oligopyrrolic compounds 
 are essential to all forms of life and play a critical role in the 
 chemistry of transition metals in living systems .
the coordination 
 chemistry of porphyrins and other oligopyrrolic macrocycles has been 
 investigated intensely ; however , linear oligopyrroles and particularly 
 dipyrrolic fragments are gaining increasing attention . presenting an electron - rich scaffold and an array of pyrrolic nitrogen 
 donors ,
linear oligopyrrolic fragments are typically well - poised for 
 metal coordination . in addition , these fully or partially conjugated 
 compounds can offer diverse coordinating abilities toward transition 
 metals in multiple oxidation states , as well as highly tunable , potentially 
 redox - active , ligand behavior .
such properties have been observed 
 in studies of reactivity and catalytic applications of complexes of 
 dipyrranes , dipyrrins , and other linear oligopyrrolic ligands .
herein , we examine in the context of metal coordination 
 a tripyrrolic scaffold found in several naturally occurring pigments 
 of bacterial origin . the pyrrolyldipyrrin motif characterizes 
 the natural product prodigiosin ( 1 in chart 1 , showing the common letter designation of the three 
 pyrrole rings ) , a red pigment produced by certain serratia , streptomyces , and bacillus bacteria strains .
this tripyrrolic species is the parent compound of a large family 
 of natural and synthetic analogues , termed prodigiosenes ( or less 
 commonly prodiginines ) , which are currently undergoing intense scrutiny 
 in medicinal chemistry studies because of their diverse biological 
 activity profiles .
multiple studies document the efficacy of numerous 
 pyrrolyldipyrrins as immunosuppressive , antimicrobial , antimalarial , and 
 anticancer agents .
the reported ability of prodigiosenes to induce apoptosis 
 has been connected to dna intercalation , perturbation of intracellular ph through h / cl symport and/or cl / hco3 antiport mechanisms , and oxidative dna damage .
prodigiosin cleaves double - stranded dna in the presence 
 of o2 and cu(ii ) cations without the need of an added reductant .
both metal binding and redox interplay between 
 the electron - rich tripyrrole and the redox - active cation , possibly 
 resulting in formation of a ligand - based -radical cation , have 
 been proposed to explain the observed nuclease activity .
consistently , modifications of the prodigiosin scaffold that rendered 
 the ligand less coordinating or harder to oxidize decreased dna cleavage 
 activity . in spite of 
 the interest in the role of metal binding and redox chemistry in the 
 biological activity of prodigiosenes
, however , the coordination chemistry 
 of these tripyrrolic fragments remains rather unexplored , and copper 
 complexes of pyrrolyldipyrrins have been elusive .
bidentate 
 coordination modes to the dipyrrin unit of prodigiosin analogues have 
 been observed in fluorescent boron difluoride complexes , and two such compounds are available commercially as longer - wavelength 
 members of the bodipy family of fluorescent dyes ( molecular probes ) . 

similarly , several homoleptic zinc complexes of pyrrolyldipyrrins , 
 such as 2 ( chart 1 ) , share the characteristics of 
 other complexes within the large family of simple dipyrrins , which 
 coordinate as bidentate monoanionic ligands .
the additional pyrrolic 
 ring on the prodigiosin - type scaffolds behaves as a ligand in fluorescent 
 dialkyl and diaryl tin(iv ) complexes such as 3 ( chart 1 ) , for which structural 
 characterization revealed tridentate coordination of all nitrogen 
 donors on the fully conjugated pyrrolyldipyrrin scaffold .
a similar 
 tridentate coordination mode was recently proposed for a zn(ii ) complex , 
 which was not characterized fully but was inferred from uv 
studies aimed at cu(ii ) coordination of prodigiosin led to 
 the isolation of complex 4 ( chart 1 ) following reaction of the free ligand with cupric chloride in the 
 presence of potassium tert - butoxide in tert - butyl alcohol .
notably , the tripyrrolic 
 scaffold behaves as a tridentate ligand , but oxidation of pyrrole 
 ring c yielded an sp - hybridized hydroxyl - bound carbon 
 atom in 4 and confirmed the occurrence of ligand - centered 
 redox reactivity in solution .
additional coordination studies conducted 
 on a c - ring modified analogue of prodigiosin indicated copper  ligand 
 binding interactions of 1:1 and 1:2 stoichiometry , as inferred by 
 spectrophotometric titrations and mass spectrometry , but the resulting 
 copper complexes were not isolated . interestingly , 
 oxidative degradation was also observed during cu(ii ) insertion in 
 another tripyrrolic ligand , a tripyrrane that was found to undergo 
 oxidation at the methylene bridges . in spite of their electron - rich scaffold featuring an array of three 
 pyrrolic nitrogen donors ,
herein , we describe the 
 design and synthesis of a pyrrolyldipyrrin ligand of enhanced metal - coordinating 
 ability when compared to that of natural systems and current synthetic 
 analogues .
binding of divalent zinc is observed as well as the prompt 
 and hitherto elusive coordination of divalent copper ions in the absence 
 of bases and without oxidative degradation of the ligand . the spectroscopic 
 and structural characterization of the resulting complexes documents 
 two available coordination modes for the tripyrrolic fragment .
the 
 reported synthetic findings will offer access to new classes of prodigiosin 
 analogues ; concurrently , our prototype ligand system provides a new 
 platform for the study of metal - bound pyrrolyldipyrrins and their 
 potential applications in medicinal chemistry , small - molecule activation , 
 and catalysis .
aiming to build a pyrrolyldipyrrin of higher metal - binding affinity 
 when compared to that of natural systems , we introduced two electron - withdrawing 
 groups in the first - generation scaffold h2pd1 ( scheme 1 ) : ( i ) a phenyl group in the meso - type position and ( ii ) an ethyl ester group on the c - ring .
these 
 substituents were expected to increase the acidity of the pyrrolic 
 n  h protons in order to facilitate deprotonation and coordination 
 of metal cations .
in addition , the -ester functionality was 
 envisioned as an additional ligand to contribute to metal coordination 
 with a neutral oxygen donor , as previously observed for -substituted 
 dipyrrins . further supporting our ligand design featuring 
 two electron - withdrawing substituents ,
h2pd1 presents a 
 stabilized  system when compared to naturally occurring analogues . 
 as such
, we anticipated that such construct would be less prone to 
 the type of oxidative degradation observed in complex 4 ( chart 1 ) in the presence of redox - active 
 transition metal species such as cu(ii ) ions .
meso - aryl pyrrolyldipyrrin scaffolds 
 have recently appeared in studies on the preparation of pyrrolylbodipy 
 dyes .
specifically , substitution reactions on meso - aryl dipyrrin substrates and the one - pot 
 reaction of acyl chlorides with excess 
 pyrrole under an oxygen atmosphere afford boron pyrrolyldipyrrins . 

alternatively , a recent synthetic route 
 to this class of compounds requires the low - yielding acylation of 
 2,2-bipyrrole , leading to a mixture of products .
these synthetic methods for the preparation 
 of meso - aryl pyrrolyldipyrrin , however , generally 
 afford modest - to - moderate yields and have not been employed on -substituted 
 pyrroles .
our stepwise assembly of the three pyrrolic rings is designed 
 to provide flexibility of substitution patterns for the overall structure .
similar to several reported preparations of c - ring - modified prodigiosenes , our synthetic pathway begins with the heterocycle that will become 
 the c - ring in the final product .
the pyrrolic precursor ethyl 5-benzoyl-1h - pyrrole-2-carboxylate 5 , which carries the 
 desired ethyl ester substitution and a benzoyl group for further functionalization , 
 was reduced with nabh4 to give alcohol 6 . 

this reactive species was utilized promptly upon isolation , and the 
 b - ring was introduced by condensation with excess pyrrole under acidic 
 conditions . alternatively , asymmetric 
 dipyrrane 7 could be prepared via known methods requiring 
 synthesis of a 5-substituted dipyrran and subsequent grignard - mediated 
 acylation using a pyridyl carbonothioate ( mukaiyama reagent ) .
these transformations , however , are typically 
 characterized by low - to - moderate yields and challenging purifications . because bromodipyrrins are reliable precursors in the synthesis 
 of prodigiosenes , dipyrromethane 7 was brominated with n - bromosuccinimide and then oxidized with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone 
 ( ddq ) to afford asymmetric bromodipyrrin 9 .
compound 9 is susceptible to rapid decomposition under acidic conditions , 
 and the addition of a base during the oxidation reaction proved to 
 be critical .
the a - ring completing the pyrrolyldipyrrin scaffold was 
 then introduced using a protected pyrrole-2-boronic acid through a 
 suzuki  miyaura coupling reaction , giving the target tripyrrolic 
 pigment h2pd1 .
a full assignment of the pyrrolic 
 proton resonances for the pyrrolyldipyrrin ligand was performed by 
 cosy and noesy 2d nmr techniques ( see supporting 
 information ) .
these experiments also indicated that free base 
 h2pd1 exists in solution as the rotamer shown in scheme 2 .
although three alternative rotameric structures 
 are available for this scaffold , this pyrrolyldipyrrin is best represented 
 by the structure featuring all three pyrrolic nitrogen atoms on the 
 inner side of the cleft .
this rotamer is also the one observed experimentally 
 by 2d nmr experiments and was found to be most stable by dft analysis 
 in a recent study on a close analogue of natural prodigiosin .
in addition , our 2d nmr data allowed identification 
 of the nh proton on ring a ( figure s3 , supporting information ) but left undetermined 
 the position of the other nh proton , which was not observed , likely 
 because of rapid exchange equilibrium between the two tautomeric forms 
 of the dipyrrin moiety ( scheme 2 ) .
the nmr 
 data summarized above indicate that free base h2pd1 maintains 
 the orientation of pyrrolic nitrogen donors in a tridentate array 
 poised for metal coordination and/or multiple hydrogen - bonding interactions , 
 two aspects of its solution chemistry that have been invoked in the 
 biological mechanisms of action of prodigiosin analogues .
pyrrolyldipyrrin h2pd1 is a dark red pigment characterized by an intense visible absorption 
 band at max 476 nm (  , 29  600 m cm in ch3oh ) ; thus , 
 the coordination of metal cations could be monitored by uv 
addition of 0.5 equiv of zn(oac)22h2o to a solution of h2pd1 in methanol 
 ( figure 1 ) or thf led to prompt formation of 
 a new metal complex featuring two red - shifted absorption bands .
clear 
 isosbesticity was maintained over the course of the metal - binding 
 study , and further additions of zinc salt did not elicit any changes 
 in the absorption spectra ; therefore , the formation of a single complex 
 of 2:1 ligand - to - metal stoichiometry was inferred . because absorbance 
 values changed almost linearly with metal ion additions , and hence 
 the fraction of ligand - bound metal approached 100% , these binding 
 studies of zinc and copper ( see below ) ions revealed binding stoichiometry 
 but did not allow reliable determination of the high - affinity equilibrium 
 constants .
spectral changes and binding isotherms observed upon addition of 
 zn(oac)22h2o ( left panel ) or cu(oac)2h2o ( right panel ) to pyrrolyldipyrrin h2pd1 ( 36 m ) in methanol at 298 k. complex zn(hpd1)2 was isolated and first characterized 
 by nmr spectroscopy .
the proton spectrum displayed a single set of 
 resonances for the tripyrrolic ligand , consistent with a 1:1 stoichiometry 
 of binding or with formation of a symmetric 2:1 complex .
two - dimensional 
 experiments allowed identification of the proton on the pyrrolic nitrogen 
 atom on ring a ( figures s5s6 , supporting 
 information ) , which is shifted downfield with respect to the 
 corresponding resonance in the free ligand ( at 9.75 vs 9.35 ppm in 
 h2pd1 ) and does not participate in metal binding . in addition , 
 a noesy crosspeak between the  c  h proton on ring a 
 and the phenyl multiplet was identified as a correlation between two 
 ligands held in close proximity by coordination to the zinc center 
 and therefore consistent with 2:1 ligand - to - metal binding stoichiometry . 

the expected coordination of the zinc(ii ) ion to two ligands through 
 the bidentate dipyrrin moieties was confirmed in the solid state by 
 x - ray diffraction analysis on a single crystal of complex zn(hpd1)2 ( figure 2 ) .
crystal structure of 
 zinc complex zn(hpd1)2 showing a partial labeling scheme . 
 for clarity ,
the two pyrrolyldipyrrin ligands are shown in different 
 colors , and the hydrogen atoms in calculated positions are shown only 
 for one of the ligands .
anisotropic thermal displacement ellipsoids 
 are set at the 50% probability level ( ccdc 994299 ) .
the crystallographic metric parameters of complex 
 zn(hpd1)2 are similar to those of the zinc complex of natural 
 prodigiosin 1 , in which 
 the zinc center coordinates with tetrahedral geometry to two bidentate 
 monoanionic dipyrrin units .
interestingly , the noncoordinating a - ring 
 of one of the ligands in the structure of zn(hpd1)2 features 
 a pyrrolic nh group pointing away from the zinc center and hence is 
 in a different rotameric structure when compared to that of the free 
 ligand .
this packing effect is attributed to an intermolecular hydrogen - bonding 
 interaction with the carbonyl group of a neighboring complex ( figure 
 s7 , supporting information ) and is not 
 observed in chloroform solution according to our 2d nmr data . partly because copper is a biologically relevant metal and partly 
 because of the documented interplay of cu(ii ) ions and natural prodigiosin 
 in the cleavage of double - stranded dna , the copper binding properties of pyrrolyldipyrrin 
 scaffolds have been previously investigated .
nevertheless , copper - bound 
 prodigiosenes have remained elusive , and coordination studies reported 
 oxidative degradation of the ligand in complex 4 ( chart 1 ) or formation of multiple 
 complexes that could not be isolated and fully characterized . because ligand h2pd1 was designed 
 for enhanced metal - binding properties , we sought to investigate its 
 coordination of the cu(ii ) cation .
the reaction of h2pd1 with cu(oac)2h2o could be monitored 
 by uv  vis spectrophotometry in ch3oh ( figure 1 , right panel ) or thf .
the spectral changes observed 
 upon addition of the copper salt presented a clear isosbestic point , 
 and full saturation of the ligand was reached when the concentration 
 of cu(ii ) ions amounted to 1 equiv , therefore indicating formation 
 of a single copper complex of high affinity and 1:1 binding stoichiometry . 

h2pd1 is an excellent receptor for copper coordination , 
 and , unlike previously reported binding studies , complex formation in this case did not require addition of a base 
 to facilitate deprotonation of pyrrolic nh groups .
the solid - state 
 structure of the isolated copper complex cu(pd1 ) was investigated 
 by single - crystal x - ray diffraction analysis .
although the refinement 
 was complicated by the presence of disordered solvent molecules ( see experimental section ) , this analysis allowed for 
 the determination of the copper coordination mode in the complex ( figure 3 ) .
pyrrolyldipyrrin pd1 behaves 
 as a tetradentate dianionic ligand , and the copper center exhibits 
 a slightly distorted square planar coordination geometry in the resulting 
 neutral complex .
all three pyrrolic nitrogen atoms are engaged as 
 donor groups , and the ester group on the c - ring assumes the expected 
 role of neutral ligand through the carbonyl oxygen atom to complete 
 the copper coordination sphere .
npyrrole ( 1.900(8)1.931(9 ) 
  ) and cu  ocarbonyl ( 2.074(7 )  ) bond 
 lengths compare well with those found in cu(ii ) complexes of prodigiosin and -substituted dipyrrin ligands .
n bond distance to pyrrole ring a ( 1.931(9 )  ) 
 is longer than those to rings b and c ( 1.909(8 ) and 1.900(8 )  , 
 respectively ) .
n and c  c bond metric 
 comparisons with free pyrrolyldipyrrin ligands and with zn(ii ) 
 complex zn(hpd1)2 confirm a fully conjugated tripyrrolic 
 scaffold in cu(pd1 ) .
such considerations , together with the absence 
 of counterions , indicate that cu(ii ) ions bind to deprotonated ligand 
 pd1 without complications arising from interfering 
 redox events .
top and side views of the crystal structure of copper(ii ) 
 complex cu(pd1 ) showing a partial labeling scheme .
anisotropic thermal 
 displacement ellipsoids are scaled to the 50% probability level ( ccdc 
 994298 ) .
the coordination environment of the copper center 
 in cu(pd1 ) was investigated in solution by electron paramagnetic resonance 
 ( epr ) spectroscopy .
the x - band ( 9.5 ghz ) continuous - wave ( cw ) 
 epr and the ka - band ( 30 ghz ) electron 
 spin echo ( ese ) field - sweep spectra ( figure 4 ) are characterized by nearly axial g and acu tensors ( where acu denotes the hyperfine interaction ( hfi ) of the 
 central cu nucleus ) with ( g , g ) = ( 2.188 , 2.043 ) and ( acu , acu )  
 ( 17.6 ,
< 4 ) mt , indicative of the unpaired electron predominantly 
 localized in the dx  y orbital . ( a ) x - band cw epr and 
 ( b ) ka - band two - pulse ese field - sweep 
 spectra of a cu(pd1 ) solution in toluene . the asterisk in panel b 
 indicates the epr position where the pulsed endor measurements ( figure 5 ) were performed .
experimental conditions : ( a ) microwave 
 frequency , 9.450 ghz ; microwave power , 2 mw ; magnetic field modulation 
 amplitude , 0.2 mt ; temperature , 77 k. ( b ) microwave frequency , 30.360 
 ghz ; microwave pulses , 24 and 42 ns ; time interval between microwave 
 pulses ,  = 400 ns ; temperature , 15 k. the n hyperfine splittings in the cw epr spectrum 
 ( figure 4a ) are not sufficiently resolved to 
 permit the determination of the number and detailed parameters of 
 the n ligands . in order to reveal the ( relative ) number 
 of copper - bound nitrogen atoms in cu(pd1 ) in solution
, we employed 
 a pulsed electron  nuclear double resonance ( endor ) technique 
 due to davies , which is particularly 
 suitable for detecting the strong ( tens of megahertz ) hfi of n in cu(ii ) complexes . because we were mostly 
 interested in quantification of the n nuclei
, we performed 
 only the measurements at the low - field g turning point of the epr spectrum ( marked by an asterisk in figure 4 ) , which corresponds to a single - crystal - like situation 
 and to the highest resolution in the endor spectra .
the relevant theoretical 
 background and the experimental details are given in the experimental section .
here , we will mention only 
 that the microwave ( mw ) pulses used were sufficiently long to make 
 the davies endor response independent of the hfi constants 
 of the detected n nuclei .
in addition , to minimize the 
 dependence of the n endor line amplitudes on the transition 
 probabilities , the experiment was performed in a 2d fashion ( figure 
 s8 , supporting information ) : radiofrequency 
 ( rf ) versus the rf pulse length , trf , 
 and then the 2d set was integrated over trf to obtain the 1d spectrum .
the obtained n davies 
 endor spectrum ( figure 5 ) shows three pairs of features attributable to n nuclei ( labeled na , nb , and nc in figure 5 ) , with the splitting within each 
 pair equal to twice the zeeman frequency of n : 2n  6 mhz in the applied magnetic field , b0  1 t. the smaller quadrupole splittings are 
 poorly resolved because of the line broadening .
these three pairs 
 of lines are centered at the frequencies of 12.6 , 21.9 , and 30.2 mhz , 
 resulting in the n hfi constants an = 25.2 , 43.8 , and 60.4 mhz , respectively .
n davies endor spectrum of a cu(pd1 ) solution in toluene ( top panel ) 
 and integrals under the endor features belonging to different n ligand nuclei ( bottom panel ) .
the experiment was performed 
 in a 2d fashion , rf vs the rf pulse length , trf , and then the 2d set was integrated over trf to obtain the 1d spectrum shown in the top 
 panel .
experimental conditions : microwave frequency , 30.360 ghz ; magnetic 
 field , b0 = 970 mt ( marked by an asterisk 
 in figure 4b ) ; microwave pulses , 160 , 80 , and 
 160 ns ; time interval between the first and second microwave pulses , 
 36 s ; time interval between the second and third microwave 
 pulses , 400 ns ; trf variation range , 232 
 s ; temperature , 15 k. in order to estimate the relative numbers of nitrogen nuclei 
 contributing to each pair of n endor features , we have 
 integrated the spectrum within the regions occupied by each line group 
 ( figure 5 , bottom panel ) . the similar areas 
 under each feature correspond to three types of copper - bound nitrogen 
 donors in equal numbers .
we conclude , therefore , that the solution 
 structure of cu(pd1 ) is similar to that determined by single - crystal 
 x - ray diffraction analysis ( figure 3 ) , with 
 a single pd1 ligand coordinated in tetradentate 
 fashion to the cu(ii ) center .
alternative structures formally having 
 three types of nitrogen ligands in equal numbers can be discarded : 
 three - coordinate cu(ii ) complexes are quite unusual , and they exhibit acu  913 mt , significantly lower than that found in our case , whereas cu(ii ) 
 complexes with six nitrogen ligands have g values in excess of 2.23 , significantly 
 greater than that observed in this work . the hfi constants an found in this work 
 are within the range known for n ligands in cu(ii ) complexes .
the largest hfi constant , an = 60.4 mhz ( nc in figure 5 ) , is close to those found in cu(ii ) complexes of 
 tetraphenylporphyrin ( tpp ) ( four equivalent nitrogen donors with an = 54.2 mhz ) and n - confused tpp ( nctpp ) ( two of the larger hfi constants an = 60 mhz ) . for pyrrolic nitrogens coordinated trans to oxygen ligands ,
hfi constants are reduced to 
 40 mhz , and an of nb is of similar magnitude ( 43.8 mhz ) .
the remaining an = 25.2 mhz ( na ) found in 
 this work appears to be much smaller than the hfi constants found for pyrrole or imidazole ligands of cu(ii ) in nitrogen 
oxygen 
 coordination environments to be explained 
 by electronic factors only . because the cu  n1 bond distance 
 is longer than the other nitrogen contacts in the crystal structure 
 of cu(pd1 ) ( see structural characterization and figure 3 above ) , we tentatively assign na to n1 , whereas 
 nb and nc are assigned to n2 and n3 , respectively . together with the visible absorption data , the epr and endor spectroscopic 
 analysis of the paramagnetic complex cu(pd1 ) indicated that prodigiosin 
 analogue h2pd1 coordinates cu(ii ) ions with 1:1 stoichiometry , 
 employing all three nitrogen donors on the ligand in the absence of 
 any added base in organic solvents .
the 
 electron - rich tripyrrolic scaffold and preorganized array of nitrogen 
 donor groups of pyrrolyldipyrrin motifs have made them long - standing 
 candidates for binding of transition metals . in spite of these features , 
 these oligopyrrolic fragments are not characterized by a rich coordination 
 chemistry . here , we report a molecular design of the substitution 
 pattern on this tripyrrolic motif that leads to the construction of 
 an effective platform for metal coordination . specifically , the addition 
 of a meso - aryl group and an ester group on the c - ring 
 resulted in ligand system h2pd1 , which not only maintains 
 the known monoanionic bidentate binding mode shown in complex zn(hpd1)2 but also offers an unprecedented dianionic tetradentate coordination 
 mode for cu(ii ) in a pyrrolyldipyrrin complex .
the latter was established 
 by x - ray crystallography in the solid state and confirmed in solution 
 by pulsed endor .
the described spectroscopic analysis provides a basis 
 for the study of metal - bound pyrrolyldipyrrins in other paramagnetic 
 complexes .
the modular construction of meso - substituted pyrrolyldipyrrins described herein is anticipated to 
 produce a class of ligands featuring high tunability of donor capacity 
 and redox potentials .
in addition , lacking the rigid structure of 
 porphyrin and other pyrrole - based macrocycles , tripyrrolic ligands 
 enable the formation of complexes in which the metal center is possibly 
 more accessible for substrate coordination in catalytic applications . 

these expectations reflect recent reports on the coordination compounds 
 of several linear oligopyrroles that testify to the rich redox chemistry and catalytic applications of transition 
 metal complexes of this class of ligands .
our findings offer new opportunities 
 in the construction and untapped reactivity of metal complexes of 
 pyrrolyldipyrrin ligands .
these studies could provide insight into 
 the involvement of transition metals in the biological activities 
 of prodigiosin compounds and their synthetic analogues .
all reactions 
 were carried out under an inert ( n2 or ar ) atmosphere using 
 dry solvents unless otherwise noted .
tetrahydrofuran ( thf ) , methanol 
 ( meoh ) , pentane , diethyl ether ( et2o ) , and dichloromethane 
 ( ch2cl2 ) were dried by passage through a vacuum 
 atmospheres solvent purifier .
flash column chromatography was carried 
 out using siliaflash p60 silica ( 4063 m particle size , 
 230400 mesh , silicycle ) or brockmann grade i neutral aluminum 
 oxide ( 58  , 60 mesh , alfa aesar ) .
reactions were monitored by 
 thin - layer chromatography ( tlc ) on silica gel plates ( aluminum - backed , 
 60 w f254s , emd millipore ) .
h and c nmr spectra 
 were recorded at the university of arizona nmr facility on bruker 
 drx-600 , drx-500 , or aviii-400 instruments and calibrated using residual 
 undeuterated solvent or tetramethylsilane as an internal reference . 

low- and high - resolution mass spectra were acquired at the university 
 of arizona mass spectrometry facility .
vis spectra 
 were recorded on an agilent 8453 uv  vis spectrophotometer , 
 and solutions were freshly prepared in meoh .
the epr measurements 
 were performed at the university of arizona epr facility ( see the 
 section below for details ) .
ethyl 
 5-benzoyl-1h - pyrrole-2-carboxylate ( 1.72 g , 7.07 mmol ) was dissolved in meoh ( 15 ml ) in a round - bottomed 
 flask at 0 c .
nabh4 ( 0.802 g , 21.2 mmol ) was added 
 to the flask in three portions over 30 min .
the reaction mixture was 
 warmed to room temperature and stirred for 8 h. the reaction mixture 
 was then cooled to 0 c and carefully quenched by adding saturated 
 aqueous nahco3 .
the aqueous layer was extracted three times 
 with ethyl acetate ( 20 ml ) , and the combined organic layers were washed 
 with brine ( 10 ml ) and dried over anhydrous na2so4 . following solvent evaporation under reduced pressure , crude product 6 was used directly in the next step without further purification 
 ( 1.47 g , 6.01 mmol , 75% ) .
h nmr ( 500 mhz , cdcl3 ,  ) : 9.69 ( s , 1h ) , 7.447.33 ( m , 5h ) , 6.85 ( dd , j = 3.8 , 2.6 hz , 1h ) , 5.985.96 ( m , 1h ) , 5.92 ( d , j = 4.1 hz , 1h ) , 4.29 ( q , j = 7.1 hz , 2h ) , 
 3.23 ( d , j = 4.1 hz , 1h ) , 1.35 ( t , j = 7.1 hz , 3h ) .
c nmr ( 125 mhz , cdcl3 ,  ) : 
 161.57 , 141.74 , 139.21 , 128.71 , 128.30 , 126.60 , 122.31 , 115.80 , 108.36 , 
 60.46 , 14.46 .
compound 6 ( 1.47 g , 6.01 mmol ) was dissolved in glacial acetic acid 
 ( 68 ml ) and acetic anhydride ( 6.6 ml ) in a round - bottomed flask .
pyrrole 
 ( 2.1 ml , 30.1 mmol ) was added , and the reaction mixture was refluxed 
 for 8 h. following solvent evaporation under reduced pressure ( to 
 remove the acetic acid ) , the crude compound was purified by flash 
 chromatography ( silica gel , 25% ethyl acetate in hexanes ) to yield 7 as an orange - brown oil ( 1.27 g , 4.33 mmol , 72% ) .
h nmr ( 500 mhz , cdcl3 ,  ) : 8.84 ( s , 1h ) , 7.92 ( s , 
 1h ) , 7.397.30 ( m , 3h ) , 7.257.21 ( m , 2h ) , 6.88 ( dd , j = 3.7 , 
 2.5 hz , 1h ) , 6.75 ( ddd , j = 2.7 , 1.6 , 0.7 hz , 1h ) , 
 6.20 ( dd , j = 6.1 , 2.7 hz , 1h ) , 6.00 ( ddd , j = 3.6 , 2.7 , 0.7 hz , 1h ) , 5.97 ( dddd , j = 3.7 , 2.5 , 1.6 , 0.9 hz , 1h ) , 5.51 ( s , 1h ) , 4.30 ( q , j = 7.1 hz , 2h ) , 1.36 ( t , j = 7.1 hz , 3h ) .
c nmr ( 125 mhz , cdcl3 ,  ) : 161.11 , 140.83 , 138.15 , 
 131.08 , 128.88 , 128.31 , 127.30 , 122.15 , 117.74 , 115.54 , 109.82 , 108.56 , 
 107.74 , 60.27 , 44.16 , 14.94 . lrms - esim / z ( relative intensity ) : 294.0 ( 4% ) , 228.0 ( 100% ) .
compound 7 ( 0.100 g , 0.340 mmol ) was dissolved in thf ( 6 ml ) at 78 
 c .
n - bromosuccinimide ( 61 mg , 0.340 mmol ) was 
 added to the reaction flask in one portion , and the mixture was stirred 
 at 78 c for 30 min .
the reaction mixture was diluted 
 with hexanes ( 5 ml ) and with water ( 5 ml ) .
the aqueous layer was extracted 
 three times with ethyl acetate ( 20 ml ) , and the combined organic layers 
 were washed with brine ( 10 ml ) and dried over anhydrous na2so4 .
solvent evaporation under reduced pressure afforded 
 compound 8 as a brown oil ( 0.114 g , 0.241 mmol , 90% ) , 
 which was used directly in the next step without further purification . 

( note that in order to obtain the desired compound in high yields 
 and free of side products , this reaction could not be conducted on 
 more than 0.150 g of 7 . )
h nmr ( 500 mhz , 
 cdcl3 ,  ) : 8.79 ( s , 1h ) , 7.82 ( s , 1h ) , 7.407.32 
 ( m , 3h ) , 7.247.20 ( m , 2h ) , 6.87 ( dd , j = 
 3.7 , 2.5 hz , 1h ) , 6.11 ( dd , j = 3.6 , 2.7 hz , 1h ) , 
 6.01 ( ddd , j = 3.6 , 2.7 , 0.7 hz , 1h ) , 5.88 ( ddd , j = 3.7 , 2.5 , 0.9 hz , 1h ) , 5.44 ( s , 1h ) , 4.31 ( q , j = 7.1 hz , 2h ) , 1.36 ( t , j = 7.1 hz , 3h ) .
c nmr ( 125 mhz , cdcl3 ,  ) : 161.71 , 140.36 , 
 137.84 , 132.19 , 128.65 , 128.14 , 127.34 , 122.29 , 116.01 , 110.47 , 109.97 , 
 109.45 , 97.54 , 60.47 , 44.21 , 14.35 . lrms - esim / z ( relative intensity ) : 372.1 ( 33% ) , 327.0 ( 100% ) .
compound 8 ( 0.114 g , 0.241 mmol ) was dissolved in thf ( 6.7 ml ) at 0 
 c .
2,3-dichloro-5,6-dicyano-1,4-benzoquinone ( ddq , 55 mg , 0.241 
 mmol ) was dissolved in thf ( 1.4 ml ) and added dropwise .
1,5-diazabicyclo(4.3.0)non-5-ene 
 ( dbn , 30 l , 0.241 mmol ) was added , and the mixture was stirred 
 at room temperature for 7 h. the reaction mixture was quenched by 
 adding saturated aqueous nahco3 ( 10 ml ) , and the aqueous 
 layer was extracted three times with ch2cl2 ( 10 
 ml ) .
the combined organic layers were washed with brine ( 10 ml ) and 
 dried over anhydrous na2so4 .
the crude product 
 was redissolved in 1:1 mixture of ethyl acetate / hexanes and filtered 
 through a silica pad in order to give compound 9 ( 75 
 mg , 0.202 mmol , 84% ) as a yellow oil .
h nmr ( 500 mhz , 
 cdcl3 ,  ) : 7.557.45 ( m , 5h ) , 6.87 ( dd , j = 4.1 , 2.4 hz , 1h ) , 6.76 ( d , j = 4.5 
 hz , 1h ) , 6.52 ( d , j = 4.5 hz , 1h ) , 6.33 ( dd , j = 4.1 , 2.4 hz , 1h ) , 4.43 ( q , j = 7.1 
 hz , 2h ) , 1.46 ( t , j = 7.1 hz , 3h ) .
c 
 nmr ( 125 mhz , cdcl3 ,  ) : 160.54 , 150.17 , 149.00 , 
 139.47 , 137.00 , 135.65 , 134.87 , 130.65 , 129.57 , 128.39 , 127.99 , 121.63 , 
 115.54 , 60.76 , 14.26 . lrms - esim / z ( relative intensity ) : 370.9 ( 19% ) , 325.1 ( 100% ) .
compound 9 ( 75 mg , 0.202 mmol ) , licl ( 30 mg , 0.707 mmol ) , pyrrole-2-boronic 
 acid ( 64 mg , 0.303 mmol ) , and pd(pph3)4 ( 23 
 mg , 10 mol % , 20.2 mol ) were dissolved in 1,2-dimethoxyethane 
 ( 6.1 ml ) , and the solution was degassed for 2 h. a degassed solution 
 of aqueous na2co3 ( 2 m , 0.5 ml ) was added dropwise , 
 and the mixture was refluxed for 2 h. the reaction mixture was cooled 
 to room temperature and diluted with water ( 10 ml ) .
the aqueous layer 
 was extracted three times with ch2cl2 ( 10 ml ) . 

the combined organic layers were washed with brine ( 10 ml ) and dried 
 over anhydrous na2so4 .
solvent evaporation under 
 reduced pressure afforded the crude product , which was dissolved in 
 ch2cl2 ( 10 ml ) .
the solution was cooled to 0 
 c , and trifluoroacetic acid ( 0.8 ml ) was added dropwise .
the 
 mixture was stirred at room temperature for 8 h , cooled to 0 c , 
 and carefully quenched with saturated aqueous nahco3 ( 20 
 ml ) .
the mixture was extracted three times with ch2cl2 ( 10 ml ) , and the combined organic layers were washed with 
 brine ( 10 ml ) and dried over anhydrous na2so4 .
solvent evaporation followed by flash chromatography ( neutral alumina , 
 1030% ethyl acetate in hexanes ) gave pyrrolyldipyrrin h2pd1 as a dark red solid ( 38 mg , 0.107 mmol , 48% ) .
( note that 
 this reaction gives lower yields when conducted on more than 0.100 
 g of 9 . )
h nmr ( 400 mhz , cdcl3 , tms  ) : 9.35 ( bs , 1h ) , 7.497.41 ( m , 5h ) , 7.10 ( bs , 
 1h ) , 6.92 ( d , j = 4.7 hz , 1h ) , 6.90 ( d , j = 4.7 hz , 1h ) , 6.856.83 ( m , 2h ) , 6.406.37 ( m , 1h ) , 
 6.24 ( d , j = 4.0 hz , 1h ) , 4.41 ( q , j = 7.1 hz , 2h ) , 1.46 ( t , j = 7.1 hz , 3h ) .
c nmr ( 125 mhz , cdcl3 ,  ) : 160.30 , 153.05 , 138.25 , 
 137.70 , 136.68 , 132.58 , 132.11 , 131.51 , 131.23 , 129.92 , 128.69 , 125.46 , 
 122.69 , 122.24 , 122.15 , 117.59 , 113.82 , 61.48 , 14.40 . hrms - maldi ( m / z ) : [ m + h ] calcd for [ c22h20n3o2 ] , 358.1555 ; found , 
 358.1536 .
vis ( meoh ) max (  ) , 476 
 nm ( 29  600 m cm ) .
pyrrolyldipyrrin h2pd1 ( 20 mg , 5.6 mol ) was dissolved in thf ( 6 ml ) , and 
 zn(oac)22h2o ( 6.0 mg , 2.8 mol ) 
 was added .
, the solvent was removed under high vacuum , and the 
 resulting crude solid was dissolved in dichloromethane ( 0.5 ml ) .
filtration 
 through a celite pad to remove any unreacted zinc salt followed by 
 evaporation of the solvent and recrystallization from thf / pentane 
 gave the zinc complex as a dark orange / red powder ( 10 mg , 1.3 mol , 
 46% ) .
single crystals for x - ray diffraction analysis and elemental 
 analysis were grown from thf / pentane mixtures .
h nmr ( 400 
 mhz , cdcl3 , tms  ) : 9.75 ( bs , 2h ) , 7.587.48 
 ( m , 10h ) , 6.96 ( d , j = 4.0 hz , 2h ) , 6.85 ( d , j = 4.7 hz , 2h ) , 6.79 ( d , j = 4.7 hz , 2h ) , 
 6.67 ( ddd , j = 3.8 , 2.5 , 1.4 hz , 2h ) , 6.58 ( td , j = 2.7 , 1.4 hz , 2h ) , 6.45 ( d , j = 4.0 
 hz , 2h ) , 6.14 ( dt , j = 3.7 , 2.4 hz , 2h ) , 4.053.98 
 ( m , 4h ) , 0.98 ( t , j = 7.1 hz , 6h ) . hrms ( m / z ) [ m + h ] calcd for [ c22h17n3o2zn ] , 777.2168 ; found , 
 777.2163 . uv
 vis ( meoh ) max (  ) : 512 
 nm ( 56  607 m cm ) , 544 
 nm ( 50  200 m cm ) .
calcd for c44h37n6o4zn2thf4h2o : c , 62.80 ; h , 6.08 ; n , 8.45% .
pyrrolyldipyrrin h2pd1 ( 20 mg , 5.6 mol ) was dissolved in thf ( 6 
 ml ) , and cu(oac)2h2o ( 11 mg , 5.6 mol ) 
 was added .
, the solvent was removed under high vacuum and the 
 resulting crude solid was dissolved in thf ( 0.5 ml ) .
filtration through 
 a celite pad followed by slow evaporation of the solvent gave the 
 copper complex as a dark blue microcrystalline powder ( 12 mg , 2.9 
 mol , 52% ) .
crystals for x - ray diffraction analysis and elemental 
 analysis were grown in et2o / n - hexane mixtures . 
 hrms - maldi ( m / z ) : [ m + h ] calcd for [ c22h17n3o2cu ] , 418.0617 ; found , 418.0611 .
vis ( meoh ) max (  ) : 586 nm ( 18  200 mc 
 m ) .
calcd for c44h37n6o4cun - hexaneet2o2h2o : c , 62.70 ; h , 6.04 ; n , 8.13% . found : 
 c , 62.80 ; h , 5.92 ; n , 7.87% .
data 
 were collected at the university of arizona x - ray diffraction facility . 

crystals were mounted onto a mitegen micromount under a protective 
 film of paratone oil , and diffraction data for both crystals were 
 measured using a bruker kappa apex ii duo diffractometer with graphite - monochromated 
 mo k radiation (  = 0.71073  ) generated by a sealed 
 tube and an apex ii ccd area detector .
the diffractometer was fitted 
 with an oxford cryostream low - temperature device , and the data sets 
 were collected using the apex2 software package .
experimental 
 details of the structure determinations are given in table s1 ( see supporting information ) .
all structures were 
 solved by direct methods ( shelxs-97 ) , and developed by full least - squares 
 refinement based on f ( shelxl ) .
data were collected , solved , and refined 
 in the triclinic space group p1 .
the asymmetric 
 unit contains one full complex molecule with no other significant 
 peaks in the fourier map .
all non - hydrogen atoms were located in the 
 fourier map and refined anisotropically , whereas all hydrogen atoms 
 were placed in calculated positions and refined using a riding model . 

the highest residual fourier peak is 0.7 e  , located 1.0  from zn(1 ) , and the deepest fourier 
 hole is 0.45 e  , located 0.93  from zn(1 ) . although multiple crystallizations were attempted 
 under different conditions , the best single crystals obtained for 
 this complex diffracted significantly only to 2max = 40 and presented substantial solvent disorder , which further 
 complicated the analysis
. data were collected , solved , and refined 
 in the monoclinic space group p21/c .
the asymmetric unit contains one full complex molecule 
 and a solvent channel running parallel to ( 100 ) filled with electron 
 density that refined reasonably as three partially occupied oxygen 
 atoms of a water molecule ( labeled o(3a ) , o(3b ) , and o(3c ) ) .
two of 
 these were modeled with molar occupancies of 20% and one with 15% . 

alternative solvent molecules of crystallization were tentatively 
 fitted in this solvent channel but failed to offer a stable refinement 
 possibly because of the low observed data / parameter ratio ( 6.8 ) .
carbon atom c(10 ) was refined with a 
 rigid bond restraint because this atom continually refined as nonpositive 
 definite without restraints .
all hydrogen atoms were placed in calculated 
 positions and refined using a riding model . a squeeze analysis of a model containing only the complex molecule identified 330  of total void space , equivalent to 16.3% of the unit cell 
 volume .
these voids contained 73 electrons per unit cell , or approximately 
 18 per asymmetric unit .
this could equate approximately to one molecule 
 of hexane ( 50 electrons each ) and one - half molecule of diethyl ether 
 ( 42 electrons each ) or seven molecules of water ( 10 electrons each ) 
 per unit cell , or a combination of all three with partial molar occupancies . 

because only three partially occupied molecules of water could be 
 positively identified in the fourier map , a formula of complex1.8(h2o ) was used for the density and f(000 ) 
 calculations .
the highest residual fourier peak of 0.9 e a is located within the solvent accessible void , 
 and the deepest residual fourier hole of 0.5 e a is located 1.1  from n(3 ) . the x - band ( 9 ghz )
cw epr 
 experiments were performed at room temperature and 77 k using a bruker 
 e500 ( elexsys ) spectrometer .
the pulsed epr measurements were performed 
 on a ka - band ( 2640 ghz ) pulsed 
 epr spectrometer at 15 k. in order to 
 establish the relative number of copper - bound nitrogen ligands in 
 cu(pd1 ) , ka - band pulsed ( davies ) endor 
 spectroscopy was used . here
, we briefly describe the endor spectra 
 expected for n ligands in cu(ii ) complexes under our 
 experimental conditions .
the n transition lines in such 
 spectra are located at the frequencies1where an is the diagonal part of the n hfi ( predominantly isotropic ) , n  3 mhz is the n zeeman frequency in 
 the applied magnetic field , b0
 
 1 t , and qn is the diagonal part of the n nqi : qn  
 0.9 mhz for the pyrrole n at g. for the nitrogen 
 ligands in cu(ii ) complexes , an is on 
 the order of tens of megahertz .
therefore , under our experimental 
 conditions , the relationship between the various terms in eq 1 is an/2 > n > qn . without the nqi , the endor pattern for the n nucleus would 
 consist of two lines centered at  = an/2 , with the splitting between them equal to 2n  6 mhz .
the nqi will split each 
 of these lines into a doublet , with the splitting equal to 2qn ( 1.8 mhz at g ) .
however , a broadening of the individual lines caused 
 by even an insignificant degree of structural disorder can result 
 in a partial or complete loss of the quadrupolar splitting and observation 
 of only two broader lines for each n nucleus at the frequencies 
  = an/2  n .
such a situation is observed in the spectrum of cu(pd1 ) ( figure 5 ) . in order to make the davies endor response 
 independent of the hfi constants of the detected 
 nuclei
, one has to ensure that the amplitudes of the mw pulses were 
 much smaller than that of the hfi constants while 
 keeping the spin flip angles close to optimal (  for the preparation 
 ( inversion ) pulse and /2 and  for the two - pulse detection 
 sequence ) .
the hfi constants 
 of n ligands in cu(ii ) complexes are on the order of 
 tens of megahertz and therefore this requirement is easily satisfied 
 for mw pulses with durations 100 ns ( the mw amplitude 5 
 mhz ) . because of the strong hfi and non - negligible 
 nuclear quadrupole interaction ( nqi ) , the probabilities 
 of transitions of nonequivalent n nuclei , and even different 
 transitions of the same n nucleus , induced by the rf 
 field are expected to be noticeably different . therefore ,
to approximately 
 equalize the contributions of different nitrogens to the endor spectrum , 
 a 2d experiment was performed , with one dimension being the radiofrequency , 
 and the other being the rf pulse duration .
the 2d data set was then 
 integrated over the rf pulse duration to obtain the 1d endor spectrum 
 with the relative intensities of the n lines reflecting 
 relative numbers of nuclei rather then relative transition probabilities . 

the 2d endor data set ( from which the 1d spectrum in figure 5 was obtained ) is shown in figure s8 ( supporting information ) .
 the 
 pyrrolyldipyrrin motif is found in several naturally occurring prodigiosin 
 pigments . 
 the potential roles of the interactions of prodigiosins 
 with transition metals and the properties of metal - bound pyrrolyldipyrrins , 
 however , have been difficult to assess because of the very limited 
 number of well - characterized stable complexes . here , we show that 
 the introduction of a meso - aryl substituent and an 
 ethyl ester group during the sequential assembly of the three heterocycles 
 affords a pyrrolyldipyrrin of enhanced coordinating abilities when 
 compared to that of natural prodigiosins . 
 uv  
 visible absorption 
 studies indicate that this ligand promptly binds zn(ii ) ions with 
 2:1 ligand - to - metal stoichiometry and cu(ii ) ions with 1:1 stoichiometry . 
 
 notably , no addition of base is required for the formation of the 
 resulting stable complexes . 
 the crystal structures reveal that whereas 
 the tetrahedral zinc center engages two nitrogen donors on each ligand , 
 the pseudosquare planar copper complex features coordination of all 
 three pyrrolic nitrogen atoms and employs the ester group as a neutral 
 ligand . 
 this first example of coordination of a redox - active transition 
 metal within a fully conjugated pyrrolyldipyrrin framework was investigated 
 spectroscopically by electron paramagnetic resonance to show that 
 the 1:1 metal - to - ligand ratio found in the crystal structure is also 
 maintained in solution . 
Introduction
Results and Discussion
Conclusions
Experimental Section