Evaluation of Octaethyl-7,17-dioxobacteriochlorin as a Ligand for Transition Metals

David Schnable, Nivedita Chaudhri, Ruoshi Li, Matthias Zeller, and Christian Bruckner *

Article

Evaluation of Octaethyl-7,17-dioxobacteriochlorin as a Ligand for

Transition Metals

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sı Supporting Information

ABSTRACT: The propensity of octaethyl-7,17-dioxobacteriochlorin toward the

formation of transition metal complexes was evaluated. A variety of M ions (M =

Co, Ni, Cu, Zn, Pd, Ag, and Cd) and Fe(III) could be inserted using standard

methodologies or, more often, using more forcing conditions. The stable products

were spectroscopically characterized. The solid-state structures of the Ni(II),

Cu(II), Pd(II), and Ag(II) complexes could also be determined by single crystal X-

ray diﬀractometry, whereby the [7,17-dioxobacteriochlorinato] chromophore was

found to be largely planar in all cases. The rate of Zn(II) insertion into octaethyl-

,17-dioxobacteriochlorin was less than half that into the corresponding 7-oxochlorin, which itself was about half the rate into the

parent octaethylporphyrin. These rate diﬀerences reﬂect the relative decreased basicity of the β-oxo-substituted chromophores and

possibly also their decreased conformational ﬂexibility. We compare the basicity of the dioxobacteriochlorin to that of a range of

related products of varying reduction state (porphyrin, chlorin, bacteriochlorin), an isomer, and the absence or presence of oxo-

functionality, like oxochlorin, chlorin, oxobacteriochlorins, and bacteriochlorin, quantifying the eﬀects of these macrocycle

modiﬁcations. The work rationalizes earlier reports of the inability of tolyporphin A, a natural product possessing a 7,17-

dioxobacteriochlorin chromophore, to form metal complexes and provide a more quantitative understanding of the degree of

modulation that β-oxo groups have on the coordination properties of porphyrinoids.

INTRODUCTION

Tolyporphins are a family of tetrapyrroles isolated from the

cyanobacterium Tolypothrix nodosa.

,17-dioxobacteriochlorin chromophore carrying also C-glyco-

side moieties at their β-positions.

well-studied member of this class is tolyporphin A (1).

that detoxiﬁes cells by exporting hundreds of chemically

unrelated toxins out of cells, thereby lowering their intracellular

concentrations. Finding drugs that reverse this signiﬁcant

limitation of cancer chemotherapies is important.

■

−4

They share a unique

−8

The tolyporphins, however, also exhibit signiﬁcant cytotox-

icity, limiting their therapeutic potential as MDR reversal

drugs. Furthermore, it is also known that tolyporphins are

eﬀective photosensitizers; like many tetrapyrrolic pigments,

upon irradiation with visible light and in the presence of triplet

The most prevalent and

oxygen ( O ) they produce toxic singlet oxygen ( O ).

Therefore, to more conveniently utilize tolyporphins as

potential pharmaceuticals to reverse MDR, at least their

phototoxicity must be reduced. Prinsep et al. hypothesized that

the insertion of a metal ion into the dioxobacteriochlorin core

may reduce its (photo)cytotoxicity; after all, certain metal

ions switch oﬀ the ability of a photosensitizer to generate

singlet oxygen. The authors thus reported the preparation of

the Ag(II) and Cu(II) complexes of tolyporphins. These

complexes showed considerably lower cytotoxicity. Alas, they

were also less potent in reversing MDR.

In general, tetrapyrrolic macrocycles are excellent metal

chelators for a wide range of metal ions. Thus, it was

Received: November 4, 2019

Tolyporphin A eﬀectively reverses multidrug resistance

(

MDR) of cancer cells. MDR describes the phenomenon

that cells can become resistant to many chemotherapeutics by

an overexpression of a transmembrane P-glycoprotein pump

XXXX American Chemical Society

Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry

Article

Scheme 1. Synthetic Pathway

Synthesis of octaethyl-7,17-dioxobacteriochlorin 2, together with 7-oxochlorin 3 and 7,18-dioxobacteriochlorin 8 from octaethylporphyrin 4,

51,57

formation of the metal complexes 2M, reduction of 7-oxochlorin 3 and dioxobacteriochlorin 2, and dihydroxylation of octaethylporphyrin 4.

Numbering system used shown in compound 4.

surprising that Prinsep et al. reported that, besides the Cu(II)

and Ag(II) complexes of 1, no other metal complexes could be

prepared. Using stoichiometric excess of the metal salts MgCl₂·

The assumption that the 7,17-dioxobacteriochlorin is

deactivated toward the chelation of metal ions is likely because

of two eﬀects. First, bacteriochlorins are much less basic than

H O, VO(SO ), FeCl ·4H O (in air), CoCl ·6H O (in air),

the corresponding chlorins or porphyrins. Compared to the

Ni(NO ) ·6H O, ZnSO ·7H O (the Zn(II) complex was

broadly investigated coordination properties of porphyrins,

those of the bacteriochlorins have been studied to a much

observed under the conditions of ESI+ MS), Na [PdCl ] or

14−16

Pd(NO ) , Cd(ClO ) , and Pb(NO ) , all in MeOH

lesser degree.

Second, the basicity of the two imine

3 2

containing NEt at reﬂux temperature (65−70 °C) over 20−

nitrogens in the framework is expected to be further reduced

by the presence of the β-oxo-functionalities.

0 min did not form the expected complexes. Regular

porphyrins, however, would have been expected to have

A wide range of β-oxo-porphyrins or β-oxo-hydroporphyrins

(excluding here β,β′-dioxo-porphyrins and their secochlorin

inserted at least some of the metal ions. The inability to form

the metal complexes might have its origins in an intrinsic

inhibition of the 7,17-dioxobacteriochlorin framework toward

metal insertion, requiring the use of more forcing conditions.

Even if this was not stated, we suspect the thermal instability of

tolyporphin A made this approach impossible.

17−19

analogues)

has become available, either through manip-

,20−23

ulations of porphyrins or total syntheses.

The strong

electronic inﬂuences of the β-oxo-auxochrome were described

3−27

(in oxoporphyrins as well as porpholactones).

The

28,31

8,29

zinc(II),

iron(III),

nickel(II),

copper(II),

Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry

Article

palladium(II), and platinum(II) complexes of 7-oxochlorin

3) were reported. 7,12-Dioxoisobacteriochlorin iron(III)

typical chlorin UV−vis spectrum, β-hydroxyoxobacteriochlorin

6 possesses a red-shifted chlorin-type spectrum, whereas β-

dihydroxybacteriochlorin 7 exhibits a typical bacteriochlorin

spectrum (see SI). Lastly, we included another regular chlorin

(

complexes are found as prosthetic groups in nature and

were utilized in the study of the metal complexes of 7,12-

dioxoisobacteriochlorin model systems aimed at the under-

in this investigation, known vic-dihydroxychlorin 9, prepared

33−41

51,57

standing of the role of the oxo-substituted chromophore.

by OsO -mediated dihydroxylation of porphyrin 4.

Comparably less is known about the coordination properties of

the isomeric 7,17-dioxobacteriochlorin system. Nonetheless, in

addition to the tolyporphin A copper(II) and silver(II)

Metal Insertions. The insertion of metal ions into

porphyrinic compounds is typically accomplished by heating

a solution of the porphyrin and a metal salt in a (coordinating)

42,43

complexes the nickel(II), copper(II),

palladium(II),

solvent. The reaction may require the presence of an

and platinum(II) complexes of octaethyl-7,17-dioxobacterio-

chlorin 2 were formed and characterized. No explicit reference

to an assessment of any diﬃculties to insert the metal ions was

made in any of the reports. The group of Lindsey evaluated the

conditions for the insertion of metals into a wider range of

additional base (or basic solvent). Alternative mechanochem-

58,59

ical methods have emerged for some metal ions.

Generally,

the rate-limiting steps of the metal insertion are determined by

the considerable kinetic barrier of the planar and relatively

rigid porphyrin to distort from planarity to present the imine-

type nitrogen atoms to the metal ions in solution, the basicity

of the ligand nitrogen atoms, and the intrinsic kinetic lability of

bacteriochlorins, including β-oxo-derivatives. Other 7,17-

dioxobacteriochlorin complexes were formed as a consequence

of the synthetic strategy chosen to assemble the macrocycle.

the metal ion to be inserted. The sum of these factors

We thus set out to characterize the chelation properties of

the 7,17-dioxo-8,18-bis-gem-dialkylbacteriochlorin chromo-

phore of the tolyporphins in a more systematic fashion. For

this purpose, we chose the model compound octaethyl-7,17-

dioxobacteriochlorin 2 for its accessibility and predicted

determines the solvent/reaction temperature needed for the

metal insertion reaction to be successful.

The results of the metal insertion reactions to generate the

Fe(III), Co(II), Ni(II), Cu(II), Zn(II), Pd(II), Ag(II), and

Cd(II) complexes 2M are presented in Scheme 1. The

conditions were derived from a screen of a range of organic

and mineral bases. The often modest yields are the result of the

small-scale reaction and their workup, including crystalliza-

tions; only under the harshest conditions was some minor

degree of ligand decomposition observed. Remarkably, the

reaction conditions to aﬀect eﬃcient metal insertion are in

thermal stability. We assessed in a qualitative fashion its

coordination ability by comparison of the conditions needed to

form a range of complexes with other porphyrinic macrocycles.

We compared its rate of insertion in comparison to that of the

corresponding 7-oxochlorin and porphyrin. We also deter-

mined the basicity of the dioxobacteriochlorin chromophore to

that of a range of related chromophores of varying reduction

state (porphyrin, chlorin, bacteriochlorin) and in the absence

or presence of oxo-functionalities. We will present evidence

that suggest that the 7,17-dioxobacteriochlorin macrocycle is

competent in forming a range of metal complexes but that they

require signiﬁcantly harsher conditions for their formation than

the corresponding complexes of the mono-oxochlorin,

bacteriochlorin, chlorin, or parent porphyrin. This can be

largely attributed to the much-reduced basicity of the 7,17-

dioxobacteriochlorin chromophore.

most cases harsher than the standard reaction conditions for

the insertion of the respective metal ion into regular

porphyrins. For instance, the insertion of zinc into porphyrins

under standard conditions (Zn(II) source in CHCl /MeOH at

∼

65 °C; no need for an extraneous base) failed to yield 2Zn.

Instead, hot pyridine (115 °C) or DMF (153 °C) in the

presence of lithium carbonate was required. Likewise,

expedient nickel insertion required PhCN (at 191 °C) instead

of hot pyridine or DMF. Others, like the insertion of Ag(II) by

disproportionation of an Ag(I) source, take place in the

customary solvent pyridine, albeit the yield of the reaction is

relatively low after 60 min and we found it necessary to degas

the solution to prevent a further reduction of yield by way of

decomposition of the ligand. Otherwise we note the thermal

stability of the dioxobacteriochlorin ligand, even at extended

times at elevated temperatures under oxic conditions. Other

metals were tested but failed to form complexes with 2 under

all conventional, thermal conditions tested, including V(IV)

RESULTS AND DISCUSSION

Preparation of 7-Oxochlorin and 7,17- and 7,18-

Dioxobacteriochlorins. Octaethyl-7,17-dioxobacteriochlorin

■

and octaethyl-7-oxochlorin 3, together with all other isomers

of the β-diketone series (such as 7,18-dioxobacteriochlorin 8),

were prepared by H O /H SO oxidation of multigram

quantities of octaethylporphyrin 4, as described by Inhoﬀen

8,46

and Nolte (Scheme 1).

The reaction itself can be traced

(as vanadyl, VO ), Cr(II), Sn(II), and Au(III). However,

47,48

back to the work of the groups of Fischer and Johnson.

Alternate syntheses are available.

some of those (kinetically inert) metals are also not readily

49−52

inserted into porphyrins.

Reduction Products of Dioxobacteriochlorin 2 and

Oxochlorin 3. To isolate the electronic eﬀect of the β-oxo

group(s) from the eﬀects of the degree of macrocycle

reduction (porphyrin, chlorin, bacteriochlorin), we prepared

three derivatives by hydride reduction of the carbonyl groups

in β-oxohydroporphyrins 2 and 3 (Scheme 1): known β-

UV−vis Spectroscopic Properties of the Metal

Complexes. The normalized UV−vis absorption spectra of

free base 2 and its metal complexes 2M are shown in Figure 1

(and tabulated in Table S1 ). Upon insertion of the metal ions

into free base 2, the UV−vis absorption spectra of 2M amplify

the split of the Soret bands already present in the free base.

The prominent single Q-band (and λ_m_a_xband) of the free base

is retained and, depending on the particular metal ion, at

essentially the same position (for 2Fe), slightly hypsochromi-

cally (for the 4d element complexes 2Cd, 2Ag, and 2Pd), or

bathochromically (for the 3d element complexes 2Co, 2Cu,

2Zn, and 2Ni) shifted. The other less prominent Q-bands of

the free base become even less so upon metalation.

28,51,53,54

hydroxyoctaethylchlorin 5,

and novel monoreduced

products β-hydroxyoxobacteriochlorin 6 and bis-reduced β-

dihydroxybacteriochlorin 7, respectively. Only the low polarity

isomer of the two possible stereoisomers of 7 was utilized. The

spectroscopic properties of the alcohols 6 and 7 are equivalent

5,56

to those of related derivatives

and support their

connectivity (see SI for details). Hydroxychlorin 5 shows a

Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry

inserting metals into it. Others have argued on the basis of

Article

electrochemical experiments that the oxo-groups increase the

ﬂexibility of the macrocycle. For all four complexes, the

displacement of the metal from the N plane is found to be less

than 0.01 Å. This necessitates increased in-plane “stretching”

of the macrocycle to accommodate larger metal ions within the

ring. This is observed by the generally increasing diagonal N −

N distances as the size of the metal ion increases (e.g., from

.107(2) to 4.263(4) Å for 2Cu and 2Ag, respectively).

Relative Metal Insertion Rates. To provide a more

quantitative measure of the generally perceived slower metal

ion insertion rates for dioxobacteriochlorin 2, we directly

compared its zinc(II) insertion rate with that for oxochlorin 3

8,29

(

forming 3Zn)

and the parent octaethylporphyrin 4

forming 4Zn) using identical metal ion insertion conditions

Figure 3 ). Evidently, the multistep metathesis reactions are

Figure 1. Stacked normalized UV−vis spectra (CH Cl ) of free-base

and its metal complexes 2M indicated. A vertical dotted line at 677

nm (λ_m_a_xof 2) serves as a reference line. See Supporting Information

for full-scale spectra.

Crystallographic Analysis. XRD-quality single crystals

could be grown for the Cu(II), Ni(II), Ag(II), and Pd(II)

complexes of octaethyl-7,17-dioxobacteriochlorin 2 (Figure 2;

for details, see SI ). All of the structures were found to be

Figure 3. Relative rates of zinc insertion into porphyrin 4, oxochlorin

, and dioxobacteriochlorin 2 under identical reaction conditions

−4

(

starting concentrations: [X] = 8.8 × 10 M, [Zn(OAc) ] = 4.4 ×

almost perfectly planar, possessing Δ₂RMS value of

−3

M (5.00 equiv); combined in 10.0 mL DMF with 15.0 mg

signiﬁcantly less than 0.1 Å with the largest deviation observed,

Li CO , 154 °C). The lines of best ﬁt are higher order polynomial

as expected, for the complex with the smallest ion, 2Ni. A

survey of crystal structures of 4M deposited at the CCDC

reveals that the complexes of 2 tend toward more planar

conformations, that is, exhibiting smaller Δ₂₄values when

compared to most complexes of 4 with the same metal ion.

functions. The horizontal markers at 0.45 M, the 50% conversion

point, indicate the points at which the slope was determined; error

bars indicate standard error.

complex as we could not ﬁt the reaction kinetics to simple rate

The Δ values for some 4Ni complexes are larger (0.46 or

laws. Thus, for the purpose of this comparison the slope of

.30 ) than that for 2Ni (0.075), though more planar

the best-ﬁt function at the point where the product

concentration [XZn] reaches the half-conversion point

(0.445 mM) was determined. In this manner, the relative

rates are measured to be 7.53, 14.6, and 56.5 μM/min for 2, 3,

and 4 , respectively. Thus, relative to the rate of the fastest

polymorphs are also known (0.03). Overall, this may suggest

a larger stiﬀness of the 7,17-dioxobacteriochlorin chromophore

and may contribute to the markedly increased diﬃculty of

Figure 2. Stick representation of the X-ray single-crystal structures of the metal complexes 2M indicated. The arrow in the top view indicates the

direction of the side view below. Δ = RMSD of all macrocycle C and N atoms from the mean plane deﬁned by them. For experimental details, see

SI .

Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry

Article

−

−5

Figure 4. UV−vis titration of octaethylporphyrin 4 (7.18 × 10 M), 7-oxochlorin 3 (1.82 × 10 M), 7,17-dioxochlorin 2 (2.12 × 10 M), its

−

−5

isomer 7,18-dioxochlorin 8 (1.41 × 10 M), 7-hydroxychlorin 5 (1.52 × 10 M), 7-hydroxy-17-oxobacteriochlorin 6 (4.23 × 10 M), 7,17-

dihydroxybacteriochlorin 7 (5.88 × 10⁻M), and 7,8-dihydroxychlorin 9 (1.83 × 10 M) (all in CH Cl ) with TFA in the [TFA] range indicated.

−5

Insets show a best ﬁt Hill plot. Color ﬁelds show the color of the porphyrinoids before and after the addition of TFA. For further details, see SI .

ligand porphyrin 4 (set to 1), oxochlorin 3 is about four times

slower and dioxobacteriochlorin 2 is about another factor of 2

slower (for a total of 7.5-fold relative to the rate for 4).

UV−vis Titrations. To quantitatively determine the

diﬀerences in basicity of the oxohydroporphyrins versus

porphyrins and the corresponding hydroporphyrins, we

performed UV−vis titrations with triﬂuoroacetic acid (TFA)

and base (tetrabutylammonium hydroxide, TBAOH). Next to

the three species porphyrin 4, oxochlorin 3, and dioxobacterio-

chlorin 2, we also included hydroxychlorin 5, hydroxyox-

obacteriochlorin 6, dihydroxybacteriochlorin 7, and 2,3-

51,57

dihydroxychlorin 9.

This allows us to distinguish between

the eﬀects of the oxo-functionalities and the intrinsic change of

basicity of the various reduction states of the chromophore

3,65

(plus the alcohol functionality).

Lastly, we also included

7,18-dioxobacteriochlorin 8, an isomer of the 7,17-

dioxobacteriochlorin 2, as a test for the inﬂuence of the

relative positions of the two β-oxo-functionalities.

Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry

groups drastically decreases the basicity of the chromophore

Article

All compounds showed strong halochromic responses upon

addition of TFA (Figure 4). Across the series, the colors of the

compounds (free base as well as protonated) and, correspond-

ingly, their general UV−vis spectra, vary widely. Generalized,

however, the changes follow the established patterns for many

porphyrinoids: Upon protonation, the free base Soret bands

give way to new, often hypsochromically shifted bands, and the

number of Q-bands is reduced, simplifying the overall

appearance of the spectra; the new λ_m_a_xband is frequently

red-shifted.

over 3 orders of magnitude (comparing basicity of 4 to that of

3 and 2/8). Inversely, stepwise reduction of the β-oxo

functionalities in the bacteriochlorin (2 to 6 to 7) and chlorin

series (3 to 5) increases the basicity signiﬁcantly, whereby the

removal of one of two oxo-groups has less of an eﬀect than the

removal of the second. The basicities of the dioxobacterio-

chlorin regioisomers 2 and 8 vary slightly from each other,

reﬂecting their electronic diﬀerences, a circumstance also

observed and rationalized in the meso-aryldilactone re-

27,70−72

gioisomers.

Bacteriochlorins are, as expected, less

The titration curves of some porphyrinoids (like porphyrin 4

or chlorin 5) show clear isosbestic points and the

corresponding Hill plots are linear and show positive

cooperativity, indicating one-step protonation (by two

protons), as observed for regular porphyrins and chlorins

basic than the porphyrins and chlorins but we ﬁnd against

expectations the β-hydroxychlorins 5 and 9 to be slightly more

basic than the corresponding porphyrin 4. We attribute this to

the eﬀects of the electron-rich benzylic alcohol functionalities.

None of the compounds described above showed any major

halochromic response upon addition of base (TBAOH in

CH Cl ), even at large stoichiometric excess (see SI). At most,

(

with the ﬁrst protonation constant lower than the

6−68

second).

monoprotonated.

Select chlorins are also known that can be

65,69

On the other hand, all β-oxo-function-

minor changes (like in 9) may be attributable to an onset of

the deprotonation of an alcohol moiety. Thus, the NH

functionalities of the dioxobacteriochlorins neither possess a

alized derivatives show no isosbestic points and convoluted

Hill plots, indicative of complex protonation behavior

involving multiple binding sites; for diketone isomer 2, the

complex, multistage protonation behavior was noted pre-

particularly strong acidity (as corroles, for example, exhibit),

nor are the β-oxo functionalities accessible to nucleophilic

attack under the conditions tested (as the β-oxo functions of

some meso-pentaﬂuorophenyl-substituted porpholactones

viously. Whether diprotonation is always achieved also

remains unclear. Likewise, the IR spectra of oxochlorin 3

and dioxobacteriochlorin 2 in the presence of TFA were

inconclusive as to whether oxo-protonation is taking place.

74−77

are).

Thus, no pK values were derived. Nonetheless, we took the

CONCLUSIONS

■

absolute [TFA] concentrations at half the end point value of

[TFA]

In conclusion, the metal ions Fe(III), Co(II), Ni(II), Cu(II),

Zn(II), Cd(II), Ag(II), and Pd(II) can be inserted into

octaethyl-7,17-dioxobacteriochlorin 2 to form the correspond-

ing complexes 2M. The single crystal X-ray structures of 2Cu,

the titration of the porphyrinoids with acid (

/₂value) as a

suitable metric to compare their relative basicities.

_T_h_e[TFA]

/₂value ranks the porphyrinoids investigated in the

order of decreasing amount of [TFA] needed for half-

protonation, that is, increasing order of basicity: dioxobacterio-

Ni, 2Pd, and 2Ag prove the complexes to be essentially

−

planar. Arguably, they are slightly more planar than the

corresponding oxochlorin or porphyrin complexes, suggestive

of a larger conformational rigidity of the dioxobacteriochlorin

chromophore. The zinc(II) insertion kinetics for dioxobacter-

iochlorin isomer 2 is ∼4-fold slower than the corresponding

reaction for oxochlorin 3, and ∼7.5-fold slower compared to

the rate observed for octaethylporphyrin 4. The slow kinetics

necessitate the use of more forceful reaction conditions than

traditionally employed for the metal insertion to be completed

within a few hours of reaction time. The basicity of the inner

nitrogen atoms, ranked in the order of dioxobacteriochlorins <

hydroxyoxobacteriochlorin ≪ dihydroxybacteriochlorin <

oxochlorin < porphyrin < hydroxychlorin ∼ dihydroxychlorin,

spanning a range 3 orders of magnitude, may be primarily

responsible for the slow reaction kinetics of the metal insertion

reaction, while the inferred increased rigidity of the

dioxobacteriochlorin framework may add to this. Our ﬁndings

rationalize why Prinsep et al. could not form a number of metal

complexes of tolyporphin A 1 under the relatively mild

conditions tested.

chlorin 2 (4.27 × 10 M) < dioxobacteriochlorin 8 (3.42 ×

−

−2

M) < hydroxyoxobacteriochlorin 6 (1.02 × 10 M) <

−

dihydroxybacteriochlorin 7 (4.27 × 10 M) < oxochlorin 3

−4

−5

(

1.02 × 10 M) < octaethylporphyrin 4 (6.14 × 10 M) <

−

hydroxychlorin 5 (2.14 × 10 M) < dihydroxychlorin 9 (1.36

−

10 M) (Figure 5). Thus, increase of the number of β-oxo

On the other hand, the retardation of the metal insertion

rate by the β-oxo-functionalities in, for example, 7,17-

dioxobacteriochlorin 2, are somewhat contradicting ﬁndings

by Lindsey and co-workers that found that electron-with-

drawing substituents helped in the metal insertion into

bacteriochlorins, albeit the eﬀects of β-oxo-functionalities

were not tested. This suggests that β-oxo-functionalities may

have more profound electronic and conformational eﬀects on

the macrocycle than many other substituents, and their large

eﬀect on the macrocycle electronic structure supports this.

Figure 5. Bar graph of the ^[^T^F^A^]/₂values determined for the

compounds indicated (cf. to Figure 4).

Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry

Article

Multiple examples of β-oxo- and β-dioxohydroporphyrins

have become known in recent years and the unique

auxochromic eﬀects of the β-oxo-functionality have become

under a stream of dry N

by column chromatography (silica-25% hexanes/CH Cl ). Recrystal-

lization by precipitation from DMF/water provided the nickel

overnight. The crude material was puriﬁed

−

,20−23,26

complex 2Ni in 84% yield (9.6 mg, 1.5 × 10 mol): MW = 622.3

to be understood.

Some of the free base compounds,

g/mol; R = 0.45 (silica-25% hexanes/CH Cl ). UV−vis (CH Cl )

or their metal complexes, were described to possess useful

(log ε): 370 (3.51), 419 (3.75), 699 (3.92) nm. HR-MS (ESI+,

24,28,44,78,79

max

optical or electrochemical properties.

This study

00% CH CN, TOF): m/z calc’d for C H N O Ni, 622.2812 (for

3 36 44 4 2

lays the basis for the further investigation of the metal

complexes of other β-oxoporphyrinoids for which, by

extension, we assume the same retarded metal insertion

kinetics to be operational.

M ); found, 622.2805.

Octaethyl-7,17-dioxobacteriochlorinato]cobalt(II) (2Co).

[

−

Free base dioxobacteriochlorin 2 (10.1 mg, 1.8 × 10 mol),

−

Co(NO

) ·6H O (31.2 mg, 1.1 × 10 mol, 6.0 equiv) and 15.7 mg

3 2 2

Li CO were combined in DMF (10 mL) and heated to reﬂux for 3.5

h. The solution was cooled to rt and then slowly diluted with DI water

(∼75 mL). The precipitate formed was isolated using microﬁltration.

Recrystallization by solvent exchange from CH Cl /hexanes provided

EXPERIMENTAL SECTION

■

Instruments. ¹H NMR and ¹³C NMR spectra were recorded

−

using Bruker AVANCE III 400 and 500 MHz spectrometers from

2Co as green crystals in 91% yield (10.1 mg, 1.6 × 10 mol): MW =

solutions in CDCl . UV/vis spectra were obtained using Varian Cary

623.3 g/mol; R_f= 0.38 (silica-25% hexanes/CH Cl ). UV−vis

0 or 100 Bio spectrometers in the solvents indicated. IR spectra were

(CH Cl ) λ

(log ε): 378 (4.37), 420 (4.70), 697 (4.86) nm.

max

recorded from neat material on a Bruker Alpha FTIR spectrometer

using an attenuated total reﬂection (ATR) diamond crystal. Low- and

HR-MS (ESI+, 100% CH CN, TOF): m/z calc’d for C H N O Co,

623.2796 (for M ); found, 623.2761.

3 36 44 4 2

high-resolution SI spectra were recorded from CH CN solutions

[Octaethyl-7,17-dioxobacteriochlorinato]iron(III) Chloride

−

(

∼10 M) using AB Sciex API 2000 Triple Quadrupole and AB Sciex

(2FeCl). 2FeCl was prepared by combining free base dioxobacterio-

−

QStar Elite Quadrupole-TOF MS instruments, respectively.

Materials. 7-Oxochlorin 3, 7,17-dioxobacteriochlorin 2, and 7,18-

dioxobacteriochlorin 8 were prepared by H O /H SO oxidation of

octaethylporphyrin 4, as described in the literature. Known

hydroxychlorin 5 was, in a variation to literature procedures,

chlorin 2 (9.6 mg, 1.7 × 10 mol) and FeCl ·6H O (29.0 mg, 9.9 ×

3 2

−

10 mol, 5.8 equiv) in acetic acid (10 mL) and heated to reﬂux for

40 min. The solution was chilled in an ice bath, poured onto crushed

ice (∼15 g), mixed with brine (10 mL), and then extracted with

CH Cl (∼30 mL). The organic layer was isolated, washed with 0.5 M

13,53

prepared by LiAlH reduction of 7-oxochlorin 3 (a procedure and

aq HCl, dried over anhydrous Na SO , then reduced to dryness using

2 4

complete data are included for comparison). Chlorin diol 9 was also

rotary evaporation. Recrystallization by solvent exchange from

51,57

prepared as described.

All other materials were analytical grade

CH Cl /hexanes provided green crystals of 2FeCl in 70% yield (7.7

−

from commercial sources and were used as received. Silica gel 60

aluminum-backed 250 μm analytical TLC plates, silica gel 60 glass-

backed 250 μm analytical TLC plates, 500 μm or 1 mm silica gel 60

on glass 20 × 20 cm preparative TLC plates, Brockmann I (50−200

μm) basic alumina, and ﬂash column silica gel (premium grade, 60 Å,

mg, 1.2 × 10 mol): MW = 655.3 g/mol; R = 0.05 (silica-0.5%

MeOH/CH Cl ). UV−vis (CH Cl ) λ (log ε): 377 (3.36), 411

max

(3.51), 675 (3.16) nm. HR-MS (ESI+, 100% CH CN, TOF): m/z

calc’d for C H N O Fe, 620.2814 (for M ); found, 620.2834.

[Octaethyl-7,17-dioxobacteriochlorinato]cadmium(II)

0−75 μm) were provided by Sorbent Technologies, Atlanta, GA.

(2Cd). 2Cd was prepared by combining free base dioxobacterio-

−

−5

[

Octaethyl-7,17-dioxobacteriochlorinato]zinc(II) (2Zn). Free

chlorin 2 (9.8 mg, 1.7 × 10 mol), CdCl

2 2

·H O (20.3 mg, 8.9 × 10

−

base dioxobacteriochlorin 2 (11.6 mg, 2.0 × 10 mol), ZnCl ·H O

mol, 5.1 equiv), and Li CO (15.6 mg) in DMF (10 mL) and heating

(

12.2 mg, 8.9 × 10⁻mol, 4.5 equiv), and 18 mg Li CO were

to reﬂux for 5 h. The solution was then cooled to rt and then slowly

diluted with DI water (∼75 mL). The precipitate formed was isolated

using microﬁltration. Recrystallization by solvent exchange from

dissolved in DMF (10 mL) and heated to reﬂux for 3.5 h. The

solution was cooled to rt and then slowly diluted with DI water (∼75

mL). The precipitate formed was isolated by microﬁltration.

Recrystallization by solvent exchange from CH Cl /hexanes provided

mg, 1.6 × 10 mol). MW = 676.2 g/mol; R

hexanes/CH Cl ). UV−vis (CH Cl ) λmax (log ε): 402 (3.50), 413

(3.50), 672 (3.35) nm. HR-MS (ESI+, 100% CH CN, TOF): m/z

calc’d for C H N O Cd, 678.2498 (for M ); found, 678.2538.

Cl /hexanes provided 2Cd as green crystals in 91% yield (10.7

−

= 0.20 (silica-25%

−

green microcrystals in 96% yield (12.4 mg, 2.0 × 10 mol): MW =

28.3 g/mol; R = 0.10 (silica- 25% hexanes/CH Cl ). H NMR (500

MHz, CDCl , 25 °C): δ 9.54 (s, 1H), 8.88 (s, 1H), 3.87−3.80 (m,

36 44

H), 2.69−2.65 (q, J = 7.4 Hz, 8H), 1.79−1.74 (m, 6H), 0.42 (t, J =

[Octaethyl-7,17-dioxobacteriochlorinato]silver(II) (2Ag).

.4 Hz, 6H). ¹³C NMR (125 MHz, CDCl , 25 °C): δ 209.5, 158.2,

−5

Free base dioxobacteriochlorin 2 (10.6 mg, 1.9 × 10 mol) and

−

48.5, 147.1, 143.0, 142.2, 141.4, 95.1, 94.9, 60.2, 31.7, 19.53, 19.34,

Ag(OAc) (6.4 mg, 3.8 × 10 mol, 2.0 equiv) were dissolved in

8.39, 18.23, 8.4 ppm. UV−vis (CH Cl ) λ (log ε): 382 (4.69),

deoxygenated pyridine (8 mL) and heated under N to reﬂux for 1 h.

max

07 (4.88), 691 (4.97) nm. HR-MS (ESI+, 100% CH CN, TOF): m/

The solution was then cooled to rt, diluted with CH Cl , and washed

z calc’d for C H N O Zn, 628.2750 (for M ); found, 628.2789.

twice with equal volumes of DI water. The organic fraction was

isolated and reduced to dryness by rotary evaporation. The crude

material was puriﬁed by column chromatography (silica-50%

hexanes/CH Cl ). Recrystallization from CH Cl /hexanes provided

[

Octaethyl-7,17-dioxobacteriochlorinato]copper(II) (2Cu).

−

Free base dioxobacteriochlorin 2 (9.7 mg, 1.71 × 10 mol) and

Cu(OAc) (16.2 mg, 9.2 × 10 mol, 5.4 equiv) were dissolved in

−

DMF (10 mL) and heated to reﬂux for 30 min. The solution was

cooled to room temperature and then diluted with DI water (∼75

mL) followed by microﬁltration. Recrystallization from CH Cl /

2Ag in 52% yield (6.5 mg, 9.6 × 10 mol): MW = 672.6 g/mol; R =

0.50 (silica-25% hexanes/CH Cl ). UV−vis (CH Cl ) λ (log ε):

max

391 (4.27), 411 (4.15), 435 (4.42), 673 (4.42) nm. HR-MS (ESI+,

hexanes provided the product as green crystals in 83% yield (8.8 mg,

100% CH CN, TOF): m/z calc’d for C H N O Ag, 671.2515 (for

36 44

.4 × 10⁻mol): MW = 627.3 g/mol; R = 0.37 (silica-25% hexanes/

M ); found, 671.2560.

CH Cl ). UV−vis (CH Cl ) λ (log ε): 385 (4.65), 428 (5.01), 705

4.87) nm. HR-MS (ESI+, 100% CH CN, TOF): m/z calc’d for

C H N O Cu, 627.2755 (for M ); found, 627.2805.

[Octaethyl-7,17-dioxobacteriochlorinato]palladium(II)

max

(

(2Pd). 2Pd was prepared from free base 7,17-dioxobacteriochlorin 2

−5

(10.4 mg, 1.8 × 10 mol) and PdCl ·6H O (17.4 mg, 1.8 × 10

2 2

[

Octaethyl-7,17-dioxobacteriochlorinato]nickel(II) (2Ni).

mol, 5.4 equiv) in benzonitrile (10 mL) heated to reﬂux for 1h. The

−

Free base dioxobacteriochlorin 2 (10.4 mg, 1.8 × 10 mol) and

solution was cooled to rt, diluted with CH Cl , and washed twice with

−

Ni(OAc) ·4H O (22.0 mg, 8.8 × 10 mol, 4.8 equiv) were dissolved

equal volumes of DI water, then the organic fraction was isolated,

dried over Na SO , and reduced by rotary evaporation, followed by

in benzonitrile (10 mL) and heated to reﬂux for 5 h. The solution was

cooled to rt, diluted with CH Cl , and twice washed with equal

drying under a stream of dry N overnight. The crude material was

volume of DI water. The organic fraction was isolated and dried over

Na SO , then reduced by rotary evaporation, followed by drying

puriﬁed by column chromatography (silica-25% hexanes/CH Cl ).

Recrystallization by precipitation from DMF/water provided 2Pd in

Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry

Article

1% yield (8.7 mg, 1.3 × 10⁻mol). MW = 670.3 g/mol; R = 0.67

Cryosystems low-temperature device. Examination and data collection

were performed with Cu Kα radiation (λ = 1.54178 Å) at 150 K. Data

were collected, reﬂections were indexed and processed, and the ﬁles

were scaled and corrected for absorption using APEX3 and SADABS

or TWINABS. The space groups were assigned and the structures

were solved by direct methods using XPREP within the SHELXTL

(

silica-CH Cl ). H NMR (500 MHz; CDCl ): δ 9.65 (s, 2H), 8.94

s, 2H), 3.87−3.79 (m, 8H), 2.72 (qd, J = 13.4, 7.3 Hz, 8H), 1.80 (dt,

J = 15.3, 7.6 Hz, 12H), 0.47 (t, J = 7.4 Hz, 12H). UV−vis (CH Cl )

max

(log ε): 366 (3.79), 402 (4.15), 668 (4.16) nm. HR-MS (ESI+,

00% CH CN, TOF): m/z calc’d for C H N O Pd, 670.2499 (for

3 36 44 4 2

M ); found, 670.2517.

Octaethyl-7-hydroxychlorin (5). 7-Oxochlorin 4 (50 mg, 9.07 ×

suite of programs and reﬁned by full matrix least-squares against F

with all reﬂections using Shelxl2016 using the graphical interface

ShelXle; for details, including on the software, see Supporting

Information .

−

mol) was dissolved in dry THF (2 mL). To this, a suspension of

−

LiAlH (10 mg, 2.7 × 10 mol, 3 equiv) in THF (1.5 mL) was added

at 0 °C under N and stirred for 5 min. The reaction mixture was

All four structures are isomorphic with close to identical molecular

conformations, unit cell shapes, and symmetry and packing

interactions. The structures are pseudo-B centered with a pseudo-

translation along the a−c diagonal. Exact translational symmetry is

quenched by slurrying with Glauber’s salt (Na SO ·10H O, about 1.5

g) and the resulting mixture was ﬁltered through a pad of Celite, and

the pad was washed with CH Cl . The combined ﬁltrates were

reduced by rotatory evaporation. The crude solid was dissolved in a

broken by a slight modulation of the two gem-C(Et) units, preventing

minimum amount of CH Cl and puriﬁed by column chromatography

an exact ﬁt of a larger volume C-centered monoclinic structure. The b

and c axes in the four structures are close in length, and the order of

the two axes is swapped between the structures, thus resulting in

diﬀerent standard settings for the four isomorphic structures. Each of

the two structures have the same standard setting: 2Ag and 2Cu, and

2Pd and 2Ni. The latter two were also found to be twinned by

identical twin operations based on the emulated monoclinic symmetry

(see Supporting Information for details on twinning).

(

silica, 100% CH Cl , followed by 2% acetone in CH Cl ) to provide

−

the product in 91% yield (46 mg, 8.32 × 10 mol). Data for the

known compound are included for comparison. MW = 552.8 g/mol;

R = 0.19 (silica-CH Cl ). H NMR (300 MHz, CDCl ): δ 9.78 (d, J

3.3 Hz, 2H), 9.20 (s, 1H), 8.79 (s, 1H), 6.53 (s, 1H), 4.07−3.87

(

m, 12H), 2.71 (s, 1H), 2.61−2.51 (m, 3H), 2.35−2.25 (m, 1H),

.89−1.79 (m, 18H), 0.97 (t, J = 7.2 Hz, 3H), 0.74 (t, J = 7.2 Hz,

H), 2.55 (s, 2H). UV−vis (CH Cl ) λ (log ε): 390 (5.02), 493

If not speciﬁed otherwise, H atoms attached to carbon atoms were

positioned geometrically and constrained to ride on their parent

atoms with carbon hydrogen bond distances of 0.95 Å for aromatic

CH, and 0.99 and 0.98 Å for aliphatic CH and CH moieties,

max

(3.85), 521 (3.25), 588 (3.31), 611 (3.26), 642 (4.38). HR-MS (ESI

, 100% CH CN, TOF): m/z calc’d for C H N O, 553.3901 (for

3 36 48 4

MH ); found, 553.3936.

Octaethyl-7-hydroxy-17-oxobacteriochlorin (6). A solution of

octaethyl-7,17-dioxobacteriochlorin 2 (50 mg, 8.82 × 10 mol) in

THF (3 mL) was stirred under N on an ice bath. NaBH (17 mg, 4.4

respectively. Methyl H atoms were allowed to rotate but not to tip to

−5

best ﬁt the experimental electron density. U (H) values were set to a

iso

multiple of U (C) with 1.5 for CH , and 1.2 for CH units,

−

10 mol, 5 equiv) was added (at 0 °C) and the reaction mixture

respectively.

was stirred for 24 h at ambient temperature. Then CH Cl (20 mL)

Complete crystallographic data in CIF format have been deposited

with the Cambridge Crystallographic Data Centre. CCDC 1955054−

1955057 contain the supplementary crystallographic data for this

paper. These data can be obtained free of charge from The

Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/

data_request/cif.

was added and the mixture was washed with a sat’d aq solution of

NH Cl. The organic layer was separated, dried over anhydrous

Na SO , and ﬁltered. The ﬁltrate was reduced to dryness using

rotatory evaporation. The residue was puriﬁed by silica-gel column

chromatography (silica, CH Cl ) to yield 6 in 78% (39 mg, 6.86 ×

−

mol) yield. MW = 568.8 g/mol; R = 0.33 (silica-CH Cl ). H

Kinetic Comparison. A series of parallel reactions were

conducted for porphyrin 4, oxochlorin 3, and dioxobacteriochlorin

NMR (400 MHz; CDCl ): 9.60 (s, 1H), 9.05 (s, 1H), 8.82 (s, 1H),

−

.67 (s, 1H), 6.40 (s, 1H), 3.95−3.84 (m, 8H), 2.64 (q, J = 7.3 Hz,

H), 2.57−2.44 (m, 3H), 2.26 (dt, J = 14.8, 7.4 Hz, 1H), 1.81−1.73

2 to compare their relative metal-insertion reaction rates: 8.86 × 10

mol of 2 (5.0 mg), 3 (4.9 mg), and 4 (4.7 mg), as well as 5.0 equiv.

Zn(OAc) ·2H O (4.41 × 10 mol, 9.7 mg) and Li CO (15.0 mg)

2 2 2 3

−

1.4, 7.4 Hz, 6H), −2.10 (s, 1H), −2.22 (s, 1H). UV−vis (CH Cl )

were combined in 25 mL three-necked round-bottom ﬂasks equipped

with a reﬂux condenser and stir bar. These three ﬂasks were then all

secured in the same oil bath. DMF (10 mL) was added

simultaneously to all and the mixtures were set stirring and heated

to reﬂux. Once reﬂuxing, aliquots of ∼10 μL were periodically

withdrawn and added to a small vial preloaded with 1.0 mL of HPLC-

grade CH Cl . The frequency of withdrawal was chosen such that 10

max

(log ε): 392 (4.84), 414 (4.91), 497 (3.83), 532 (3.10), 632

(

3.59), 660 (3.70), 693 (4.65). HR-MS (ESI+, 100% CH CN, TOF):

m/z calc’d for C H N O , 568.3777 (for M ); found, 568.3747.

,17-Dihydroxybacteriochlorin (7). Prepared in 48% yield (24

−

mg, 4.2 × 10 mol) from octaethyl-7,17-dioxobacteriochlorin 2 (50

mg, 8.82 × 10⁻mol) and LiAlH (17 mg, 4.4 × 10 mol, 5 equiv) as

−5

described for the preparation of 7-hydroxychlorin 5. MW = 570.8 g/

mol; R = 0.29 (silica-CH Cl ). H NMR (400 MHz; DMSO-d ):

samples were interspersed throughout the total reaction time. The

vials were then capped, inverted to mix, and placed on dry ice until all

of the samples were collected.

.00 (s, 2H), 8.62 (s, 2H), 6.41 (d, J = 5.7 Hz, 2H), 6.27 (d, J = 5.5

Hz, 2H), 3.87−3.76 (m, 8H), 2.44−2.38 (m, 6H), 2.09 (dt, J = 16.5,

.3 Hz, 2H), 1.73−1.65 (m, 12H), 0.90 (t, J = 6.1 Hz, 6H), 0.54 (t, J

6.0 Hz, 6H), −2.54 (s, 2H). UV−vis (CH Cl ) λ (log ε): 350

Once the reaction was complete, the samples were diluted to 3.0

mL with CH Cl and a UV−vis spectrum of this solution was

recorded. Then, each solution was spiked three times successively

with a small (4−10 μL) recorded volume of conc. solutions (∼0.8

mM) of pure starting material, collecting a full UV−vis spectrum

between each. Using the same solution, the same procedure was

carried out using a concentrated solution of pure product, for a total

of seven collected spectra per sample.

max

(4.72), 375 (4.79), 464 (3.56), 496 (3.96), 713 (4.42). HR-MS (ESI

, 100% CH CN, TOF): m/z calc’d for C H N O , 570.3934 (for

36 50

M ); found, 570.3893.

Crystallography. Crystals were grown of 2Ni, 2Cu, 2Pd, and 2Ag

by slow vapor diﬀusion of hexanes into a concentrated solution of the

species dissolved in CH Cl . Single crystal data for 2Pd were collected

Data analysis consisted of constructing two successive-standard-

addition plots, one for the starting material and one for the product.

Single wavelengths were selected, one corresponding to either species.

on a Bruker Quest diﬀractometer with a ﬁxed χ-angle, a sealed tube

ﬁne focus X-ray tube, single crystal curved graphite incident beam

monochromator, a Photon100 CMOS area detector and an Oxford

Cryosystems low temperature device. Examination and data collection

were performed with Mo Kα radiation (λ = 0.71073 Å) at 150 K.

Single crystal data for 2Ag, 2Ni, and 2Cu were collected on a Bruker

Quest diﬀractometer with κ-geometry, an I-μ-S microsource X-ray

tube, laterally graded multilayer (Goebel) mirror single crystal for

monochromatization, a Photon2 CMOS area detector and an Oxford

The generated plots were checked to ensure a linear response (r

value of greater than 0.998). In this plot, the x-intercept is taken to be

the absolute value of the concentration of the analyte in the original

solution. In this manner, the concentration of both materials was

determined in the sample. This value was tracked back through the

dilution procedure in order to determine the concentration of each in

the reaction mixture at the time of withdrawal.

Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry

Smith, C. D. Tolyporphin, a novel multidrug resistance reversing

Article

UV−visible Titrations. These were performed using a Varian

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Funding

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