), 3.01−3.06
(m, 1H), 3.30−3.39 (m, 1H), 3.43 (s, 3H), 3.44 (s, 3H), 4.36 (s, 1H),
5.15 (ABX, 3J = 2.2 Hz, 3J = 11.7 Hz, 1H), 5.97−5.99 (m, 1H), 6.08−
6.11 (m, 1H), 6.65−6.67 (m, 1H), 8.08 (dm, J = 95.1 Hz, 1H); 13C
NMR δ 24.17, 24.26, 26.6 (d, J = 2.3 Hz), 36.4, 45.0, 55.1, 94.7, 104.6,
107.2 (d, J = 4.6 Hz), 108.6 (d, J = 3.8 Hz), 117.7 (d, J = 13.7 Hz),
125.9 (d, J = 13.7 Hz), 203.6; 15N NMR δ −227.8; ESI-MS obsd
322.1398, calcd 322.1391 [(M + Na)+, M = C14H22N15NO5].
3
2
Hz, 2H), 3.03 (ABX, J = 2.6 Hz, J = 15.5 Hz, 1H), 3.36 (m, 1H),
3
3
3.43 (s, 3H), 3.44 (s, 3H), 4.36 (s, 1H), 5.15 (ABX, J = 2.6 Hz, J =
11.7 Hz, 1H), 5.96−6.00 (m, 1H), 6.08−6.12 (m, 1H), 6.64−6.68
(dm, J = 185 Hz, 1H), 8.08 (br s, 1H); 13C NMR δ 24.20, 24.30, 26.6,
36.4, 45.0, 55.2, 94.8, 104.7, 106.9, 117.7 (13C), 203.6; ESI-MS obsd
300.1638, calcd 300.1635 [(M + H)+, M = C1313CH22N2O5].
1,1-Dimethoxy-4,4-dimethyl-5-(15N)nitro-6-(2-pyrrolyl)-2-hexa-
none (2-15Nnitro). The above procedure with 3-15Nnitro (863 mg, 6.12
mmol) afforded the title compound as a brown solid (1.43 g, 78%):
mp 73−74 °C; 1H NMR δ 1.14 (s, 3H), 1.23 (s, 3H), 2.55, 2.77 (AB,
2J = 18.5 Hz, 2H), 3.03 (ABX, 3J = 2.6 Hz, 2J = 15.4 Hz, 1H, 3JNH = 6.6
1,1-Diethoxy-4,4-dimethyl-5-nitro-6-(2-pyrrolyl)-2-hexanone
(2Et-NA). The above procedure with 3-NA (872 mg, 4.69 mmol) and
4Et-NA (656 mg, 3.53 mmol) afforded the title compound as a yellow
liquid (1.22 g, 80%): 1H NMR δ 1.15 (s, 3H), 1.22 (s, 3H), 1.25 (t, J =
2
3
3
Hz), 3.36 (ABX, J = 11.7 Hz, 2J = 15.4 Hz, 1H, 3JNH = 1.6 Hz), 3.43
7.0 Hz, 6H), 2.61, 2.78 (AB, J = 18.3 Hz, 2H), 3.04 (ABX, J = 2.2
2
3
2
3
3
Hz, J = 15.4 Hz, 1H), 3.36 (ABX, J = 11.7 Hz, J = 15.4 Hz, 1H),
(s, 3H), 3.44 (s, 3H), 4.36 (s, 1H), 5.15 (ABX, J = 2.6 Hz, J = 11.7
3.54−3.62 (m, 2H), 3.76−3.77 (m, 2H), 4.47 (s, 1H), 5.17 (ABX, 3J =
2
Hz, 1H, JNH = 1.2 Hz), 5.97−5.99 (m, 1H), 6.08−6.11 (m, 1H),
3
6.65−6.67 (m, 1H), 8.08 (br s, 1H); 13C NMR δ 24.18, 24.28, 26.6,
36.4, 45.0, 55.2, 94.8 (d, J = 5.3 Hz), 104.7, 107.2, 108.7, 117.7, 125.9,
203.6; 15N NMR δ 10.3; ESI-MS obsd 300.1572, calcd 300.1567 [(M
+ H)+, M = C14H22N15NO5].
2.6 Hz, J = 11.8 Hz, 1H), 5.97−5.99 (m, 1H), 6.08−6.11 (m, 1H),
6.65−6.67 (m, 1H), 8.07 (br s, 1H); 13C NMR δ 15.1, 24.1, 24.4, 26.7,
36.5, 44.6, 63.8, 94.9, 103.2, 107.3, 108.7, 117.7, 204.1; ESI-MS obsd
349.1735, calcd 349.1734 [(M + Na)+, M = C16H26N2O5].
1,1-Diethoxy-4,4-dimethyl-5-nitro-6-(2-pyrrolyl)-2-(1-13C)-
hexanone (2Et-13C1). The above procedure with 3-NA (634 mg, 4.53
mmol) and 4Et-13C1 (706 mg, 3.78 mmol) afforded the title
1,1-Dimethoxy-4,4-dimethyl-5-nitro-6-(2-pyrrolyl)-2-(6-13C)-
hexanone (2-13C6). The above procedure with 3-13C1 (764 mg, 5.42
mmol) afforded the title compound as a brown solid (1.36 g, 84%):
mp 70−72 °C; 1H NMR δ 1.14 (s, 3H), 1.23 (s, 3H), 2.55, 2.77 (AB,
1
compound as a yellow liquid (928 mg, 75%): H NMR δ 1.15 (s,
3H), 1.22 (s, 3H), 1.25 (t, J = 7.0 Hz, 6H), 2.61, 2.78 (AB, J = 18.3
Hz, 2H), 3.04 (ABX, J = 2.2 Hz, J = 15.4 Hz, 1H), 3.36 (ABX, J =
11.7 Hz, J = 15.4 Hz, 1H), 3.54−3.62 (m, 2H), 3.76−3.77 (m, 2H),
4.47 (d, J = 162 Hz, 1H), 5.17 (ABX, J = 2.6 Hz, J = 11.8 Hz, 1H),
5.97−5.99 (m, 1H), 6.08−6.11 (m, 1H), 6.65−6.67 (m, 1H), 8.07 (br
s, 1H); 13C NMR δ 15.1, 24.1, 24.4, 26.7, 36.5, 44.6 (d, J = 11.4 Hz),
63.8, 94.9, 103.2 (13C), 107.3, 108.7, 117.7, 126.0, 204.1 (d, J = 54.2
Hz); ESI-MS obsd 350.1759, calcd 350.1767 [(M + Na)+, M =
C1513CH26N2O5].
2
2J = 18.5 Hz, 2H), 3.03 (ABX, J = 2.6 Hz, J = 15.4 Hz, 1H, JCH
=
3
2
1
3
2
3
128 Hz), 3.36 (ABX, J = 11.7 Hz, 2J = 15.4 Hz, 1H, 1JCH = 131 Hz),
3
2
3
3
3.43 (s, 3H), 3.44 (s, 3H), 4.36 (s, 1H), 5.15 (ABX, J = 2.6 Hz, J =
11.7 Hz, 1H, 3JCH = 2.6 Hz), 5.97−5.99 (m, 1H), 6.08−6.11 (m, 1H),
6.65−6.67 (m, 1H), 8.08 (br s, 1H); 13C NMR δ 24.10, 24.18, 26.6
(13C), 36.3, 45.0, 55.1, 94.7 (d, J = 37.4 Hz), 104.5, 107.1 (d, J = 3.8
Hz), 108.6 (d, J = 3.1 Hz), 117.6, 125.9 (d, J = 51.9 Hz), 203.6; ESI-
3
3
MS obsd 322.1457, calcd 322.1454 [(M
+ M =
Na)+,
C1313CH22N2O5].
1,1-Dimethoxy-4,4-dimethyl-5-nitro-6-(2-pyrrolyl)-2-(5-13C)-
hexanone (2-13C5). The above procedure with 3-13C2 (1.41 g, 10.0
mmol) afforded the title compound as a brown solid (2.48 g, 83%):
Dihydrodipyrrin−Acetals 1. 2,3-Dihydro-1-(1,1-dimethoxy-
methyl)-3,3-dimethyl(11-15N)dipyrrin (1-15N11). Following a standard
procedure34 with an increased amount of buffer (see the Supporting
Information), a solution of 2-15Npyrrol (1.95 g, 6.52 mmol) in freshly
distilled THF (15 mL) was treated with NaOMe (1.76 g, 32.6 mmol)
at 0 °C. The reaction mixture was stirred and degassed with argon for
30 min (first flask). In a second flask, TiCl3 (32.6 mL, 20 wt % TiCl3 in
3% HCl, 55.6 mmol), THF (67 mL), and NH4OAc (50.2 g, 652
mmol) were combined. The mixture was degassed with argon for 30
min. The mixture in the first flask was transferred via a cannula to the
buffered TiCl3 mixture. The resulting mixture was stirred at room
temperature for 16 h. Then the mixture was quenched by addition of
saturated aqueous NaHCO3 and extracted with ethyl acetate. The
organic extract was washed with water, dried (Na2SO4), and
concentrated. Chromatography (3 × 30 cm, ∼80 g of neutral alumina,
CH2Cl2) afforded a dark brown oil (939 mg, 58%): 1H NMR δ 1.21 (s,
6H), 2.61 (s, 2H), 3.45 (s, 6H), 5.02 (s, 1H), 5.88 (d, J = 3.7 Hz, 1H),
6.15−6.16 (m, 2H), 6.83−6.85 (m, 1H), 10.65 (dm, J = 97.3, 1H); 13C
NMR δ 29.1, 40.0, 48.1, 54.6, 102.8, 107.4, 108.4 (d, J = 3.1 Hz), 109.1
(d, J = 4.6 Hz), 119.4 (d, J = 13.0 Hz), 130.6 (d, J = 13.7 Hz), 159.2,
173.8; 15N NMR δ −229.0; ESI-MS obsd 272.1385, calcd 272.1387
[(M + Na)+, M = C14H20N15NO2].
1
mp 71−73 °C; H NMR δ 1.14 (d, J = 4.0 Hz, 3H), 1.23 (d, J = 4.0
2
3
Hz, 3H), 2.55, 2.77 (AB, J = 18.5 Hz, JCH = 3.8 Hz, 2H), 3.03 (m,
1H), 3.36 (ABX, J = 11.7 Hz, 2J = 15.4 Hz, 1H, JCH = 7.0 Hz), 3.43
3
2
3
3
(s, 3H), 3.44 (s, 3H), 4.36 (s, 1H), 5.15 (ABX, J = 2.6 Hz, J = 11.7
1
Hz, 1H, JCH = 151 Hz), 5.97−5.99 (m, 1H), 6.08−6.11 (m, 1H),
6.65−6.67 (m, 1H), 8.08 (br s, 1H); 13C NMR δ 24.16, 24.26, 26.6 (d,
J = 36.6 Hz), 36.4 (d, J = 32.8 Hz), 45.0, 55.1, 94.8 (13C), 104.6, 107.2,
108.6, 117.7, 125.9, 203.6; ESI-MS obsd 322.1444, calcd 322.1454
[(M + Na)+, M = C1313CH22N2O5].
1,1-Dimethoxy-4,4-dimethyl-5-nitro-6-(2-pyrrolyl)-2-(2-13C)-
hexanone (2-13C2). The above procedure with 3-NA (1.29 g, 9.21
mmol) and 4-13C2 (1.22 g, 7.67 mmol) afforded the title compound as
a brown solid (1.50 g, 65%): mp 66−68 °C; 1H NMR δ 1.14 (s, 3H),
2
2
1.23 (s, 3H), 2.55, 2.77 (AB, J = 18.5 Hz, 2H, JC3H = 6.0 Hz), 3.03
3
2
2
(ABX, J = 2.6 Hz, J = 15.4 Hz, 1H), 3.36 (ABX, J = 11.7 Hz, J =
15.4 Hz, 1H), 3.43 (s, 3H), 3.44 (s, 3H), 4.36 (s, 1H), 5.15 (ABX, 3J =
3
2.6 Hz, J = 11.7 Hz, 1H), 5.97−5.99 (m, 1H), 6.08−6.11 (m, 1H),
6.65−6.67 (m, 1H), 8.08 (br s, 1H); 13C NMR δ 24.04 (d, J = 1.5 Hz),
24.12, (d, J = 2.3 Hz), 26.6, 36.3, (d, J = 1.5 Hz), 44.9, (d, J = 39.7
Hz), 55.0, (d, J = 3.1 Hz), 94.7, 104.5 (d, J = 53.4 Hz), 107.0, 108.5,
117.6, 125.9, 203.6 (13C); ESI-MS obsd 300.1630, calcd 300.1635 [(M
+ H)+, M = C1313CH22N2O5].
2,3-Dihydro-1-(1,1-dimethoxymethyl)-3,3-dimethyl(10-15N)-
dipyrrin (1-15N10). The above procedure with 2-15Nnitro (1.43 g, 4.78
mmol) afforded the title compound as a dark brown oil (487 mg,
41%): 1H NMR δ 1.20 (s, 6H), 2.60 (d, J = 2.2 Hz, 2H), 3.44 (s, 6H),
5.01 (s, 1H), 5.87 (d, J = 5.9 Hz 1H), 6.15−6.16 (m, 2H), 6.83−6.85
(m, 1H), 10.65 (br s, 1H); 13C NMR δ 29.0, 39.9, 48.0 (d, J = 1.5 Hz),
54.5, 102.7 (d, J = 9.2 Hz), 107.4 (d, J = 3.8 Hz), 108.4, 109.1, 119.3,
130.5, 159.1 (d, J = 1.5 Hz), 173.7 (d, J = 5.3 Hz); 15N NMR δ −58.3;
ESI-MS obsd 272.1390, calcd 272.1387 [(M + Na)+, M =
C14H20N15NO2].
1,1-Dimethoxy-4,4-dimethyl-5-nitro-6-[2-(2-13C)pyrrolyl]-2-hexa-
none (2-13Cα). The above procedure with 3-13Cα (1.70 g, 12.1 mmol)
afforded the title compound as a brown solid (3.26 g, 91%): mp 70−
72 °C; 1H NMR δ 1.14 (s, 3H), 1.23 (s, 3H), 2.55, 2.77 (AB, 2J = 18.5
3
2
2
Hz, 2H), 3.03 (ABX, J = 2.6 Hz, J = 15.5 Hz, 1H, JCH = 7.1 Hz),
3.36 (m, 1H), 3.43 (s, 3H), 3.44 (s, 3H), 4.36 (s, 1H), 5.15 (ABX, 3J =
3
3
2.6 Hz, J = 11.7 Hz, 1H, JCH = 2.6 Hz), 5.96−6.00 (m, 1H), 6.08−
6.12 (m, 1H), 6.64−6.68 (m, 1H), 8.08 (br s, 1H); 13C NMR δ 24.20,
2,3-Dihydro-1-(1,1-dimethoxymethyl)-3,3-dimethyl(1-13C)-
dipyrrin (1-13C1). The above procedure with 2-13C2 (1.50 g, 5.02
2
24.30, 26.6 (d, JCC = 52.6 Hz), 36.4, 45.0, 55.2, 94.8, 104.7, 106.9,
1012
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mmol) afforded the title compound as a dark brown oil (720 mg,
58%): 1H NMR δ 1.21 (s, 6H), 2.61 (d, J = 6.2 Hz, 2H), 3.45 (s, 6H),
5.01 (s, 1H), 5.88 (s, 1H), 6.15−6.16 (m, 2H), 6.83−6.85 (m, 1H),
10.65 (br s, 1H); 13C NMR δ 29.1, 48.1 (d, J = 35.1 Hz), 54.5, 102.8
(d, J = 64.1 Hz), 107.4 (d, J = 9.9 Hz), 108.5, 109.1, 119.4, 173.8
(13C); ESI-MS obsd 250.1632, calcd 250.1631 [(M + H)+, M =
C1313CH20N2O2].
was then concentrated. Chromatography of the residue (silica,
hexanes/CH2Cl2 (2/1)) afforded a green solid (28.4 mg, 8%): H
1
NMR δ −2.38 (br s, 2H), 1.97 (s, 12H), 4.47 (s, 4H), 8.72−8.74 (m,
2H), 8.73 (s, 2H), 8.76 (dd, J = 4.0 Hz, J = 1.8 Hz, 2H), 8.83 (s, 2H);
13C NMR δ 31.1, 46.0, 51.4, 96.5, 98.7, 121.73, 121.84, 135.3, 136.2,
157.6; ESI-MS obsd 371.2223, calcd 371.2230 [(M + H)+, M =
C24H26N4]; λabs (toluene) 340, 365, 489, 713 nm.
2,3-Dihydro-1-(1,1-dimethoxymethyl)-3,3-dimethyl(4-13C)-
dipyrrin (1-13C4). The above procedure with 2-13C5 (2.47 g, 8.33
mmol) afforded the title compound as a dark brown oil (1.16 mg,
56%): 1H NMR δ 1.21 (d, J = 4.0 Hz, 6H), 2.61 (s, 2H), 3.45 (s, 6H),
5.01 (s, 1H), 5.88 (s, 1H), 6.15−6.16 (m, 2H), 6.83−6.85 (m, 1H),
10.65 (br s, 1H); 13C NMR δ 29.1, 48.1 (d, J = 4.6 Hz), 54.6, 102.8 (d,
J = 9.9 Hz), 107.4 (d, J = 82.4 Hz), 108.5, 109.1 (d, J = 6.1 Hz), 119.4,
159.2 (13C); ESI-MS obsd 250.1631, calcd 250.1631 [(M + H)+, M =
C1313CH20N2O2].
8,8,18,18-Tetramethyl(21,23-15N2)bacteriochlorin (H2BC-15N21,23).
The above procedure with 1-15N11 (934 mg, 3.75 mmol) afforded the
title compound as a green solid (46.7 mg, 7%): 1H NMR δ −2.39 (dt,
J = 99 Hz, J = 2.0 Hz, 2H), 1.97 (s, 12H), 4.47 (s, 4H), 8.72−8.74 (m,
2H), 8.73 (d, J = 4.0 Hz, 2H), 8.76−8.78 (m, 2H), 8.84 (d, J = 4.8 Hz,
2H); 13C NMR δ 31.1, 46.0, 51.4, 96.5, 98.6, 121.73 (d, J = 3.1 Hz),
121.84 (d, J = 3.8 Hz); 15N NMR δ −249.3; ESI-MS obsd 373.2179,
calcd 373.2171 [(M + H)+, M = C24H26N215N2]; λabs (toluene) 340,
365, 489, 713 nm.
2,3-Dihydro-1-(1,1-dimethoxymethyl)-3,3-dimethyl(5-13C)-
dipyrrin (1-13C5). The above procedure with 2-13C6 (1.69 g, 5.65
mmol) afforded the title compound as a dark brown oil (463 mg,
8,8,18,18-Tetramethyl(22,24-15N2)bacteriochlorin (H2BC-15N22,24).
The above procedure with 1-15N10 (487 mg, 1.96 mmol) afforded the
title compound as a green solid (28.4 mg, 8%): 1H NMR δ −2.39 (br
s, 2H), 1.97 (s, 12H), 4.47 (s, 4H), 8.72−8.74 (m, 4H), 8.76 (dd, J =
4.4 Hz, J = 2.0 Hz, 2H) 8.83 (d, J = 4.8 Hz, 2H); 13C NMR δ 31.1,
51.4, 96.5 (d, J = 3.8 Hz), 98.6 (d, J = 4.6 Hz), 121.72, 121.83; 15N
NMR δ −82.0; ESI-MS obsd 372.2093, calcd 372.2093 (M+, M =
C24H26N215N2); λabs (toluene) 340, 365, 489, 713 nm.
1
33%): H NMR δ 1.20 (s, 6H), 2.61 (s, 2H), 3.45 (s, 6H), 5.01 (s,
1H), 5.88 (d, J = 153 Hz, 1H), 6.15−6.16 (m, 2H), 6.83−6.85 (m,
1H), 10.64 (br s, 1H); 13C NMR δ 29.1, 40.0 (d, J = 5.3 Hz), 48.1,
54.5, 102.8, 107.4 (13C), 108.4 (d, J = 5.3 Hz), 109.1 (d, J = 4.6 Hz),
119.4, 130.6 (d, J = 66.4 Hz), 159.2 (d, J = 81.6 Hz), 173.8 (d, J = 9.2
Hz); ESI-MS obsd 272.1438, calcd 272.1451 [(M + Na)+, M =
C1313CH20N2O2].
8,8,18,18-Tetramethyl(1,11-13C2)bacteriochlorin (H2BC-13C1,11).
The above procedure with 1-13C6 (460 mg, 1.85 mmol) in anhydrous
CH3CN afforded the title compound as a green solid (32.2 mg, 9%):
1H NMR δ −2.38 (br s, 2H), 1.97 (s, 12H), 4.47 (s, 4H), 8.71−8.78
(m, 4H), 8.73 (d, J = 2.2 Hz, 2H), 8.84 (s, 2H); 13C NMR δ 31.1, 46.0
(d, J = 3.8 Hz), 51.4, 96.5 (d, J = 70.2 Hz), 98.6, 121.72, 121.82 (d, J =
58.0 Hz), 135.3, 136.2 (13C); ESI-MS obsd 373.2280, calcd 373.2297
[(M + H)+, M = C2213C2H26N4]; λabs (toluene) 340, 365, 489, 713 nm.
8,8,18,18-Tetramethyl(4,14-13C2)bacteriochlorin (H2BC-13C4,14).
The above procedure with 1-13C9 (615 mg, 2.47 mmol) in anhydrous
CH3CN afforded the title compound as a green solid (57.5 mg, 13%):
1H NMR δ −2.38 (br s, 2H), 1.98 (s, 12H), 4.48 (s, 4H), 8.72−8.79
(m, 4H), 8.74 (s, 2H), 8.83 (d, J = 2.2 Hz, 2H); 13C NMR δ 31.1, 46.0,
51.4 (d, J = 3.8 Hz), 96.5, 98.6 (d, J = 70.2 Hz), 121.71 (d, J = 58.0
Hz), 121.83, 135.3 (13C), 136.2; ESI-MS obsd 372.2227, calcd
372.2219 (M+, M = C2213C2H26N4); λabs (toluene) 340, 365, 489, 713
nm.
2,3-Dihydro-1-(1,1-dimethoxymethyl)-3,3-dimethyl(6-13C)-
dipyrrin (1-13C6). The above procedure with 2-13Cα (1.00 g, 3.34
mmol) afforded the title compound as a dark brown oil (354 mg,
1
43%): H NMR δ 1.21 (s, 6H), 2.61 (s, 2H), 3.45 (s, 6H), 5.01 (s,
1H), 5.87−5.88 (m, 1H), 6.15−6.17 (m, 2H), 6.83−6.85 (m, 1H),
10.65 (br s, 1H); 13C NMR δ 29.1, 40.0, 48.1, 54.5, 102.8, 107.4 (d, J =
66.4 Hz), 108.4, 109.1 (d, J = 67.1 Hz), 119.4 (d, J = 6.9 Hz), 130.6
(13C), 173.8; ESI-MS obsd 250.1628, calcd 250.1631 [(M + H)+, M =
C1313CH20N2O2].
2,3-Dihydro-1-(1,1-dimethoxymethyl)-3,3-dimethyl(9-13C)-
dipyrrin (1-13C9). The above procedure with 2-13Cγ (1.50 g, 5.02
mmol) afforded the title compound as a dark brown oil (634 mg,
1
51%): H NMR δ 1.21 (s, 6H), 2.61 (s, 2H), 3.45 (s, 6H), 5.01 (s,
1H), 5.88 (s, 1H), 6.15−6.16 (m, 2H), 6.83−6.85 (dm, J = 184 Hz,
1H), 10.65 (br s, 1H); 13C NMR δ 29.1, 40.0, 48.1, 54.6, 102.8, 107.4,
109.1, 119.4 (13C); ESI-MS obsd 250.1630, calcd 250.1631 [(M +
H)+, M = C1313CH20N2O2].
8,8,18,18-Tetramethyl(6,16-13C2)bacteriochlorin (H2BC-13C6,16).
The above procedure with 1-13C1 (720 mg, 2.89 mmol) in anhydrous
CH3CN afforded the title compound as a green solid (74.9 mg, 14%):
1H NMR δ −2.38 (br s, 2H), 1.98 (s, 12H), 4.48 (d, J = 5.1 Hz, 4H),
8.72−8.74 (m, 2H), 8.73 (s, 2H), 8.77 (dd, J = 4.0 Hz, J = 1.8 Hz,
2H), 8.84 (s, 2H); 13C NMR δ 31.1, 51.4 (d, J = 38.2 Hz), 96.5 (d, J =
8.4 Hz), 98.6 (d, J = 74.0 Hz), 121.74 (d, J = 6.1 Hz), 121.84, 157.6
(13C); ESI-MS obsd 373.2291, calcd 373.2297 [(M + H)+, M =
C2213C2H26N4]; λabs (toluene) 340, 365, 489, 713 nm.
2,3-Dihydro-1-(1,1-diethoxymethyl)-3,3-dimethyldipyrrin (1Et-
NA). The above procedure with 2Et-NA (928 mg, 2.85 mmol)
1
afforded the title compound as a dark brown oil (256 mg, 32%): H
NMR δ 1.20 (s, 6H), 1.26 (t, J = 7.1 Hz, 6H), 2.64 (s, 2H), 3.56−3.63
(m, 2H), 3.72−3.80 (m, 2H), 5.15 (s, 1H), 5.87 (s, 1H), 6.14−6.17
(m, 2H), 6.83−6.84 (m, 1H), 10.67 (br s, 1H); 13C NMR δ 15.2, 29.1,
40.0, 47.8, 62.9, 100.9, 107.1, 108.45, 108.97, 119.2, 130.8, 159.4,
174.8; ESI-MS obsd 299.1732, calcd 299.1730 [(M + Na)+, M =
C16H24N2O2].
8,8,18,18-Tetramethyl(9,19-13C2)bacteriochlorin (H2BC-13C9,19).
The above procedure with 1-13C4 (1.16 g, 4.66 mmol) in anhydrous
CH3CN afforded the title compound as a green solid (76.3 mg, 9%):
1H NMR δ −2.38 (br s, 2H), 1.97 (d, J = 3.7 Hz, 12H), 4.47 (s, 4H),
8.72−8.74 (m, 2H), 8.73 (s, 2H), 8.77 (dd, J = 4.4 Hz, J = 1.8 Hz,
2H), 8.84 (s, 2H); 13C NMR δ 31.1, 51.4 (d, J = 5.3 Hz), 96.5 (d, J =
74.5 Hz), 98.7 (d, J = 8.4 Hz), 121.73, 121.84 (d, J = 6.1 Hz), 135.3,
169.6 (13C); ESI-MS obsd 373.2294, calcd 373.2297 [(M + H)+, M =
C2213C2H26N4]; λabs (toluene) 340, 365, 489, 713 nm.
2,3-Dihydro-1-[1,1-diethoxy(13C)methyl]-3,3-dimethyldipyrrin
(1Et-13Cac). The above procedure with 2Et-13C1 (900 mg, 2.75 mmol)
1
afforded the title compound as a dark brown oil (305 mg, 40%): H
NMR δ 1.21 (s, 6H), 1.26 (t, J = 7.1 Hz, 6H), 2.64 (s, 2H), 3.55−3.64
(m, 2H), 3.72−3.80 (m, 2H), 5.15 (d, J = 161 Hz, 1H), 5.87 (s, 1H),
6.14−6.17 (m, 2H), 6.83−6.84 (m, 1H), 10.67 (br s, 1H); 13C NMR δ
15.2, 29.1, 40.0, 62.9, 100.9 (13C), 107.1, 108.45, 108.97, 119.2, 130.8;
ESI-MS obsd 278.1942, calcd 278.1194 [(M + H)+, M =
C1513CH24N2O2].
Bacteriochlorins H2BC. Note: employing anhydrous CH3CN
instead of HPLC-grade CH3CN as solvent resulted in higher yields
(9−16% versus 7−8%).
8,8,18,18-Tetramethylbacteriochlorin (H2BC-NA). Following a
standard procedure,36 a solution of 1-NA (487 mg, 1.96 mmol, 5.0
mM) in HPLC-grade CH3CN (390 mL) was treated dropwise with
neat BF3·OEt2 (2.49 mL, 19.8 mmol, 50 mM) at room temperature.
The reaction was allowed to proceed at room temperature for 16 h.
TEA (3 mL) was added to the reaction mixture. The reaction mixture
8,8,18,18-Tetramethyl(10,20-13C2)bacteriochlorin (H2BC-13C10,20).
The above procedure with 1-13C5 (463 mg, 1.86 mmol) in anhydrous
CH3CN afforded the title compound as a green solid (54.8 mg, 16%):
1H NMR δ −2.38 (br s, 2H), 1.97 (s, 12H), 4.47 (s, 4H), 8.73 (dd, J =
4.4 Hz, J = 1.8 Hz, 2H), 8.73 (d, J = 154 Hz, 2H), 8.75−8.78 (m, 2H),
8.83 (s, 2H); 13C NMR δ 31.1, 54.4, 96.5 (13C), 98.7, 121.73 (d, J =
4.6 Hz), 121.84 (d, J = 5.3 Hz); ESI-MS obsd 373.2297, calcd
373.2297 [(M + H)+, M = C2213C2H26N4]; λabs (toluene) 340, 365,
489, 713 nm.
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8,8,18,18-Tetramethylbacteriochlorin (H2BC-NA) and 5-Ethoxy-
8,8,18,18-tetramethylbacteriochlorin (EtOBC-NA) from 1Et-NA.
The above procedure was carried out with 1Et-NA (256 mg, 928
μmol, 5.0 mM) in anhydrous CH3CN. Chromatography (silica,
hexanes/CH2Cl2 (1/1)) afforded two green bands, which in order of
elution consisted of H2BC-NA (9.2 mg, 5%) and EtOBC-NA (3.8 mg,
2%). The characterization data for H2BC-NA were consistent with
μmol) afforded the title compound as a dark red solid (4.8 mg, 69%):
1H NMR (THF-d8) δ 1.97 (s, 12H), 4.46 (br s, 4H), 8.60−8.62 (m,
4H), 8.64−8.66 (m, 4H); ESI-MS obsd 434.1355, calcd 434.1354
(C2213C2H24N4Zn); λabs (toluene) 336, 375, 514, 723 nm.
Zn(II)−8,8,18,18-Tetramethyl(9,19-13C2)bacteriochlorin
(ZnBC-13C9,19). The above procedure with H2BC-13C9,19 (5.8 mg, 16
μmol) afforded the title compound as a dark red solid (2.8 mg, 40%):
1H NMR (THF-d8) δ 1.97−1.98 (m, 12H), 4.46 (br s, 4H), 8.60−8.62
1
those described above. Data for EtOBC-NA: H NMR δ −2.27 (s,
1H), −2.14 (s, 1H), 1.84 (t, J = 7.0 Hz, 3H), 1.95 (s, 6H), 1.96 (s,
6H), 4.41 (s, 2H), 4.42 (s, 2H), 4.64 (q, J = 7.0 Hz, 2H), 8.66−8.69
(m, 3H), 8.66 (s, 1H), 8.70 (s, 1H), 8.74 (dd, J = 4.6 Hz, J = 2.0 Hz,
1H), 8.92 (dd, J = 4.4 Hz, J = 1.8 Hz, 1H); ESI-MS obsd 415.2494,
calcd 415.2492 [(M + H)+, M = C26H30N4O]; λabs (CH2Cl2) 344, 354,
366, 500, 710 nm.
(m, 4H), 8.64−8.66 (m, 4H); ESI-MS obsd 434.1362, calcd 434.1354
(C2213C2H24N4Zn); λabs (toluene) 336, 375, 514, 723 nm.
Zn(II)−8,8,18,18-Tetramethyl(10,20-13C2)bacteriochlorin
(ZnBC-13C10,20). The above procedure with H2BC-13C10,20 (5.8 mg, 16
μmol) afforded the title compound as a dark red solid (4.1 mg, 59%):
1
1H NMR (THF-d8) δ 1.97 (s, 12H), 4.46 (s, 4H), 8.60 (d, JCH
=
8,8,18,18-Tetramethyl(5,15-13C2)bacteriochlorin (H2BC-13C5,15).
151.4 Hz, 2H), 8.61 (d, J = 4.4 Hz, 2H), 8.64 (s, 2H), 8.65 (d, J = 4.4
Hz, 2H); ESI-MS obsd 434.1345, calcd 434.1354 (C2213C2H24N4Zn);
λabs (toluene) 336, 375, 514, 723 nm.
The above procedure with 1Et-13Cac (305 mg, 933 μmol) afforded
1
the title compound as a green solid (5.8 mg, 3%): H NMR δ −2.39
(br s, 2H), 1.97 (s, 12H), 4.47 (s, 4H), 8.72−8.84 (m, 2H), 8.73 (s,
2H), 8.77 (dd, J = 4.4 Hz, J = 2.0 Hz, 2H), 8.83 (d, J = 155 Hz, 2H);
13C NMR δ 31.1, 51.4 (d, J = 6.9 Hz), 96.5, 98.7 (13C), 121.73 (d, J =
Copper Bacteriochlorins {CuBC}. The reaction is sensitive to
moisture. In the case that the reaction was not complete in 16 h, a
supplement of NaH (150 equiv) or LDA (10 equiv) was added and
the reaction mixture was heated at 60 °C for a further 8−16 h. Use of
Cu(OAc)2 dried in an oven for 36 h at 100 °C before use significantly
shortened the reaction time (typically <16 h). When LDA was used,
the crude mixture was chromatographed (silica, hexanes/CH2Cl2 (1/
2)) to afford the CuBC.
5.3 Hz), 121.84 (d, J = 4.6 Hz); ESI-MS obsd 373.2292, calcd
373.2297 [(M + H)+, M = C2213C2H26N4]; λabs (toluene) 340, 365,
489, 713 nm.
Zinc Bacteriochlorins {ZnBC}. Zn(II)−8,8,18,18-Tetramethyl-
(21,23-15N2)bacteriochlorin (ZnBC-15N21,23). Following a standard
procedure,35 a solution of H2BC-15N21,23 (5.8 mg, 16 μmol, 4 mM) in
freshly distilled THF (4 mL) was treated with NaH (54 mg, 2.3 mmol,
150 equiv, 95%) and Zn(OTf)2 (176 mg, 0.484 mmol, 30 equiv). The
reaction mixture was heated at 60 °C for 16 h. The reaction mixture
was diluted with CH2Cl2 and washed with saturated aqueous NaHCO3
solution. The organic layer was dried (Na2SO4) and filtered. The
filtrate was concentrated. The crude solid was treated with hexanes,
sonicated in a benchtop sonication bath, and centrifuged, and the
supernatant was discarded. A single repetition of the hexanes
Cu(II)−8,8,18,18-Tetramethyl(21,23-15N2)bacteriochlorin
(CuBC-15N21,23). Following a standard procedure,35 a solution of
H2BC-15N21,23 (6.1 mg, 16 μmol, 4 mM) in freshly distilled THF (4
mL) was treated with NaH (54 mg, 2.3 mmol, 150 equiv, 95%) and
Cu(OAc)2 (90 mg, 0.49 mmol, 30 equiv). The reaction mixture was
heated at 60 °C for 16 h. The reaction mixture was diluted with
CH2Cl2 and washed with saturated aqueous NaHCO3 solution. The
organic layer was dried (Na2SO4) and filtered. The filtrate was
concentrated. The crude solid was treated with hexanes, sonicated in a
benchtop sonication bath, and centrifuged, and the supernatant was
discarded. A single repetition of the hexanes treatment afforded a
green solid (1.9 mg, 27%): ESI-MS obsd 433.1235, calcd 433.1232
(C24H24N215N2Cu); λabs (toluene) 332, 378, 507, 728 nm.
Cu(II)−8,8,18,18-Tetramethyl(22,24-15N2)bacteriochlorin
(CuBC-15N22,24). The above procedure with H2BC-15N22,24 (5.8 mg, 16
μmol) afforded the title compound as a green solid (3.4 mg, 49%):
ESI-MS obsd 433.1234, calcd 433.1232 (C24H24N215N2Cu); λabs
(toluene) 332, 378, 507, 728 nm.
1
treatment afforded a dark red solid (2.4 mg, 35%): H NMR (THF-
d8) δ 1.97 (s, 12H), 4.46 (s, 4H), 8.60−8.62 (m, 4H), 8.64−8.66 (m,
4H); ESI-MS obsd 434.1212, calcd 434.1228 (C24H24N215N2Zn); λabs
(toluene) 336, 375, 514, 723 nm. (A peak at ∼433 m/z was found in
the ESI-mass spectrum yet did not match the exact mass of a
bacteriochlorin bearing one 15N atom. Given that the ESI-mass
spectrum of the corresponding CuBC-15N21,23 does not show such a
peak, we consider no isotopic loss in ZnBC-15N21,23; see the
Supporting Information.)
Cu(II)−8,8,18,18-Tetramethyl(1,11-13C2)bacteriochlorin
(CuBC-13C4,14). The above procedure with H2BC-13C4,14 (5.8 mg, 16
μmol) afforded the title compound as a green solid (1.9 mg, 28%):
ESI-MS obsd 433.1364, calcd 433.1359 (C2213C2H24N4Cu); λabs
(toluene) 332, 378, 507, 728 nm.
Zn(II)−8,8,18,18-Tetramethyl(22,24-15N2)bacteriochlorin
(ZnBC-15N22,24). The above procedure with H2BC-15N22,24 (5.6 mg, 15
μmol) afforded the title compound as a dark red solid (4.6 mg, 71%):
1H NMR (THF-d8) δ 1.98 (s, 12H), 4.46 (s, 4H), 8.60−8.62 (m, 4H),
8.64−8.66 (m, 4H); ESI-MS obsd 434.1235, calcd 434.1228
Cu(II)−8,8,18,18-Tetramethyl(4,14-13C2)bacteriochlorin
(CuBC-13C4,14). The above procedure with H2BC-13C6,16 (5.8 mg, 16
μmol) afforded the title compound as a green solid (2.0 mg, 30%):
ESI-MS obsd 433.1358, calcd 433.1359 (C2213C2H24N4Cu); λabs
(toluene) 332, 378, 507, 728 nm.
(C24H24N215N2Zn); λabs (toluene) 336, 375, 514, 723 nm.
Zn(II)−8,8,18,18-Tetramethyl(1,11-13C2)bacteriochlorin
(ZnBC-13C1,11). The above procedure with H2BC-13C1,11 (3.7 mg, 10
μmol) afforded the title compound as a dark red solid (3.2 mg, 73%):
1H NMR (THF-d8) δ 1.97 (s, 12H), 4.46 (s, 4H), 8.59−8.66 (m, 8H);
Cu(II)−8,8,18,18-Tetramethyl(5,15-13C2)bacteriochlorin
(CuBC-13C5,15). The above procedure with H2BC-13C5,15 (5.8 mg, 16
μmol) afforded the title compound as a green solid (2.8 mg, 40%):
ESI-MS obsd 433.1352, calcd 433.1359 (C2213C2H24N4Cu); λabs
(toluene) 332, 378, 507, 728 nm.
ESI-MS obsd 434.1362, calcd 434.1354 (C2213C2H24N4Zn); λabs
(toluene) 336, 375, 514, 723 nm.
Zn(II)−8,8,18,18-Tetramethyl(4,14-13C2)bacteriochlorin
(ZnBC-13C4,14). The above procedure with H2BC-13C4,14 (3.7 mg, 10
μmol) afforded the title compound as a dark red solid (2.2 mg, 50%):
1H NMR (THF-d8) δ 1.97 (s, 12H), 4.46 (br s, 4H), 8.59−8.67 (m,
Cu(II)−8,8,18,18-Tetramethyl(6,16-13C2)bacteriochlorin
(CuBC-13C6,16). The above procedure with H2BC-13C6,16 (5.8 mg, 16
μmol) afforded the title compound as a green solid (5.3 mg, 77%):
ESI-MS obsd 433.1362, calcd 433.1359 (C2213C2H24N4Cu); λabs
(toluene) 332, 378, 507, 728 nm.
6H), 8.60 (s, 2H); ESI-MS obsd 434.1359, calcd 434.1354
(C2213C2H24N4Zn); λabs (toluene) 336, 375, 514, 723 nm.
Zn(II)−8,8,18,18-Tetramethyl(5,15-13C2)bacteriochlorin
(ZnBC-13C5,15). The above procedure with H2BC-13C5,15 (2.9 mg, 7.8
μmol) afforded the title compound as a dark red solid (2.8 mg, 83%):
1H NMR (THF-d8) δ 1.98 (s, 12H), 4.46 (s, 4H), 8.60−8.62 (m, 4H),
Cu(II)−8,8,18,18-Tetramethyl(9,19-13C2)bacteriochlorin
(CuBC-13C9,19). The above procedure with H2BC-13C9,19 (5.8 mg, 16
μmol) afforded the title compound as a green solid (4.7 mg, 69%):
ESI-MS obsd 433.1364, calcd 433.1359 (C2213C2H24N4Cu); λabs
(toluene) 332, 378, 507, 728 nm.
8.64 (d, J = 152.5 Hz 2H), 8.65 (d, J = 4.1 Hz, 2H); ESI-MS obsd
434.1355, calcd 434.1354 (C2213C2H24N4Zn); λabs (toluene) 336, 375,
514, 723 nm.
Cu(II)−8,8,18,18-Tetramethyl(10,20-13C2)bacteriochlorin
(CuBC-13C10,20). The above procedure with H2BC-13C10,20 (5.8 mg, 16
μmol) afforded the title compound as a green solid (5.3 mg, 77%):
Zn(II)−8,8,18,18-Tetramethyl(6,16-13C2)bacteriochlorin
(ZnBC-13C6,16). The above procedure with H2BC-13C4,14 (5.8 mg, 16
1014
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The Journal of Organic Chemistry
Article
ESI-MS obsd 433.1343, calcd 433.1359 (C2213C2H24N4Cu); λabs
(toluene) 332, 378, 507, 728 nm.
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ASSOCIATED CONTENT
* Supporting Information
■
S
Text, figures, tables, and a CIF file giving X-ray data for 10-NA
(CCDC 978333), comparison of syntheses of nitrohexanone−
pyrrole 2, buffer calculations for use of TiCl3 in dihydropyrrin−
acetal formation, NMR chemical shift assignments, method for
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Compd. Radiopharm. 2009, 52, 341−349.
(20) Prakash, S.; Alia, A.; Gast, P.; de Groot, H. J. M.; Jeschke, G.;
Matysik, J. Biochemistry 2007, 46, 8953−8960.
determination of isotopic enrichment, H, 13C, and 15N NMR
1
(21) Bruckner, C.; Samankumara, L.; Ogikubo, J. In Handbook of
̈
Porphyrin Science; Kadish, K. M.; Smith, K. M., Guilard, R., Eds.; World
Scientific: Singapore, 2012; Vol. 17, pp 1−112.
spectra for all new compounds, and ESI mass spectra for
{H2BC}, {ZnBC}, and {CuBC}. This material is available free
of charge via the Internet at http://pubs.acs.org.
(22) Sasaki, S.-I.; Tamiaki, H. J. Org. Chem. 2006, 71, 2648−2654.
(23) Grin, M. A.; Mironov, A. F.; Shtil, A. A. Anti-Cancer Agents Med.
Chem. 2008, 8, 683−697.
AUTHOR INFORMATION
Corresponding Author
*E-mail: jlindsey@ncsu.edu (J.S.L.); david.bocian@ucr.edu
(D.F.B.).
■
(24) Tome,
Porphyrins Phthalocyanines 2009, 13, 408−414.
(25) Singh, S.; Aggarwal, A.; Thompson, S.; Tome,
́
A. C.; Neves, M. G. P. M. S.; Cavaleiro, J. A. S. J.
́
J. P. C.; Zhu, X.;
Samaroo, D.; Vinodu, M.; Gao, R.; Drain, C. M. Bioconjugate Chem.
2010, 21, 2136−2146.
Notes
(26) Pereira, M. M.; Monteiro, C. J. P.; Simoes, A. V. C.; Pinto, S. M.
̃
The authors declare no competing financial interest.
A.; Abreu, A. R.; Sa, G. F. F.; Silva, E. F. F.; Rocha, L. B.; Dabrowski, J.
M.; Formosinho, S. J.; Simoes, S.; Arnaut, L. G. Tetrahedron 2010, 66,
9545−9551.
ACKNOWLEDGMENTS
■
(27) Samankumara, L. P.; Wells, S.; Zeller, M.; Acuna, A. M.; Roder,
̃
̈
This work was supported by grants from the Division of
Chemical Sciences, Geosciences, and Biosciences, Office of
Basic Energy Sciences of the U.S. Department of Energy, to
D.F.B. (DE-FG02-05ER15660) and J.S.L. (DE-FG02-
96ER14632). Mass spectra were obtained at the Mass
Spectrometry Laboratory for Biotechnology at North Carolina
State University. Partial funding for the facility was obtained
from the North Carolina Biotechnology Center and the
National Science Foundation.
B.; Bruckner, C. Angew. Chem., Int. Ed. 2012, 51, 5757−5760.
̈
(28) Pereira, M. M.; Abreu, A. R.; Goncalves, N. P. F.; Calvete, M. J.
F.; Simoes, A. V. C.; Monteiro, C. J. P.; Arnaut, L. G.; Euseb
Canotilho, J. Green Chem. 2012, 14, 1666−1672.
́
io, M. E.;
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