Progress towards synthetic chlorins with graded polarity, conjugatable substituents, and wavelength tunability

Journal of Porphyrins and Phthalocyanines

J. Porphyrins Phthalocyanines 2015; 19: 1–26

DOI: 10.1142/S1088424615500042

Published at http://www.worldscinet.com/jpp/

Progress towards synthetic chlorins with graded polarity,

conjugatable substituents, and wavelength tunability

Doyoung Ra^a, Kelly A. Gauger^a, Kannan Muthukumaran^a,

Thiagarajan Balasubramanian^a, Vanampally Chandrashaker^a,

Masahiko Taniguchi^a, ZhanqianYu^b, Daniel C.Talley^b, Melanie Ehudin^b,

Marcin Ptaszek*^band Jonathan S. Lindsey*^a◊

^aDepartment of Chemistry, North Carolina State University, Raleigh, NC 27695-8204, USA

^bDepartment of Chemistry and Biochemistry, University of Maryland, Baltimore County,

Baltimore, Maryland 21250, USA

Received 14 October 2014

Accepted 19 November 2014

ABSTRACT: Advances in chlorin synthetic chemistry now enable the de novo preparation of diverse

chlorin-containing molecular architectures. Five distinct molecular designs have been explored here,

including hydrophobic bioconjugatable (oxo)chlorins; a hydrophilic bioconjugatable chlorin; a trans-

ethynyl/iodochlorin building block; a set of chlorins bearing electron-rich (methoxy, dimethylamino,

methylthio) groups at the 3-position; and a set of ten 3,13-disubstituted chlorins chieﬂy bearing groups

with extended p-moieties. Altogether 23 new chlorins (17 targets, 6 intermediates) have been prepared.

The challenge associated with molecular designs that encompass the combination of “hydrophilic,

bioconjugatable and wavelength-tunable” chieﬂy resides in the nature of the hydrophilic unit.

KEYWORDS: auxochrome, artiﬁcial photosynthesis, chlorophyll, hydroporphyrin, hydrophilic,

photomedicine

Two distinct methods for gaining access to chlorin

macrocycles entail semisynthesis, where naturally

INTRODUCTION

The central role of chlorophylls in plant photosynthesis

occurring tetrapyrroles (e.g. heme, chlorophylls, bacterio-

hasmotivatedstudiesofvastscopeconcerningtheinterplay

chlorophylls) provide the initial starting material [1–4],

of molecular structure, supramolecular chemistry, optical

and de novo synthesis, where the macrocycle is created

spectra, photochemical properties, and electronic structure

from relatively simple, acyclic starting materials [5–7].

in this family of macrocycles. Synthetic chemistry has

Semisynthesis has the advantage of abundant feedstocks

played a very strong supporting role in such studies by

making available diverse chlorins that are not accessible via

biosynthetic pathways. Studies in artiﬁcial photosynthesis

but the disadvantage of a full complement of b-pyrrolic

substituents, which can limit synthetic maneuverability.

De novo syntheses have the advantage of a tabula rasa

provide both a direct biomimetic mirror for natural

thereby enabling — at least in principle — full synthetic

photosynthesis and also enable fundamental studies of

control over all substituents, but the disadvantage of a

excited-state energy- and electron-transfer processes that

considerable amount of synthetic work to construct and

are not possible with the natural systems.

derivatize the chlorin macrocycle.

An offshoot of synthetic studies in chlorin chemistry

has entailed the preparation of chlorins for use in

photomedicine, which encompasses diagnostics, imaging

^◊SPP full member in good standing

and therapeutics. Our research groups have been engaged

in the de novo synthesis of chlorins. In Raleigh, we have

been working to develop methods for the preparation

*Correspondence to: Jonathan S. Lindsey, email: jlindsey@

ncsu.edu, fax: +1 919-513-2830; Marcin Ptaszek, email:

mptaszek@umbc.edu

2

D. RA ET AL.

of chlorins for diverse photochemical studies [8–22].

In Baltimore, we have been working to design and

synthesize chlorins for use in photomedicine, particularly

laser-guided surgery [23–28]. A common challenge in

all such studies is the ability to: (1) control molecular

polarity, (2) dial-in the position of the long-wavelength

absorption band (which determines the maximum

energy for photochemical processes emanating from the

excited singlet state), and (3) install one or more reactive

functional groups for attachment to other moieties such

as proteins, surfaces, or other molecular entities.

of a chlorin bearing two reactive aryl functional groups

attached to opposing b-pyrrole rings; and (III) the

synthesis and spectral properties of diverse 3-substituted

or 3,13-disubstituted chlorins. Studies of functional

properties of the chlorins are beyond the scope of the

present article. Taken together, this work provides an

overview of the rich capabilities of chlorin synthetic

chemistry, and provides milestones concerning versatility

of molecular design of chromophores with red-region

spectral features.

In this paper, we describe the synthesis of a collection

of chlorins for use in diverse studies. The paper is

divided into three sections. The sections encompass:

(I) the synthesis of lipophilic or hydrophilic chlorins that

bear a single (bio)conjugatable group; (II) the synthesis

RESULTS AND DISCUSSION

The methodology employed herein for preparing

chlorins is outlined in Scheme 1. Chlorin formation entails

the convergent joining of an Eastern half and a Western

Scheme 1. Synthetic methods employed herein

J. Porphyrins Phthalocyanines 2015; 19: 2–26

PROGRESS TOWARDS SYNTHETIC CHLORINS WITH GRADED POLARITY, CONJUGATABLE SUBSTITUENTS

3

half under acid-catalyzed condensation followed by

metal-mediated oxidative cyclization [8, 10]. The Eastern

half is a dipyrromethane bearing an a-bromo atom and

an a-carbinol or carboxaldehyde; the linear tetrapyrrole

derived from the former is a tetrahydrobilene-a whereas

the latter is a tetrahydrobiladiene-ab. The Western half is

a tetrahydrodipyrrin that contains the geminal-dimethyl-

substituted pyrroline ring [29]. The resulting zinc

chlorin can be modiﬁed in a number of ways, including

conversion to the 17-oxochlorin [11], derivatization

at the 15-position [12, 14], alteration of the various

pyrrolic substituents [13, 15, 17], de/remetalation, and

various combinations of such approaches. By use of

these and other approaches, access to each peripheral

position of the chlorin macrocycle is now available [22].

Complementary routes to analogous chlorins have been

developed by the groups of Battersby [30, 31], Jacobi

[32–36] and Montforts [37–44].

I. Bioconjugatable chlorins

Lipophilic (bio)conjugatable chlorins. The synthesis

of a lipophilic chlorin bearing a single bioconjugatable

group can be achieved by incorporation of the latter in

protected form as a substituent on one of the meso-aryl

units. A key design issue is that the bioconjugatable motif

must be able to survive the conditions for formation

of the Eastern half and conversion to the chlorin. Two

examples are shown here, which include a phenol and an

arylcarboxylic acid as bioconjugatable groups.

The synthesis of an oxochlorin-phenol is shown in

Scheme 2. The synthesis of the Eastern half begins with

Scheme 2. Synthesis of an oxochlorin-phenol

J. Porphyrins Phthalocyanines 2015; 19: 3–26

4

D. RA ET AL.

dipyrromethane 1 [45–47], which contains the protected

phenol. Treatment of 1 with EtMgBr at room temperature

for 10 min followed by Mukaiyama reagent 2 [48] at -78°C

for 20 min gave the 1-acyldipyrromethane 3 in crude form.

The latter was complexed with 9-borabicyclo[3.3.1]nonyl

triﬂuoromethanesulfonate (9-BBN-OTf) in the presence of

triethylamine (TEA) to afford the complex 4 in 73% yield

(two steps from 1). Such 1-acyldipyrromethane-boron com-

plexes are more readily handled and derivatized given the

masking of the a-acylpyrrole motif [48, 49]. Bromination

of 4using N-bromosuccinimide (NBS) following a standard

procedure [48] afforded 5 in 77% yield. Compound 5 was

used directly for the chlorin-forming reaction without

decomplexation of the dialkylboron moiety. Thus, treatment

of 5 with NaBH₄gave the 1-bromodipyrromethane-

monocarbinol (5–OH, not shown) as the Eastern half.

The crude Eastern half was combined with Western half 6

[10] and subjected to two-step chlorin-forming conditions

[10] to afford the zinc chlorin ZnC-1 in 36% yield. The

ZnC-1 was converted to zinc oxochlorin ZnC-2 following

a standard procedure [11]. Reaction of ZnC-2 with BBr₃

in CH₂Cl₂at room temperature [50] followed by treatment

with Zn(OAc)₂·2H₂O afforded the zinc oxochlorin-phenol

ZnC-3.

The synthesis of a chlorin-carboxylic acid followed

the same synthetic approach. The resulting chlorin-

ester (ZnC-4) [10] was treated with KF to cleave the

trimethylsilylethyl unit under relatively mild conditions,

thereby affording the chlorin-carboxylic acid ZnC-5

(Scheme 3). It warrants mention that both the oxochlorin-

phenol and the chlorin-carboxylic acid are amphiphilic

given the presence of the polar bioconjugatable group

attachedtothelipophilicchlorin.Assuch,bothcompounds

if not bioconjugated are expected to assemble at an

aqueous-surfactant interface (e.g. micelle, lipid bilayer

membrane, liposome) thereby representing an additional

application for studies with such chlorins. In this regard,

Jacobi and Ehrenberg have studied the membrane depth

penetration of members of a set of amphiphilic chlorins

that bear alkanoic chains of a range of lengths [36].

Hydrophilic bioconjugatable chlorins. A general

challenge in tetrapyrrole chemistry concerns appropriate

molecular designs to impart high solubility in either

organic or aqueous solution. The core unsaturated,

unsubstituted tetrapyrrole skeleton, porphine, is hideously

insoluble. The solubility increases upon “bulking up” the

tetrapyrrole framework with substituents that suppress

aggregation phenomena. Examples include b-alkyl (e.g.

octaethylporphyrin), meso-aryl (e.g. meso-tetraphenyl-

porphyrin), and meso-swallowtail (i.e. symmetrically

branched alkyl [51]) substituents for solubilization in

organicmedia.meso-Arylunitsthatbearortho-substituents

(e.g. methyl, ethyl, benzyloxy) provide increased

solubility in organic media vs. that of the unsubstituted

phenyl unit [52]. The ortho-substituents project above and

below the plane of the macrocycle (Fig. 1). An extension

of this approach of “facial encumbrance” has afforded

solubilization of porphyrins and chlorins [19] in aqueous

media. Thus, 2,6-disubstituted aryl groups or swallowtail

substituents with terminal polar groups (e.g. phosphate,

phosphonate) have been found to impart water solubility

of synthetic chlorins, as shown for the chlorins C-6 and

C-7 shown in Fig. 1 [19].

Our ﬁrst approach to a hydrophilic bioconjugatable

chlorin focused on a molecular architecture that (1) repre-

sented a hybrid of the meso-aryl and swallowtail motifs,

(2) incorporated a carboxylic acid for bioconjugation,

Fig. 1. Facial encumbrance to achieve increased solubility

of porphyrins in organic media (top) [51, 52]. Extension of

the approach for solubilization of chlorins in aqueous media

(bottom) [19]

Scheme 3. Synthesis of a chlorin-carboxylic acid

J. Porphyrins Phthalocyanines 2015; 19: 4–26

PROGRESS TOWARDS SYNTHETIC CHLORINS WITH GRADED POLARITY, CONJUGATABLE SUBSTITUENTS

5

Scheme 4. Synthesis of candidate snap-on units for water

solubilization and bioconjugatability

and (3) could be incorporated to the chlorin macrocycle

via Suzuki coupling. Precedence in considering this route

include phenol alkylation with diethyl chloromethyl-

phosphonate[53]aswellasSuzukicouplingwithhindered

aryl units [54] (including 2,6-dialkoxyaryl halides with

aryl boronic acids [55]), albeit under forcing conditions.

Thus, the commercially available methyl 4-bromo-

3,5-dihydroxybenzoate (I) was alkylated [19, 56] with

TfOCH₂PO(OEt)₂(II) [57] to give methyl 4-bromo-

3,5-bis(diethylphosphonomethoxy)benzoate (7) in 92%

yield (Scheme 4). Compound 7 is a potential snap-on

motif that bears the requisite facially encumbering

phosphonate groups and the bioconjugatable carboxylate

Scheme 5. Attempted snap-on of tri-substituted aryl motif for

solubilization and conjugation

pinacol) to the 15-position of the chlorin was investigated

but found non-advantageous vs. incorporation of the

2,6-dimethoxyaryl unit via the dipyrromethane in the

Eastern half synthesis. The failure to incorporate the

snap-on motif prompted return to an established route

wherein the facially encumbering diphosphonate group

is installed via the use of the Eastern half.

Chlorin C-13 is readily prepared and contains a

2,6-dimethoxyphenyl unit at the 10-position; cleavage

of the methyl ethers reveals the diphenol, which is

alkylated with II [19]. In the present work, the resulting

2,6-bis(diethylphosphonomethoxy)phenylchlorin C-14

was further manipulated to install a bioconjugatable

handle. Bromination [14, 17] of C-14 led to the 15-bromo-

10-arylchlorin C-15 in 96% yield. Suzuki coupling of

C-15 with boronic ester IV under standard conditions

employed for porphyrins [61, 62], chlorins [12] and

bacteriochlorins [63] led to the formation of chlorin C-16

unit. A homolog of 7 containing a longer alkyl spacer

between the alkoxyarene and the phosphonate moiety

also was prepared by alkylation of I with diethyl

3-bromopropylphosphonate (III) to give 8. Attempts

to convert synthon 7 or 8 to the boronate derivative,

however, were unsuccessful.

The chlorin examined for pilot studies, C-8 [17],

smoothly underwent bromination at the 15-position

to give C-9 [17] followed by Pd-mediated borylation

[58] with pinacolborane to give chlorin-boronate C-10

(Scheme 5). On the other hand, Pd-mediated coupling

of C-10 with the 2,6-dialkoxyaryl bromide (7 or 8)

proceeded quite poorly. The product in each case (C11

or C12) was suggested by a molecular ion peak upon

ESI-MSanalysis, butthetracequantitythwartedisolation.

Alternatively, attachment of 4,4,5,5-tetramethyl-2-(2,6-

dimethoxyphenyl)-1,3,2-dioxaborolane [59, 60] (derived

here from 2,6-dimethoxyphenyl boronic acid and

J. Porphyrins Phthalocyanines 2015; 19: 5–26

6

D. RA ET AL.

remaining 29 protons were identiﬁed. The characteristic

chlorin absorption spectrum and accurate (negative ion)

mass spectrum support a provisional assignment of the

target compound. In summary, this approach offers a

rational route to a chlorin bearing a facially encumbering

bis(phosphonate) group and a single bioconjugatable

group.

II. b-disubstituted chlorin building block

Chlorins bearing two orthogonal functional groups

enable successive derivatization. Two such functional

groups at diametrically opposed positions are particularly

attractive for the construction of linear multipigment

arrays that function as energy-transfer cascades or hole-

hopping relays.We have found that the extent of electronic

communication between porphyrins of a given electronic

composition depends on the site of attachment of a linker

on the macrocycle [64]. The availability of chlorins with

diverse substitution patterns would enable study of such

electronic effects in chlorins, complementing our prior

studies with porphyrins. For the construction of linear

arrays, substitution at opposing b-pyrrole positions is

quite attractive.

We previously prepared several b-substituted chlorins

wherein each bears an ethyne group and a halogen atom

in diametrically substituted (2,12-; 3,13-) positions; the

chlorins include ZnC-18 [9], ZnC-19 [13], and ZnC-20

[65] (Chart 1). Here we present the synthesis of an analog

of ZnC-18 that contains a 3,5-di-tert-butylphenyl group

(rather than a p-tolyl group) at the 5-position to impart

increased solubility in organic solvents.While in principle

either the 2,12- or 3,13-positions can be employed, given

the bulk of the 3,5-di-tert-butylphenyl group at the

5-position, we chose the 2,12-positons for installation

Scheme 6. Hydrophilic bioconjugatable chlorin-carboxylic

acid

in 50% yield. Saponiﬁcation followed by deprotection of

the ethyl phosphonate groups led to the water-soluble

bioconjugatable chlorin C-17 as a green solid in excellent

1

yield (Scheme 6). The H NMR spectrum in CD₃OD

indicated exchange of 7 protons (two NH, one CO₂H, four

P–OH), as expected, but upon integration only 26 of the

Chart 1. Prior trans-disubstituted chlorin building blocks

J. Porphyrins Phthalocyanines 2015; 19: 6–26

PROGRESS TOWARDS SYNTHETIC CHLORINS WITH GRADED POLARITY, CONJUGATABLE SUBSTITUENTS

7

affords the 2-formyl-3-arylpyrrole and the 2-formyl-

4-arylpyrrole (due to substitution at either the a- or

a′-position), which must be separated and identiﬁed. Such

distinction can be difﬁcult by ¹H NMR spectroscopy [9].

Accurate identiﬁcation of the two products (or derivatives

therefrom along the later steps of the pathway) is essential

because the two patterns of substitution ultimately yield

chlorin building blocks with substitution at different

b-positions. Subsequent nitrovinyl condensation fol-

lowed by reduction gave the 2-(2-nitroethyl)pyrrole 9

(Scheme 7). Michael reaction with mesityl oxide (V)

gave the nitrohexanone (10), which upon treatment with

zinc/acetic acid gave the tetrahydrodipyrrin-N-oxide (11)

in 43% yield. The synthesis of the tetrahydrodipyrrin

target(s) has been described previously in concise form

[66], and 9 and V have been used previously to form the

dihydrodipyrrin Western half [9]; the presentation here

supplements the prior presentation with additional data

and context.

A single-crystal X-ray structure of 11 was obtained.

The structure determination was not required to conﬁrm

the substitution pattern (Fig. 2, Table 1), which was

established previously by the X-ray structure of the

2-(2-nitroethyl)pyrrole 9 [9]. On the other hand, X-ray

structure analysis of 11 adds to the very limited data

available for hydrodipyrrins (considerable data are

available for dipyrromethanes or dipyrrins, which lack

the pyrroline ring). To our knowledge, structural data con-

cerning hydrodipyrrins related to chlorin syntheses are

available only for three tetrahydrodipyrrin-dibutylboron

complexes[22],onedihydrodipyrrin[67],onedibutylboron

complex of a dihydrodipyrrin-dibutylboron complex [22],

and one nitrohexanone (a precursor for a dihydrodipyrrin

or tetrahydrodipyrrin) [67].

Scheme 7. Synthesis of b-substituted Western halves

of the iodo and ethynyl groups. The synthesis of such

trans-b-disubstituted chlorin building blocks requires the

availability of b-substituted Eastern and Western halves.

The synthesis also makes use of improved methods,

including the intermediacy of a tetrahydrodipyrrin as

the Western half (vs. the dihydrodipyrrin employed

previously).

Substituted Western halves. The b-arylpyrrole is

conveniently prepared via a van Leusen reaction. Formyl-

ation of the resulting b-(p-iodophenyl)pyrrole [9] typically

Fig. 2. ORTEP drawing of 11, a Western half precursor. The

ellipsoids are drawn at the 50% probability level

J. Porphyrins Phthalocyanines 2015; 19: 7–26

8

D. RA ET AL.

Table 1. Summary of crystal data for 11

counterpart. Thus, deoxygenation of N-oxide 11 yielded

the b-substituted tetrahydrodipyrrin Western half 12 in

38% yield (Scheme 7). Sonogashira coupling of 12 with

(trimethylsilyl)ethyne afforded the trimethylsilylethynyl

substituted Western half 13 in 76% yield.

Crystal data

Formula

C₁₈H₂₁IN₂O

408.28

Formula weight, g/mol

Substituted Eastern half. The synthesis of the

b-substitutedEasternhalfbeganinthesamemannerasour

prior synthesis of b-substituted dipyrromethanes [9, 68].

A tert-butoxycarbonyl (BOC)-protected dipyrromethane

(14) was obtained from 2-formyl-3-(4-iodophenyl)-

pyrrole through the protection of the pyrrolic nitrogen,

reduction of the aldehyde and condensation with pyrrole

(not shown) [9]. Treatment of the BOC-protected

dipyrromethane 14 with 3.0 equiv of EtMgBr in THF

followed by 3,5-di-tert-butylbenzoyl chloride afforded

themonoacyldipyrromethane15in45%yield(Scheme8).

Removal of the BOC group under standard conditions

[69] gave 16. Sonogashira coupling [70] of 16 with

trimethylsilylethyne afforded trimethylsilylethynyl-

dipyrromethane 17 in 82% yield. Reaction of 17 with

NBS at -78°C gave the corresponding monobromo-

monoacyldipyrromethane 18 in 72% yield. Compound 18

servesastheprecursortotheEasternhalfdipyrromethane-

monocarbinol 18-OH.

Crystal dimensions, mm

0.58 × 0.24 × 0.06

colorless plate

monoclinic

P 2₁/n

Crystal color and habit

Crystal system

Space group

Temperature, K

148

a, Å

13.9428 (9)

8.2765 (5)

15.1619 (11)

90.0

b, Å

c, Å

a, °

b, °

93.346 (8)

90.0

g, °

V, Å³

1746.66 (20)

4

Z

D_x, Mg.m^-3

1.553

l, Å, (MoKa)

m, cm^-1

0.71073

1.84

Chlorin formation. The chlorin-forming reaction was

carried out using a two-step procedure of acid-catalyzed

condensation followed by metal-mediated oxidative

cyclization. Thus, treatment of 18 with NaBH₄in methanol

gave the corresponding dipyrromethane-monocarbinol

(18-OH), which was used without extensive puriﬁcation

in the next step. The reaction of 12 and 18-OH employed

early conditions for metal-mediated oxidative cyclization

(using AgIO₃and piperidine, subsequently replaced with

AgOTf and 2,2,6,6-tetramethylpiperidine [10]), which

afforded chlorin ZnC-21 in 8% yield (Scheme 9). The

absorption spectrum was characteristic of a chlorin, with

a molar absorption coefﬁcient (log e = 4.86 at 629 nm)

in close accord with that of the p-tolylchlorin counterpart

ZnC-18 (log e = 4.90 at 629 nm) [13]. ¹H NMR

spectroscopy conﬁrmed the expected structure: (i) the

geminal dimethyl groups of ZnC-21 resonate as a singlet

at d 1.97 ppm, (ii) the CH₂in the pyrroline ring gives

rise to a singlet downﬁeld at d 4.51 ppm, (iii) the four

b-pyrrole protons resonate in the region of d 8.56–8.81

ppm, and (iv) the eight protons of the b-aryl rings resonate

in the region of d 7.82–8.14 ppm as two pairs of doublets.

In summary, the b-substituted Eastern and Western halves

enable the rational synthesis of a chlorin building block

with synthetic handles at diametrically opposed positions

at the perimeter of the macrocycle. Such a building block

should be quite valuable for the construction of model

systems in biomimetic or materials chemistry.

Data collection

No. of reﬂections measured

No. of unique reﬂections

No. of reﬂections with I > s(I)

3046

2671

25.00

q_max,°

Index range

-16 ≤ h ≤ 16

0 ≤ k ≤ 9

0 ≤ l ≤ 17

Reﬁnement

No. of reﬂections in least-squares

2670

199

No. of parameters in least-squares

R₁^a

wR₂^b

R₁(all data)^a

wR₂(all data)^b

GOF^c

0.033

0.043

0.033

0.043

1.54

Maximum shift/error

Dr_max, e.Å^-3

Dr_min, e.Å^-3

0.000

1.17

-1.54

b

2

^aR₁=S(|F_o|–|F_c|)/SF_owR₂=[S(w(F_o–F_c) )/S(wF_o)] ^cGOF=

½

,

2

[S(w( F_o– F_c) )/(no. of reﬂections-no. of parameters)]

Completion of the synthesis required deoxygenation

of the N-oxide 11. The prior route to a b-substituted dihy-

drodipyrrin Western half [9] was used herein with modiﬁ-

cation to obtain the b-substituted tetrahydrodipyrrin

III. Wavelength-tunable chlorins

A major ﬁnding from the preparation of chlorins

that bear diverse substituents is that the position of

J. Porphyrins Phthalocyanines 2015; 19: 8–26

PROGRESS TOWARDS SYNTHETIC CHLORINS WITH GRADED POLARITY, CONJUGATABLE SUBSTITUENTS

9

Scheme 9. Synthesis of a trans-disubstituted chlorin building

block

the long-wavelength absorption band can be tuned

across the 600–700 nm region. The chief method for

such tuning entails placement of auxochromes at the

3- and 13-positions [13]. The 3- and 13-positions

are both in a pyrrole ring that lies along the Q_yaxis,

with the 3-position distal and 13-position proximal

to the pyrroline ring. Auxochromes such as ethynyl,

phenylethynyl, ethoxycarbonyl, acetyl, or formyl at the

3- and/or 13-position result in a bathochromic shift of the

Q_yband as well as an increase in the intensity of the Q_y

band relative to that of the B-band. Such substituents are

regarded as electron-withdrawing groups. By contrast,

few studies have concerned the effects of electron-

donating groups on the chlorin spectral properties.

This lacuna prompted us to prepare three chlorins with

groups that are electron-donating by resonance (methoxy,

methylthio, and dimethylamino) in the 3-position

[71], which is described in the ﬁrst section below. In

the second section, we have prepared a collection of

3,13-disubstituted chlorins that bear aryl groups with

extended conjugation. The motivation for preparing

both classes of chlorins reﬂects the dual desires to gain a

deeper understanding of chlorin electronic/photophysical

properties and to understand how to design chlorins with

deep-red (or near-infrared) absorption and (preferably

intense) ﬂuorescent properties. Such chlorins could be

used as ﬂuorophores for in vivo bioimaging applications

(e.g. ﬂuorescence-guided surgery [23, 24]) or as the

energy donor in energy-transfer arrays for artiﬁcial

photosynthesis or in vivo multicolor bioimaging [18, 20,

Scheme 8. Synthesis of a b-substituted Eastern half precursor

25, 26].

J. Porphyrins Phthalocyanines 2015; 19: 9–26

10

D. RA ET AL.

Fig. 3. (a) Absorption spectra normalized at the B-band in

tolueneatroomtemperatureof(a)3-unsubstitutedchlorin,ZnC-

26, (b) 3-methoxychlorin, ZnC-25, (c) 3-methylthiochlorin,

ZnC-24, and (d) 3-(N,N-dimethylamino)chlorin, ZnC-23. (B)

Corresponding ﬂuorescence spectra upon excitation at the peak

of the B-band

Scheme 10. Synthesis of 3-substituted chlorins (top) and

benchmark chlorins (bottom)

0.57 mmol reactants gave 119 mg of the chlorin (34%)

as shown in Scheme 10. Palladium coupling of ZnC-22

and dimethylamine (10 equiv) with Pd(OAc)₂(40 mol%),

(tert-Bu)₃PHBF₄(40 mol%), and tert-BuONa (3 equiv) in

reﬂuxingtoluenefor48h[72]afforded3-(dimethylamino)

chlorin ZnC-23 in 49% yield. Palladium coupling of

3-substituted chlorins. The requisite 3-bromochlorin

building block has been prepared previously using

0.20 mmol reactants (Western half 19 [13] and Eastern

half 20 [13]), which afforded 45 mg of the chlorin ZnC-

22 (37%) [13]. The same synthesis carried out here at

Table 2. Absorption and ﬂuorescence spectral properties^a

Compound

l_B, nm

Dn_B, cm^-1b

l_Qy, nm

Dn_Qy, cm^-1b

I_B/I_Q

l_em, nm

ZnC-26

ZnC-25

ZnC-24

ZnC-23

405

404

410

0

-61

301

606

603

616

612

0

-82

268

162

4.2

4.3

3.0

2.5

609

606

621

617

^aIn toluene at room temperature. ^bSpectral shift vs. that of ZnC-26.

J. Porphyrins Phthalocyanines 2015; 19: 10–26

PROGRESS TOWARDS SYNTHETIC CHLORINS WITH GRADED POLARITY, CONJUGATABLE SUBSTITUENTS

11

ZnC-22 with sodium thiomethoxide under conditions

used for aryl thioether formation (20 mol% of Pd₂(dba)₃

and Xantphos in reﬂuxing xylenes) [73] afforded

3-methylthiochlorin ZnC-24 in 95% yield. Similarly,

palladium coupling of ZnC-22 with sodium methoxide

in the presence of 20 mol% of Pd₂(dba)₃and Xantphos

in reﬂuxing xylenes gave 3-methoxychlorin ZnC-25

in 16% yield. Attempts to mitigate the low yield of the

3-methoxychlorin ZnC-25, either by methoxylation

[74] of the tosyl-protected Western half 19-Ts [13] (not

shown here) or by use of modiﬁed Pd-mediated coupling

conditions (as used for the meso-position of a porphyrin)

[75] were ineffective [71].

The spectral properties of the zinc chlorins obtained in

toluene are listed in Table 2 and displayed in Fig. 3. The

absorption spectrum in each case is typical of a chlorin,

as is the ﬂuorescence emission spectrum, with a stronger

Q(0, 0) band and weaker Q(0, 1) band. The absorption

spectral properties of the three 3-substituted chlorins

(ZnC-23, ZnC-24, and ZnC-25) can be compared with

the benchmark zinc chlorin ZnC-26, which lacks a

3-substituent. The spectral shift of the B-band and the

Q_yband is listed for each compound. While the former is

more intense, the position of the latter is of greater interest

given that the Q_yband position sets an upper limit on the

energy of the excited singlet state, and consequently that

of the excited triplet stated derived therefrom. The Q_y

band spans the range from 603–616 nm along the series

of chlorins with 3-methoxy (ZnC-25), 3-unsubstituted

(benchmark ZnC-26), 3-(N,N-dimethylamino) (ZnC-

23), and 3-methylthio (ZnC-24) substituents. The Q_y

band of ZnC-25 is thus shifted hypsochromically with

respect to that of the unsubstituted chlorin ZnC-26. A

similar effect of the methoxy group has been noted with

bacteriochlorins [76]. In parallel with the progressive

bathochromic shift of the Q_yband position, the relative

intensity of the Q_yband also increased (i.e. I_B/I_Q

decreased from 4.3 to 2.5). The 603-nm absorption band

of the methoxychlorin (ZnC-25) is identical to that of the

corresponding zinc chlorin that lacks any substituents,

not even the 10-mesityl group (ZnC-27) [77]. We have

not determined the molar absorption coefﬁcient of

the various chlorins but instead rely on the I_B/I_Qratio

to indicate the relative intensity of long-wavelength

absorption, which can be reliably determined regardless

of sample quantity. For perspective, however, the molar

absorption coefﬁcient for each benchmark chlorin is

as follows [13]: ZnC-26, log e = 4.81 (606 nm) and

ZnC-27, log e = 4.84 (603 nm). The molar absorption

coefﬁcients of some 50 other gem-dimethyl substituted

chlorins also have been determined [8, 9, 11, 13, 14]. In

summary, the effects of the three substituents examined

here, methoxy, dimethylamino, and methylthio are rather

insubstantial in altering the position of the Q_yband. The

extent to which the little-changed spectra stem from

intrinsically weak interactions of such groups with the

four individual frontier molecular orbitals of the chlorin,

Chart 2. A prior 3,13-bis(phenylethynyl)chlorin

or stronger interactions that are muted by cancellation

of opposing effects (e.g. induction vs. resonance of the

substituent) will require in-depth experimental and

theoretical studies.

3,13-disubstituted chlorins. Phenylethynyl substitu-

ents, which effectively expand the conjugated system

of tetrapyrrolic macrocycles, are known to signiﬁcantly

alter the electronic and optical properties of porphyrins

[78], chlorins [15, 16], and bacteriochlorins [28, 79]. For

example, 3,13-bis(phenylethynyl)chlorin C-28 (Chart 2)

exhibits a signiﬁcant bathochromic shift of absorption and

emission (l_abs= 676 nm, l_em= 678 nm), and large increase

in ﬂuorescence quantum yield (F_f= 0.37, in toluene),

compared to the analogous chlorin (C-26, not shown here)

that lacks substituents at the 3,13-positions [18].

We aimed to determine whether a further bathochromic

shift in absorption and emission for chlorins could be

achieved by more elaborate substituents at the chlorin

3- and 13-positions. The synthesis makes use of the

3,13-dibromo-10-p-tolylchlorin (C-29) building block

(Scheme 11), which has been prepared following a

reported procedure [13, 21]. Thus, condensation of the

8-bromotetrahydrodipyrrin (19) [29] and 7,8-dibromo-1-

formyl-10-p-tolyldipyrromethane(21)[23]inthepresence

of p-toluenesulfonic acid monohydrate (p-TsOH·H₂O)

followed by oxidative cyclization (mediated by Zn(OAc)₂

in the presence of 2,2,6,6-tetramethylpiperidine, TMPi)

and demetalation (dilute triﬂuoroacetic acid (TFA) in

dichloromethane) afforded free base chlorin C-29 in

12% yield. The lower yield of C-29 compared to that

of analogous chlorins reported previously [13, 21] may

be due to the poor solubility of Eastern half 21 (and

presumably the resulting tetrahydrobiladiene) in the

reaction medium.

With the 3,13-dibromochlorin building block in hand,

we prepared a series of 3,13-diethynylchlorins to probe

the effect of several factors on the optical properties of

chlorins (Table 3). The members of the collection of

J. Porphyrins Phthalocyanines 2015; 19: 11–26

12

D. RA ET AL.

was a consequence of the presence of a small amount

1

of impurities visible in the aromatic region of the H

NMR spectrum. These impurities were most probably

unreacted starting 4-formylphenylethyne (or product of

its homocoupling reaction) and/or dibenzylideneacetone

(dba) remnants, the removal of which required two

additional column chromatography puriﬁcations. A

sample of C-32, puriﬁed by column chromatography,

contained a trace amount of blue-ﬂuorescent contaminant

(visible upon TLC analysis and in the ﬂuorescence

1

emission spectrum, but not in the H NMR spectrum).

This contaminant co-eluted with the product. Conversion

of C-32to the corresponding Zn(II) complex (by reaction

with Zn(OAc)₂·2H₂O in CHCl₃/MeOH) caused an increase

in polarity and thereby allowed separation from the blue-

ﬂuorescent contaminant; subsequent demetalation (using

dilute TFA in CH₂Cl₂) afforded a spectroscopically pure

sample. The 3,13-diethynylchlorin (C-40) was obtained

by deprotection of the corresponding TMS-ethynyl-

substituted parent chlorin (C-39) using K₂CO₃in MeOH/

THF. It is noteworthy that attempts to obtain C-40 by

deprotection of the corresponding TIPS-ethynyl species,

using TBAF in THF, led to decomposition of the chlorin.

1

All new chlorins were characterized by H NMR

spectroscopy, LD-MS or ESI-MS; selected chlorins

also were characterized by ¹³C NMR spectroscopy. The

characterization data are consistent with the expected

1

structures. In particular, each H NMR spectrum shows

two sets of resonances from the 3,13-substituents, as

expected given the presence of the geminal dimethyl

group at position 18 and the p-tolyl group at the

10-position.

Scheme 11. Synthesis of a 3,13-dibromochlorin building block

(top) and a chlorin benchmark (bottom)

Absorption and emission maxima of the chlorins in

toluene are listed in Table 4, and selected spectra are

displayed in Fig. 4. The benchmark lacking any b-pyrrole

substituents in this case is the 10-p-tolylchlorin (C-30).

Analysis of these data leads to the following conclusions:

(1) The position of the Q_yband of the ethynylchlorin

C-40 is bathochromically shifted by ~30 nm vs.

the unsubstituted benchmark chlorin C-30. (2) The

position of the Q_yband of the phenylethynylchlorin

C-31 is bathochromically shifted by ~10 nm vs. the

ethynylchlorin C-38 or C-40). (3) The further expansion

of the size of the p-conjugated substituent attached

to the terminus of the ethyne (phenanthryl, C-37) or

extension by addition of a second arylethynyl unit

(C-32, C-33) affords a rather minute bathochromic shift

(~5–6 nm) of the Q_yband compared to C-31. (4) The

largest bathochromic shift occurs with the electron-

withdrawing 4-formylphenylethynyl substituent (C-35),

though even in that case the shift is 8 nm and 9 nm for

absorption and emission, respectively. (5) Attachment

of the electron-donating 4-(N,N-dimethylamino)phenyl-

ethynyl substituent (C-36) results in the largest relative

Q_yabsorption intensity (I_B/I_Q= 1.2; log e = 5.0 at 679 nm,

which is comparable with log e = 4.90 at 675 nm for

a dyad containing a 3,13-bis(phenylethynyl)chlorin

diethynylchlorins differ in the nature of the substituents at

the ethynyl termini. One reference compound is a chlorin

with no 3,13-diethynyl substituents at all (C-30) [17]

whereas a second reference is a chlorin with 3,13-bis(2-

phenylethynyl) substituents (C-31). Among the ethynyl

substituents, the factors examined include the following:

length of the conjugated substituents (compounds C-32 and

C-33), presence of electron-withdrawing (C-33–C-35) or

electron-donating groups (C-36), size of the aromatic moiety

(C-37), and replacement of the aryl group with an alkyl

group (C-38), TMS group (C-39), or no substituent (C-40).

The installation of ethynyl substituents was achieved

via Sonogashira reaction of the corresponding ethynes

with C-29. Two sets of copper-free conditions, which were

previously reported for Sonogashira reaction of hydro-

porphyrins, have been followed: (A) (PPh₃)₂PdCl₂in DMF/

TEA [28] or (B) Pd₂(dba)₃and P(o-tol)₃in toluene/TEA

[13]. The requisite ethynes were obtained commercially,

or for the case of methyl 4-ethynylbenzoate [80],

4-ethynyl-1-(2-phenylethynyl)benzene [81], and methyl

4-[2-(4-ethynylphenyl)ethynyl]benzoate [82], prepared

as described in the literature. The yield ranged from

16–91% (Table 3). In the case of C-35, the low yield

J. Porphyrins Phthalocyanines 2015; 19: 12–26

PROGRESS TOWARDS SYNTHETIC CHLORINS WITH GRADED POLARITY, CONJUGATABLE SUBSTITUENTS

13

Table 3. Synthesis of 3,13-disubstituted chlorins

Entry

Conditions^a

A

Yield

91%

R

C-31

C-32

C-33

C-34

C-35

C-36

C-37

A

B

A

80%^b

42%

43%

16%

61%

27%

MeO₂C

OHC

N

C-38

A

88%

N

C-39

C-40

B

44%

79%

TMS

c

H

^aA: (PPh₃)₂PdCl₂, DMF/TEA (2:1), 80°C. B: Pd₂(dba)₃, PPh₃, toluene/TEA (5:1), 60°C.

^bThe synthetic product contained a trace amount of blue-ﬂuorescent contaminant, which

c

was removed for ﬂuorescence studies (see text for details). C-40 was synthesized by

deprotection of the TMS groups of C-39 using K₂CO₃.

constituent [20]). At the same time, C-36 exhibits a

by environmental factors (e.g. solvent, temperature).

Regardless, the difference between the unsubstituted

reference chlorin C-30 (I_B/I_Q= 2.8) and all of the

3,13-diethynylchlorin analogs (C-31–C-38, C-40; I_B/

I_Q= 1.8–1.3) is pronounced, and reﬂects the shifting

of oscillator strength from the B-bands to the Q_yband.

A more pronounced bathochromic shift than observed

herein appears to require more extensive modiﬁcation

of the macrocyclic structure. The research reported here

signiﬁcant broadening of the B-band, compared to the

other chlorins in the series. Overall, elaboration of the

arylethynyl substituents at the 3,13-positions has a rather

small effect on the position of the long-wavelength Q_y

band and emission maxima.

It warrants mention that the I_B/I_Qratio can depend on

the extent to which the B_xand B_ybands are spectrally

separated or overlapped, which in turn can be affected

J. Porphyrins Phthalocyanines 2015; 19: 13–26

14

D. RA ET AL.

Table 4.Absorption and emission maxima for 3,13-disubstituted

predated and somewhat inspired our recent pivot toward

studies of strongly conjugated hydroporphyrin arrays,

the design of which appears to be an efﬁcient way to

bathochromically shift the chlorin absorption [27].

chlorins^a

Compound

l_B(nm)

l_Qy

I_B/I_Q

l_em(nm)

C-30^b

C-31

C-32

C-33

C-34

C-35

C-36

C-37

C-38

C-40

405

427

433

434

431

435

428

431

422

635

674

679

680

679

682

679

665

666

2.8

1.6

1.4

1.5

1.4

1.3

1.6

1.8

1.5

639

678

684

685

687

684

668

669

EXPERIMENTAL

General

¹H NMR and ¹³C NMR spectra were collected at

room temperature unless noted otherwise. Absorption

spectra were obtained in CH₂Cl₂at room temperature

unless noted otherwise. Hydrophobic chlorins were

analyzed by fast-atom bombardment mass spectrometry

(FAB-MS), laser desorption mass spectrometry (LD-MS)

in the absence of a matrix [83], or matrix-assisted laser

desorption mass spectrometry (MALDI-MS) with the

matrix 1,4-bis(5-phenyloxazol-2-yl)benzene (POPOP).

Water-soluble chlorins were analyzed by direct infusion

of water/methanol (60:40) solutions by atmospheric

pressure electrospray ionization mass spectrometry

(ESI-MS). In FAB-MS, LD-MS, MALDI-MS and

ESI-MS analyses, positive ions were detected unless

noted otherwise. Melting points are uncorrected. All

commercially available materials including compounds

I–V were used as received. All palladium-coupling

reactions were carried out using standard Schlenk-line

techniques. All bromination reactions were performed

using freshly recrystallized NBS.

^aAll data in toluene at room temperature. Absorption data are

in Ref. 17 and in Fig. 4.

b

Fluorescence spectroscopy

All chlorins were excited at the peak of the B-band

where the absorption was set to ~0.1. Spectra were

obtained in toluene at room temperature unless noted

otherwise. The spectra were corrected for detector

sensitivity and instrument response.

Synthesis

Non-commercial compounds. Dipyrromethane 1

[45–47] was synthesized following a streamlined one-

ﬂask procedure [46] whereas dipyrromethane 14 [9]

was prepared via a stepwise procedure. The following

compounds were prepared via literature procedures:

Mukaiyama reagent 2 [48]; Western half precursors 9 [9]

and 10 [9]; Western halves 6 [10] and 19 [13]; Eastern

halves 20 [13] and 21 [27]; known chlorins as precursors

ZnC-4 [10]; C-8 [17], C-9 [17], C-13 [19], and C-14

[19]; and ethynes methyl 4-ethynylbenzoate [80],

4-ethynyl-1-(2-phenylethynyl)benzene [81], and methyl

4-[2-(4-ethynylphenyl)ethynyl]benzoate [82]. Known

chlorin ZnC-22 [13] was synthesized at larger scale here.

Spectroscopic data for the benchmark chlorins ZnC-26

[13], ZnC-27 [13], and C-30 [17] were taken from the

literature.

Fig. 4. (a) Absorption spectra normalized at the B-band in

toluene at room temperature of (a) benchmark C-30, (b) C-40,

(c) C-31, and (d) C-32. (b) Corresponding ﬂuorescence spectra

upon excitation at the peak of the B-band

J. Porphyrins Phthalocyanines 2015; 19: 14–26

PROGRESS TOWARDS SYNTHETIC CHLORINS WITH GRADED POLARITY, CONJUGATABLE SUBSTITUENTS

15

10-(9-Borabicyclo[3.3.1]non-9-yl)-5-(4-methoxy-

phenyl)-1-(4-methylbenzoyl)dipyrromethane (4).

Following a standard procedure [49], a solution of

EtMgBr (10.0 mL, 10. mmol, 1.0 M in THF) was added

slowly to a solution of 1 (1.26 g, 5.00 mmol) in THF

(5 mL) under argon. The resulting mixture was stirred at

roomtemperaturefor10min, andthencooledto-78°C.A

solution of S-2-pyridyl 4-methylbenzothioate (2, 1.15 g,

5.00 mmol) in THF (5 mL) was added. The solution

was stirred at -78°C for 10 min, then allowed to warm

to room temperature. The reaction mixture was

quenched by the addition of saturated aqueous

NH₄Cl (40 mL). The mixture was extracted with

ethyl acetate (30 mL). The organic layer was washed

(water and brine), dried (Na₂SO₄), and ﬁltered. The

ﬁltrate was concentrated. The crude product (a red-

orange oil) thus obtained was dissolved in CH₂Cl₂

(10 mL) and treated with TEA (1.68 mL, 12.0 mmol)

followed by 9-BBN-OTf (20 mL, 10.0 mmol, 0.5 M in

hexane) with stirring at room temperature. After 1 h,

the mixture was poured onto a pad of silica (4 × 8 cm)

eluting with CH₂Cl₂. The product eluted as a fast-moving

yellow band, which upon concentration afforded a

yellow-orange solid (1.78 g, 73%): mp 88°C (dec.). ¹H

NMR (400 MHz, CDCl₃): d, ppm 0.67–0.71 (m, 2H),

1.62–1.83 (m, 6H), 1.95–2.22 (m, 6H), 2.48 (s, 3H),

3.79 (s, 3H), 5.85 (s, 1H), 5.96 (s, 1H), 6.13–6.17 (m,

1H), 6.40–6.43 (m, 1H), 6.69–6.85 (m, 1H), 6.85 (d, J =

8.0 Hz, 2H), 7.11 (d, J = 8.0 Hz, 2H), 7.30–7.38 (m,

4H), 7.80–7.92 (br, 1H), 8.12 (d, J = 8.0 Hz, 2H). ¹³C

NMR (100 MHz, CDCl₃) d 22.1, 23.9, 25.2, 26.0, 26.5,

30.7, 30.9, 34.7, 44.1, 55.5, 108.0, 108.6, 114.1, 117.4,

118.3, 120.8, 128.3, 129.6, 129.8, 130.0, 132.9, 134.3,

134.9, 145.0, 152.5, 158.7, 174.4. Integration indicated

C₃₂H₃₄BBrN₂O₂), and the product was used in the next

step without further puriﬁcation.

Zn(II)-17,18-dihydro-18,18-dimethyl-10-(4-

methoxyphenyl)-5-(4-methylphenyl)porphyrin (ZnC-1).

A solution of 5 (0.285 g, 0.500 mmol) in THF/methanol

[12.5 mL (4:1)] was treated with NaBH₄(0.190 g,

5.0mmol). After 30 min (TLC indicated complete

reaction), the reaction mixture was quenched by the

addition of cold water and then extracted with CH₂Cl₂.

The organic layer was dried (K₂CO₃) and concentrated

under reduced pressure without heating to afford the

dipyrromethane-monocarbinol 5-OH. The foam-like

residue was dissolved in CH₃CN (5 mL), whereupon

Western half (6, 0.094 g, 0.50 mmol) was added

followed by TFA (39 mL, 0.50 mmol). The reaction

mixture was stirred at room temperature for 30 min, and

then diluted with CH₃CN (27 mL). Samples of AgOTf

(0.385 g, 1.50 mmol), Zn(OAc)₂(1.38 g, 7.50 mmol),

and 2,2,6,6-tetramethylpiperidine (2.53 mL,15.0 mmol)

were added. The resulting mixture was reﬂuxed open to

the air for 21 h. The reaction mixture was concentrated

under reduced pressure. The residue thus obtained was

chromatographed [silica, CH₂Cl₂/ethyl acetate (2:1)] to

1

afford a purple-green solid (0.108 g, 36%): H NMR

(400 MHz, CDCl₃): d, ppm 2.02 (s, 6H), 2.66 (s, 3H), 4.04

(s, 3H), 4.49 (s, 2H), 7.19 (d, J = 8.0 Hz, 2H), 7.48 (d, J =

8.0 Hz, 2H), 7.91–8.00 (m, 4H), 8.37–8.42 (m, 2H), 8.55

(s, 1H), 8.58–8.70 (m, 5H). LD-MS: m/z obsd. 598.5.

FAB-MS: m/z obsd. 598.1733, calcd. 598.1705 ([M]⁺, M =

C₃₆H₃₀N₄OZn). UV-vis (THF): l_abs, nm 412, 609.

Zn(II)-17,18-dihydro-18,18-dimethyl-10-(4-meth-

oxyphenyl)-17-oxo-5-(4-methylphenyl)porphyrin

(ZnC-2). Following a general procedure [11], a mixture

of ZnC-1 (0.060 g, 0.10 mmol) and basic alumina

(activity I, 3.0 g) in toluene (4 mL) was stirred at room

temperature for 7 h exposed to air. Solvent was removed

under reduced pressure and the residue obtained was

suspended in CH₂Cl₂/MeOH (19:1). The suspension of

alumina and chlorin was ﬁltered. The ﬁltered material was

washed with a mixture of CH₂Cl₂/MeOH (19:1) until the

washings were colorless. The ﬁltrate was concentrated.

The resulting residue was dissolved in toluene (40 mL)

and treated with DDQ (0.045 g, 0.20 mmol)

for 5 min. The reaction was quenched by the

addition of TEA, and the solvent was evaporated.

Chromatography [silica, CH₂Cl₂/MeOH (98:2)]

1

one additional proton in the H NMR spectrum (vs.

formula C₃₂H₃₅BN₂O₂), and the product was used in the

next step without further puriﬁcation.

10-(9-Borabicyclo[3.3.1]non-9-yl)-1-bromo-5-(4-

methoxyphenyl)-9-(4-methylbenzoyl)-dipyrromethane

(5). Following a general procedure [48], a solution of 4

(0.491 g, 1.00 mmol) in dry THF (10 mL) was cooled

to -78°C under argon. NBS (178 mg, 1.00 mmol) was

added, and the reaction mixture was stirred for 1 h

at -78°C. Hexanes (10 mL) and water (10 mL) were

added, and the mixture was allowed to warm to room

temperature. The organic phase was extracted with

hexanes, dried (Na₂SO₄) and concentrated under reduced

pressure without heating. Chromatography [silica,

hexanes/CH₂Cl₂(1:1)] afforded a yellow orange powder

1

afforded a green-purple solid (0.036 g, 59%): H NMR

(400 MHz, CDCl₃) d 1.98 (s, 6H), 2.67 (s, 3H), 4.00

(s, 3H), 7.17 (d, J = 8.0 Hz, 2H), 7.50 (d, J = 8.0 Hz,

2H), 7.93–7.99 (m, 4H), 8.55–8.63 (m, 2H), 8.75–8.83

(m, 2H), 8.86–8.92 (m, 3H), 9.44 (s, 1H). LD-MS:

m/z obsd. 612.4. FAB-MS: m/z obsd. 612.1478, calcd.

612.1498 ([M]⁺, M = C₃₆H₂₈N₄O₂Zn). UV-vis (THF):

l_abs, nm 420, 608.

Zn(II)-17,18-dihydro-18,18-dimethyl-10-(4-

hydroxyphenyl)-17-oxo-5-(4-methylphenyl)por-

phyrin (ZnC-3). Following a literature procedure [50]

1

(0.439 g, 77%): mp 121°C (dec.). H NMR (400 MHz,

CDCl₃): d, ppm 0.64–0.72 (m, 2H), 1.64–1.88 (m, 6H),

1.94–2.24 (m, 6H), 2.48 (s, 3H), 3.80 (s, 3H), 5.85 (s,

1H), 5.72–5.77 (m, 1H), 5.90 (s, 1H), 6.05–6.08 (m,

1H), 6.40–6.43 (m, 1H), 6.86 (d, J = 7.2 Hz, 2H), 7.11

(d, J = 7.2 Hz, 2H), 7.32–7.39 (m, 4H), 7.70–7.79 (br,

1H), 8.13 (d, J = 8.0 Hz, 2H). Integration indicated two

additional protons in the ¹H NMR spectrum (vs. formula

J. Porphyrins Phthalocyanines 2015; 19: 15–26

16

D. RA ET AL.

with slight modiﬁcation, a mixture of ZnC-2 (0.032 g,

0.050 mmol) and BBr₃(0.20 mL, 0.20 mmol, 1M in

CH₂Cl₂) in CH₂Cl₂(5 mL) was stirred at room temperature

under argon. After 15 h, the reaction mixture was

quenched by the addition of saturated aqueous NaHCO₃.

The organic layer upon extraction with CH₂Cl₂was dried

(Na₂SO₄) and concentrated. The residue was dissolved

in CH₂Cl₂/MeOH (4:1) and treated with Zn(OAc)₂·2H₂O

(0.055 g, 0.25 mmol) at room temperature for 4 h. The

mixture was washed with saturated aqueous NaHCO₃,

dried (Na₂SO₄) and concentrated. Chromatography

[silica, CH₂Cl₂/MeOH (9:1)] afforded a green-purple

solid (0.026 g, 87%): ¹H NMR (400 MHz, CDCl₃) d 2.05

(s,6H),2.68(s,3H),5.40–5.44(br,1H),7.15(d,J=8.0Hz,

2H), 7.51 (d, J = 8.0 Hz, 2H), 7.93–7.99 (m, 4H),

8.55–8.63 (m, 2H), 8.75–8.83 (m, 2H), 8.87–8.96 (m,

2H), 9.56 (s, 1H). LD-MS: m/z obsd. 598.5. FAB-MS:

m/z obsd. 598.1371, calcd. 598.1341 ([M]⁺, M =

C₃₅H₂₆N₄O₂Zn). UV-vis (THF): l_abs, nm 420, 608.

Zn(II)-10-(4-carboxyphenyl)-17,18-dihydro-10-

mesityl-18,18-dimethyl-5-(4-methylphenyl)porphyrin

(ZnC-5). AsolutionofZnC-4(14.3mg, 20.0mmol)indry

DMF (2 mL) was treated with KF (23.2 mg, 0.400 mmol)

at 75°C for 18 h. The reaction mixture was concentrated

to dryness under reduced pressure. Chromatography

[silica, CH₂Cl₂/methanol (20:1)] followed by ﬁltration

through a 0.65 mm ﬁlter (CH₂Cl₂, to remove silica)

afforded a ﬁltrate that upon concentration gave a greenish

purple solid (6.8 mg, 55%): ¹H NMR (400 MHz, CDCl₃)

d 2.03 (s, 6H), 2.66 (s, 3H), 4.52 (s, 2H), 7.46–7.51 (m,

2H), 7.93–7.97 (m, 2H), 8.17–8.22 (m, 2H), 8.31–8.34

(m, 1H), 8.39–8.45 (m, 3H), 8.58–8.70 (m, 6H). LD-MS:

m/z obsd. 612.5. FAB-MS: m/z obsd. 612.1531, calcd.

612.1498 ([M]⁺, M = C₃₆H₂₈N₄O₂Zn). UV-vis (CH₂Cl₂):

l_abs, nm 413, 608.

Methyl 4-bromo-3,5-bis(diethylphosphonometh-

oxy)benzoate (7). A mixture of methyl 4-bromo-3,5-

dihydroxybenzoate (I, 741 mg, 3.00 mmol) and K₂CO₃

(1.65g, 12.0mmol)inCH₃CN(10mL)wasstirredatroom

temperature for 30 min. A sample of TfOCH₂PO(OEt)₂

(II, 2.10 g, 7.00 mmol) was added, and the mixture

was reﬂuxed for 4 h. The reaction mixture was allowed

to cool to room temperature. The reaction mixture was

treated with CH₂Cl₂and water. The organic layer was

separated, washed (water, brine), dried (Na₂SO₄) and

concentrated. The resulting solid was chromatographed

[silica, hexanes/ethyl acetate (1:1) → ethyl acetate →

ethyl acetate/MeOH (98:2)] to give a white solid (1.52 g,

92%): mp 62–63°C. ¹H NMR (400 MHz, CDCl₃) d 1.37

(t, J = 7.2 Hz, 12H), 3.92 (s, 3H), 4.24–4.33 (m, 8H), 4.38

(d, J = 10.4 Hz, 4H), 7.32 (s, 2H). ¹³C NMR (100 MHz,

CDCl₃) d 16.5 (d, J = 6.1 Hz), 52.6 (d, J = 3.1 Hz), 63.3 (d,

J = 6.1 Hz), 63.5 (d, J = 169.1 Hz, P-C coupling), 107.3,

107.8, 130.3, 156.8, 165.7. ESI-MS: m/z obsd. 547.0502,

calcd. 547.0492 ([M + H]⁺, M = C₁₈H₂₉BrO₁₀P₂). Anal.

calcd. for C₁₈H₂₉BrO₁₀P₂: C, 39.50; H, 5.34. Found C,

39.74; H, 5.46.

Methyl 4-bromo-3,5-bis[3-(diethylphosphono)pro-

poxy]benzoate (8). A mixture of I (1.23 g, 5.00 mmol),

K₂CO₃(1.38 g, 10.0 mmol) and KI (830 mg, 5.00 mmol)

in CH₃CN (10 mL) was stirred at room temperature for

30 min.A sample of diethyl (3-bromopropyl)phosphonate

(III, 2.59 g, 10.0 mmol) was added, and the mixture was

reﬂuxed for 15 h. The reaction mixture was allowed to

cool to room temperature. The reaction mixture was

treated with CH₂Cl₂and water. The organic layer was

separated, washed (water, brine), dried (Na₂SO₄) and

concentrated. The resulting solid was chromatographed

[silica, hexanes/ethyl acetate (1:1) → ethyl acetate →

ethyl acetate/MeOH (97:3)] to give a viscous yellow oil

1

(2.78 g, 92%): H NMR (400 MHz, DMSO-d₆) d 1.21

(t, J = 7.2 Hz, 12H), 1.84–2.02 (m, 8H), 3.86 (s, 3H),

3.92–4.07 (m, 8H), 4.15 (t, J = 5.4 Hz, 4H), 7.17 (s, 2H).

¹³C NMR (100 MHz, DMSO-d₆) d 16.2 (d, J = 6.1 Hz),

21.0 (d, J = 140.3 Hz, P-C coupling), 22.2, (d, J = 4.6 Hz),

52.4, 60.9 (d, J = 6.1 Hz), 68.5 (d, J = 17.4 Hz), 106.1,

106.5, 130.0, 155.8, 165.5. ESI-MS: m/z obsd. 603.1115,

calcd. 603.1118 ([M + H]⁺, M = C₂₂H₃₇BrO₁₀P₂).

4,4,5,5-Tetramethyl-2-(2,6-dimethoxyphenyl)-

1,3,2-dioxaborolane. A solution of 2,6-dimethoxy-

phenylboronic acid (909 mg, 4.99 mmol) in toluene

(25 mL) was treated with pinacol (2.95 g, 25.0 mmol)

and reﬂuxed with continuous azeotropic removal of

water (Dean–Stark trap) for 15 h. The reaction mixture

was allowed to cool to room temperature and washed

with water (5 × 25 mL). The organic layer was separated,

dried (Na₂SO₄) and concentrated. The resulting residue

was dried under high vacuum to obtain a white solid (1.30

g, 98%): mp 78°C. ¹H NMR (300 MHz, CDCl₃): d, ppm

1.19 (s, 12H), 3.78 (s, 6H), 6.46 (d, J = 8.4 Hz, 2H), 7.23

(t, J = 8.4 Hz, 1H). ¹³C NMR (75 MHz, CDCl₃): d, ppm

24.8, 55.7, 83.8, 103.3, 131.4, 163.5. GC-MS: m/z obsd.

264, calcd. 264 ([M]⁺, M = C₁₄H₂₁BO₄). Anal. calcd. for

C₁₄H₂₁BO₄: C, 63.66; H, 8.01. Found C, 63.87; H, 8.03.

17,18-Dihydro-15-(4,4,5,5-tetramethyl-1,3,2-dioxa-

borolan-2-yl)-18,18-dimethyl-10-(4-methylphenyl)-

porphyrin (C-10). Following a procedure for Pd-

mediated borylation [58], a mixture of C-9 (36.8 mg,

0.0722 mmol) and (PPh₃)₂PdCl₂(5.0 mg, 0.0072 mmol,

10 mol%) was dried in a Schlenk ﬂask for 1 h.

1,2-Dichloroethane (8.5 mL), 4,4,5,5-tetramethyl-1,3,2-

dioxaborolane (89 mL, 0.61 mmol) and TEA (100 mL,

0.722mmol)wereadded.Thereactionmixturewasheated

at90°Cfor3h.Thereactionmixturewasallowedtocoolto

room temperature. The reaction mixture was treated with

CH₂Cl₂andwater.Theorganiclayerwasseparated,washed

(water, brine), dried (Na₂SO₄) and concentrated. The

resulting solid was chromatographed [silica, hexanes →

hexanes/CH₂Cl₂(1:3)] to afford a purple solid (35.5 mg,

88%): ¹H NMR (400 MHz, CDCl₃) d -1.67 (brs, 2H), 1.73

(s, 12H), 2.04 (s, 6H), 2.69 (s, 3H), 4.79 (s, 2H), 7.52 (d,

J=8.0Hz, 2H), 8.00(d, J=8.0Hz, 2H), 8.55(d, J=4.4Hz,

1H), 8.78 (d, J = 4.4 Hz, 1H), 8.84 (s, 1H), 8.87 (d, J =

4.4 Hz, 1H), 8.89 (d, J = 4.4 Hz, 1H), 9.16 (d, J = 4.4 Hz,

J. Porphyrins Phthalocyanines 2015; 19: 16–26

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17

1H), 9.34 (d, J = 4.4 Hz, 1H), 9.71 (s, 1H). LD-MS: m/z

obsd. 556.6; calcd. 556.3 ([M]⁺, M = C₃₅H₃₇BN₄O₂).

15-[2,6-Bis(diethylphosphonomethoxy)-4-(metho-

xycarbonyl)phenyl]-17,18-dihydro-18,18-dimethyl-

10-(4-methylphenyl)porphyrin (C-11). Following a

reported procedure for Pd-mediated Suzuki-coupling at

the15-positionofchlorins[12],samplesofC-10(20.8mg,

0.0373 mmol), 7 (20.4 mg, 0.0373 mmol), (Pd(PPh₃)₄

(12.9mg,0.0112mmol)andK₂CO₃(41.2mg,0.298mmol)

were placed in a Schlenk ﬂask. The ﬂask was pumped-

purged with argon three times. A degassed sample of

DMF was added. The resulting mixture was stirred at

90°C for 18 h. The reaction mixture was allowed to cool

to room temperature. The reaction mixture was diluted

with CH₂Cl₂and ﬁltered. The ﬁltrate was concentrated.

The resulting crude product was dissolved in CH₂Cl₂

and chromatographed [silica, hexanes/CH₂Cl₂(1:1) →

CH₂Cl₂→ CH₂Cl₂/MeOH (98:2)] to afford deborylated

chlorin (C-8, 14.4 mg, 90%) followed by a trace amount

of the title compound admixed with de-brominated 7,

which could not be puriﬁed. The presence of the product

was strongly suggested by ESI-MS: m/z obsd. 897.3512,

calcd. 897.3388 ([M + H]⁺, M = C₄₇H₅₄N₄O₁₀P₂).

15-[2,6-Bis[3-(diethylphosphono)propoxy]-4-

(methoxycarbonyl)phenyl]-17,18-dihydro-18,18-dime-

thyl-10-(4-methylphenyl)porphyrin (C-12). Following

a reported procedure for Pd-mediated Suzuki-coupling

[12], samples of C-10 (7.1 mg, 0.012 mmol), Pd(PPh₃)₄

(4.4 mg, 0.0038 mmol) and K₂CO₃(14 mg, 0.10 mmol)

were placed in a Schlenk ﬂask. The ﬂask was pumped-

purged with argon three times. A solution of 8 (7.6 mg,

0.012 mmol) in toluene/DMF (1 mL, 2:1) was added.

The resulting mixture was stirred at 90°C for 18 h. The

reaction mixture was allowed to cool to room temperature.

The reaction mixture was diluted with CH₂Cl₂and

ﬁltered. The ﬁltrate was concentrated. The crude

product was dissolved in CH₂Cl₂and chromatographed

[silica, hexanes/CH₂Cl₂(1:1) → CH₂Cl₂→ CH₂Cl₂/

MeOH (98:2)] to afford the deborylated chlorin (C-8,

4.8 mg, 87%) followed by a trace amount of the title

compound admixed with de-brominated 8, which could

not be puriﬁed. The presence of the product was strongly

suggested by ESI-MS: m/z obsd. 953.4008, calcd.

953.4013 ([M + H]⁺, M = C₅₁H₆₂N₄O₁₀P₂).

CDCl₃) d -2.18 (brs, 1H), -2.11 (brs, 1H), -0.20 (m,

12H), 2.08 (s, 6H), 2.5 (m, 8H), 4.15 (s, 2H), 4.18 (s,

2H), 4.70 (s, 2H), 7.07 (d, J = 8.4 Hz, 2H), 7.75 (t, J =

8.4 Hz, 1H), 8.49 (d, J = 4.4 Hz, 1H), 8.68 (d, J = 5.2 Hz,

1H), 8.81 (d, J = 4.4 Hz, 1H), 8.88 (s, 1H), 8.95 (d,

J = 4.4 Hz, 1H), 9.18 (m, 2H), 9.68 (s, 1H). ESI-MS:

m/z obsd. 827.1966, calcd. 827.1969 ([M + H]⁺, M =

C₃₈H₄₅BrN₄O₈P₂). UV-vis (CH₂Cl₂): l_abs, nm 361, 402,

503, 643.

15-[4-(Ethoxycarbonylmethoxy)phenyl]-10-

[2,6-bis(diethylphosphonomethoxy)phenyl]-17,18-

dihydro-18,18-dimethylporphyrin (C-16).A mixture of

chlorin C-15 (25 mg, 0.030 mmol), Pd(PPh₃)₄(5.00 mg,

0.00433 mmol), anhydrous K₂CO₃(8.5 mg, 0.060 mmol)

and IV (14 mg, 0.045 mmol) was dried in a Schlenk

ﬂask for 1 h. Toluene (6 mL) and DMF (3 mL) were

degassed for 10 min and then added to the Schlenk ﬂask

under an inert atmosphere. The mixture was heated to

90°C for 24 h. After cooling to room temperature, the

suspension was diluted with ethyl acetate and ﬁltered

over Celite. The ﬂask and the ﬁlter cake were rinsed with

ethyl acetate until the ﬁltrate was colorless. The ﬁltrate

was washed (H₂O, brine), dried (Na₂SO₄) and ﬁltered.

The new ﬁltrate was concentrated. The resulting residue

was subjected to column chromatography [silica, ethyl

acetate/MeOH (0 → 5%)] to afford a green solid (14 mg,

1

50%): H NMR (400 MHz, CD₃OD) d -0.31 (m, 12H),

1.39 (t, J = 6.8 Hz, 3H), 2.01 (s, 6H), 2.31–2.55 (m, 8H),

4.24 (s, 2H), 4.29 (s, 2H), 4.32 (s, 2H), 4.37 (q, J = 6.8 Hz,

2H), 4.63 (s, 2H), 7.23 (d, J = 8.8 Hz, 2H), 7.31 (d, J =

8.4 Hz, 2H), 7.80 (d, J = 8.8 Hz, 2H), 7.83 (t, J = 8.4 Hz,

1H), 8.29 (d, J = 4.8 Hz, 1H), 8.49 (d, J = 4.4 Hz, 1H),

8.61 (d, J = 4.8 Hz, 1H), 8.94 (d, J = 4.0 Hz, 1H), 9.09

(d, J = 4.8 Hz, 1H), 9.10 (s, 1H), 9.34 (d, J = 4.4 Hz, 1H),

9.86 (s, 1H) (two protons were not observed). ESI-MS:

m/z obsd. 926.3416, calcd. 926.3421 ([M + H]⁺, M =

C₄₈H₅₆N₄O₁₁P₂). UV-vis (CH₂Cl₂): l_abs, nm 361, 409, 502,

590, 642.

15-(4-(Carboxymethoxy)phenyl-10-[2,6-

bis(phosphonomethoxy)phenyl]-17,18-dihydro-18,18-

dimethylporphyrin (C-17). A solution of chlorin C-16

(14 mg, 0.015 mmol) in THF/H₂O (5 mL, 4:1) was

treated with aqueous 2M KOH (100 mL, 0.200 mmol).

The mixture was stirred for 24 h at room temperature.

Then, THF was removed under vacuum. The residue

was partitioned between water (5 mL) and CH₂Cl₂

(5 mL). The aqueous layer was freeze-dried to obtain the

potassium salt of the chlorin. The solid was dissolved in

CH₂Cl₂(5 mL), whereupon a few drops of acetic acid

were added. The mixture was ﬁltered. The ﬁltrate was

concentrated to dryness. The resulting green solid was

dried under high vacuum. The solid was dissolved in

CH₂Cl₂(3 mL), whereupon TMSBr (140 mL, excess)

was added. The mixture was stirred for 4 h at room

temperature. The solvent and excess TMSBr were

removed in vacuo, then methanol/water (5 mL, 4:1) was

added. The mixture was stirred for 1 h. The solvent was

15-Bromo-10-[2,6-bis(diethylphosphonomethoxy)

phenyl]-17,18-dihydro-18,18-dimethylporphyrin

(C-15). Following a reported procedure for selective

bromination of chlorins [14, 17], a solution of chlorin

C-14 (30. mg, 0.040 mmol) in anhydrous THF (17 mL)

was treated with NBS (7.2 mg, 0.040 mmol). The

reaction mixture was stirred for 2 h at room temperature.

The mixture was diluted with CH₂Cl₂(50 mL) and

washed (saturated aqueous NaHCO₃, H₂O, brine). The

organic phase was dried (Na₂SO₄) and ﬁltered. The

ﬁltrate was concentrated to obtain a blue solid. Column

chromatography [silica, CH₂Cl₂/MeOH (0 → 5%)]

afforded a blue solid (32 mg, 96%): ¹H NMR (400 MHz,

J. Porphyrins Phthalocyanines 2015; 19: 17–26

18

D. RA ET AL.

removed under high vacuum, and the resulting green solid

was dried under high vacuum. The residue was triturated

with CH₂Cl₂(3 × 10 mL) and dried to obtain a green

solid (12 mg, quantitative): ¹H NMR (400 MHz, CD₃OD)

d 2.01 (s, 6H), 4.13 (s, 2H), 4.15 (s, 2H), 5.49 (s, 2H),

7.33 (m, 4H), 7.91 (m, 3H), 8.71 (m, 1H), 8.85 (d, J =

4.8 Hz, 1H), 9.25 (d, J = 4.4 Hz, 1H), 9.36 (d, J = 4.4 Hz,

1H), 9.51 (s, 1H), 9.65 (d, J = 4.4 Hz, 1H), 10.45 (s, 1H),

the integration was deﬁcient by 10 protons, of which 7

are exchangeable. ESI-MS: m/z obsd. 785.1813, calcd.

785.1783 ([M – H]^-, M = C₃₈H₃₆N₄O₁₁P₂). UV-vis (H₂O):

l_abs, nm 405, 503, 583, 634.

1,3,3-Trimethyl-7-[4-[2-(trimethylsilyl)ethynyl]

phenyl]-2,3,4,5-tetrahydrodipyrrin (13). Samples of

12 (450 mg, 1.15 mmol), Pd₂(dba)₃(81 mg, 0.090 mmol),

Ph₃As(220mg, 0.72mmol), andCuI(17mg, 0.090mmol)

were added to a 50 mL Schlenk ﬂask. The ﬂask was

evacuated and purged with argon three times. Then

deaerated anhydrous THF/TEA (12 mL, 1:1) was added

followed by (trimethylsilyl)ethyne (243 mL, 1.72 mmol).

The ﬂask was sealed, immersed in an oil bath (37°C),

and the mixture was stirred overnight. Then CH₂Cl₂

(30 mL) was added, and the mixture was ﬁltered (Celite)

and washed (CH₂Cl₂). The ﬁltrate was concentrated. The

resulting residue was puriﬁed by ﬂash chromatography

(silica, ethyl acetate) to afford a dark brown viscous oil

1,3,3-Trimethyl-7-(4-iodophenyl)-2,3,4,5-tetrahy-

drodipyrrin N¹⁰-oxide (11). A solution of 10 (0.500 g,

1.14 mmol) in acetic acid (10 mL) was treated with

zinc dust (1.74 g, 26.5 mmol) all-at-once, and the

resulting mixture was stirred vigorously for 1 h at room

temperature. The crude reaction mixture was ﬁltered

(Celite) and concentrated. The residue was dissolved

in CH₂Cl₂. The resulting solution was washed (10% aq

Na₂CO₃), dried (Na₂SO₄) and concentrated to afford a

yellow solid. Recrystallization from ethyl acetate gave a

1

(316 mg, 76%): H NMR (300 MHz, CDCl₃) d 0.25 (s,

9H), 0.92 (s, 3H), 1.07 (s, 3H), 2.05 (s, 3H), 2.34 (m,

2H), 2.61 (m, 1H), 2.95 (m, 1H), 3.65 (d, J = 11.7 Hz,

1H), 6.29 (m, 1H), 6.74 (m, 1H), 7.32 (d, J = 7.8 Hz,

2H), 7.47 (d, J = 7.8 Hz, 2H), 10.27 (br, 1H). ¹³C NMR

(75 MHz, CDCl₃) d 0.7, 21.1, 23.5, 27.1, 27.7, 42.6,

54.8, 80.5, 94.1, 106.3, 108.4, 117.0, 119.8, 120.9,

128.3, 129.3, 132.7, 138.7, 175.4. FAB-MS: m/z obsd.

363.2271, calcd. 363.2172 ([M]⁺, M = C₂₃H₃₀N₂Si).

3-(4-Iodophenyl)-9-(3,5-di-tert-butylbenzoyl)-

10-N-(tert-butoxycarbonyl)dipyrromethane (15). A

solution of 14 (0.90 g, 2.0 mmol) in anhydrous THF

(30 mL) under argon at 0°C was treated slowly with

EtMgBr (1M in THF, 6 mL, 6.0 mmol). The mixture was

stirred for 10 min at 0°C. Then a solution of 3,5-di-tert-

butylbenzoyl chloride (760 mg, 3.0 mmol) in anhydrous

THF (5 mL) was added slowly, and stirring was continued

for 1.5 h at 0°C. The reaction was quenched by the

addition of saturated aqueous NH₄Cl and then extracted

(CH₂Cl₂). The organic extract was washed (water

and brine), dried (Na₂SO₄), and concentrated. Flash

chromatography [silica, hexanes/ethyl acetate (4:1)]

afforded a brown viscous oil, which then was cooled

overnight. A minimum amount of hexanes was added

followed by sonication to afford a white solid (598 mg,

1

white powder (200 mg, 43% yield): mp 173–174°C. H

NMR (300 MHz, CDCl₃) d 0.98 (s, 3H), 1.17 (s, 3H), 2.10

(s, 3H), 2.36 (d, J = 17.4 Hz, 1H), 2.52 (d, J = 17.4 Hz,

1H), 3.07 (m, 2H), 3.96 (m, 1H), 6.20 (m, 1H), 6.74

(m, 1H), 7.08 (d, J = 7.8 Hz, 2H), 7.67 (d, J = 7.8 Hz,

2H), 11.31 (br, 1H). ¹³C NMR (75 MHz, CDCl₃) d 13.2,

22.7, 23.5, 26.8, 37.8, 46.8, 81.0, 90.1, 107.8, 117.0,

120.6, 125.7, 130.2, 137.0, 137.3, 145.5. Anal. calcd. for

C₁₈H₂₁N₂IO: C, 52.95; H, 5.18; N, 6.86. Found C, 52.91;

H, 5.23; N, 6.78.

1,3,3-Trimethyl-7-(4-iodophenyl)-2,3,4,5-

tetrahydrodipyrrin (12). Following a procedure for the

deoxygenation of N-oxides [10], TiCl₄(1.0 mL, 8.8 mmol)

was slowly added to a stirred solution of dry THF (20 mL)

under argon at 0°C. To the resulting yellow solution,

LiAlH₄(220 mg, 5.9 mmol) was added slowly, and the

resulting black mixture was stirred at room temperature for

15 min. Then, TEA (7.7 mL) was added. The black mixture

was then poured into a solution of 11 (500 mg, 1.22 mmol)

in THF (20 mL). The mixture was stirred for 2 h at room

temperature, and then water (20 mL) was added. The

mixture was ﬁltered to remove inorganic materials. The

aqueous-THF ﬁltrate was poured into a separatory funnel

and extracted (CH₂Cl₂). The organic layer was dried

(Na₂SO₄) and concentrated under reduced pressure. The

resulting brown oil was puriﬁed by chromatography (silica,

ethyl acetate) to give a light brown oil which solidiﬁed on

cooling (180 mg, 38%): mp 90–91°C. ¹H NMR (300 MHz,

CDCl₃) d 0.92 (s, 3H), 1.08 (s, 3H), 2.05 (s, 3H), 2.34 (m,

2H), 2.59 (m, 1H), 2.92 (m, 1H), 3.64 (d, J = 11.7 Hz, 1H),

6.25 (m, 1H), 6.73 (m, 1H), 7.13 (d, J = 6.6 Hz, 2H), 7.66 (d,

J = 6.6 Hz, 2H), 10.30 (br, 1H). ¹³C NMR (75 MHz, CDCl₃)

d 21.2, 23.5, 27.0, 27.8, 42.6, 54.9, 80.5, 90.4, 108.4, 117.0,

120.3, 128.9, 130.6, 137.8, 137.9, 175.3. FAB-MS: m/z

obsd. 393.0841, calcd. 393.0743 ([M]⁺, M = C₁₈H₂₁IN₂).

1

45%): mp 178–179°C. H NMR (300 MHz, CDCl₃) d

1.35 (s, 18H), 1.58 (s, 9H), 4.30 (s, 2H), 5.97 (m, 1H),

6.26 (m, 1H), 6.73 (m, 1H), 7.11 (d, J = 6.6 Hz, 2H), 7.30

(m, 1H), 7.60 (m, 1H), 7.70 (m, 2H), 7.72 (m, 2H), 9.92

(br, 1H). ¹³C NMR (75 MHz, CDCl₃) d 25.8, 28.5, 32.0,

35.6, 85.5, 93.0, 110.1, 112.3, 120.4, 122.1, 123.9, 126.3,

127.1, 128.2, 131.2, 131.3, 135.4, 138.2, 138.6, 139.2,

150.5, 151.3, 185.7. Anal. calcd. for C₃₅H₄₁IN₂O₃: C,

63.25; H, 6.22; N, 4.21. Found C, 64.03; H, 6.35; N, 4.15.

3-(4-Iodophenyl)-9-(3,5-di-tert-butylbenzoyl)

dipyrromethane (16). A solution of 15 (0.60 g, 0.90

mmol) in anhydrous THF (10 mL) under argon at room

temperaturewastreatedwithmethanolicNaOMe(146mg,

2.70 mmol, in 1.0 mL of anhydrous methanol). After

10 min, the reaction was quenched by the addition of

a mixture of hexanes and water (20 mL, 1:1) followed

by extraction with ethyl acetate. The organic extract

was washed (water and brine), dried (Na₂SO₄), and

J. Porphyrins Phthalocyanines 2015; 19: 18–26

PROGRESS TOWARDS SYNTHETIC CHLORINS WITH GRADED POLARITY, CONJUGATABLE SUBSTITUENTS

19

concentrated. The residue was recrystallized from ethanol

to give a pale brown solid (430 mg, 84%): mp 202–

203°C. ¹H NMR (300 MHz, CDCl₃) d 1.30 (s, 18H), 4.18

(s, 2H), 6.23 (m, 2H), 6.48 (m, 1H), 6.93 (m, 1H), 7.25

(d, J = 8.1 Hz, 2H), 7.68 (m, 1H), 7.75 (m, 4H), 10.23 (br,

1H), 11.85 (br, 1H). ¹³C NMR (75 MHz, CDCl₃) d 25.6,

31.9, 35.6, 91.1, 109.0, 111.2, 118.1, 121.6, 124.0, 124.2,

124.8, 127.0, 130.9, 131.5, 137.3, 138.0, 138.2, 141.5,

151.8, 187.5. Anal. calcd. for C₃₀H₃₃IN₂O: C, 63.83; H,

5.89; N, 4.96. Found C, 63.74; H, 6.09; N, 5.00.

C₃₅H₄₁BrN₂OSi: C, 68.50; H, 6.73; N, 4.56. Found C,

68.06; H, 6.64; N, 4.49.

Zn(II)-17,18-dihydro-18,18-dimethyl-2-(4-

iodophenyl)-5-(3,5-di-tert-butylphenyl)-12-[4-(2-

(trimethylsilyl)ethynyl)phenyl]porphyrin (ZnC-21).

Following a two-step procedure [10], a solution of 18

(123 mg, 0.200 mmol) in anhydrous THF/methanol

(7.5 mL, 4:1) was treated with excess NaBH₄(100 mg,

2.60 mmol) in small portions at room temperature. The

reaction was monitored by TLC [alumina, hexanes/

ethyl acetate (1:1)]. Upon completion, the reaction was

quenched by the addition of cold water (10 mL), and

then the mixture was extracted with distilled CH₂Cl₂(3 ×

25 mL). The combined organic extract was washed with

brine (50 mL), dried (K₂CO₃) and concentrated in vacuo

without heating to leave the resulting dipyrromethane-

monocarbinol 18-OH in ~1–2 mL of CH₂Cl₂. A solution

of12 (78 mg, 0.20 mmol) in a few milliliters of anhydrous

CH₃CN was combined with 18-OH, then additional

anhydrous CH₃CN was added to give a total of 20 mL

of CH₃CN. The solution was stirred at room temperature

under argon, and TFA (20 mL, 0.26 mmol) was added. The

reaction was monitored by TLC [alumina, hexanes/ethyl

acetate (3:1)]. After 1 h, 18-OH had disappeared. The

reaction mixture was quenched by the addition of 10%

aqueous NaHCO₃and extracted with distilled CH₂Cl₂

(3 × 25 mL). The combined organic extract was washed

(water and brine), dried (Na₂SO₄), and concentrated in

vacuo at room temperature. The residue was dissolved

in 14 mL of anhydrous toluene under argon, then AgIO₃

(848 mg, 3.00 mmol), piperidine (300. mL, 3.00 mmol)

and Zn(OAc)₂(550 mg, 3.00 mmol) were added. The

resulting mixture was heated at 80°C exposed to air for

3 h. The reaction was monitored by TLC [silica, hexanes/

CH₂Cl₂(1:1)], which showed a single green spot. The

mixture was allowed to cool to room temperature, and

then passed through a short column (silica, CH₂Cl₂).

The major fraction was concentrated and again

chromatographed [silica, hexanes/CH₂Cl₂(2:1 then 1:1)]

to give a greenish blue solid (15 mg, 8%): ¹H NMR (300

MHz, CDCl₃) d 0.35 (s, 9H), 1.51 (s, 18H), 1.97 (s, 6H),

4.51 (s, 2H), 7.42 (s, 1H), 7.82 (d, J = 9.0 Hz, 2H), 7.87

(d, J = 7.8 Hz, 2H), 7.96 (m, 2H), 8.03 (d, J = 8.1 Hz, 2H),

8.14 (d, J = 8.1 Hz, 2H), 8.56 (d, J = 4.5 Hz, 1H), 8.66 (m,

2H), 8.72 (m, 2H), 8.81 (d, J = 4.5 Hz, 1H), 9.61 (s, 1H).

LD-MS: m/z obsd. 964.60. FAB-MS: m/z obsd. 964.2382,

calcd. 964.2370 ([M]⁺, M = C₅₃H₅₃IN₄SiZn). UV-vis

(toluene): l_abs, nm 417 (log e = 5.30, fwhm = 20 nm),

629 (4.86); l_em, nm 634, 691.

3-[4-(2-(Trimethylsilyl)ethynyl)phenyl]-9-(3,5-di-

tert-butylbenzoyl)dipyrromethane (17). Samples of

16 (1.0 g, 1.8 mmol), Pd₂(dba)₃(125 mg, 0.140 mmol),

Ph₃As (334 mg, 1.09 mmol), and CuI (26 mg, 0.14 mmol)

were added to a 50 mL Schlenk ﬂask. The ﬂask was

evacuated and purged with argon three times. Then

deaerated anhydrous THF/TEA (18 mL, 1:1) was added

followed by (trimethylsilyl)ethyne (376 mL, 2.66 mmol).

The ﬂask was sealed and immersed in an oil bath (37°C),

and then the mixture was stirred for 18 h. Then CH₂Cl₂

(30 mL) was added, and the mixture was ﬁltered (Celite)

and washed (CH₂Cl₂). The ﬁltrate was concentrated. Flash

chromatography [silica, hexanes/ethyl acetate (3:1)]

afforded a yellow oil which solidiﬁed on cooling (780 mg,

1

82%): mp 126–127°C. H NMR (300 MHz, CDCl₃) d

0.26 (s, 9H), 1.27 (s, 18H), 4.20 (s, 2H), 6.20 (m, 2H),

6.44 (m, 1H), 6.87 (m, 1H), 7.40 (d, J = 8.1 Hz, 2H), 7.50

(d, J = 8.1 Hz, 2H), 7.64 (m, 1H), 7.72 (m, 2H), 10.14

(br, 1H), 11.73 (br, 1H). ¹³C NMR (75 MHz, CDCl₃) d

0.7, 25.7, 31.9, 35.5, 94.4, 106.2, 109.1, 111.1, 118.1,

120.4, 122.0, 123.9, 124.1, 124.9, 126.9, 128.5, 131.5,

132.7, 138.1, 138.2, 141.3, 151.7, 187.45. Anal. calcd.

for C₃₅H₄₂N₂OSi: C, 78.60; H, 7.92; N, 5.24. Found C,

78.09; H, 8.03; N, 5.13.

1-Bromo-3-[4-(2-(trimethylsilyl)ethynyl)phenyl]-

9-(3,5-di-tert-butylbenzoyl)dipyrromethane (18). A

solution of 17 (100 mg, 0.19 mmol) in anhydrous THF

(6 mL) was cooled to -78 °C under argon. NBS (33 mg,

0.19 mmol) was added, and the reaction mixture was

stirred for 1 h (-78°C), whereupon the reaction was

quenched by the addition of a mixture of hexanes

and water (20 mL, 1:1). The mixture was allowed to

warm to 0°C. The aqueous portion was extracted with

anhydrous ether, and the combined organic extract

was dried (K₂CO₃). The solvent was evaporated under

vacuum without heating. Flash chromatography

[silica, hexanes/ether (2:1)] afforded a pale yellow

1

solid (83 mg, 72%): mp 163–165 °C (dec.). H NMR

(300 MHz, CDCl₃) d 0.27 (s, 9H), 1.30 (s, 18H), 4.20

(s, 2H), 6.08 (m, 1H), 6.23 (m, 1H), 6.94 (m, 1H), 7.36

(d, J = 7.8 Hz, 2H), 7.52 (d, J = 7.8 Hz, 2H), 7.66 (s,

1H), 7.74 (s, 2H), 10.75 (br, 1H), 12.14 (br, 1H). ¹³C

NMR (75 MHz, CDCl₃) d 0.7, 24.8, 31.2, 34.9, 94.0,

97.9, 105.2, 110.0, 110.7, 120.3, 123.1, 123.7, 123.8,

125.5, 126.5, 127.9, 130.8, 132.0, 136.3, 137.3, 140.5,

151.1, 187.3. FAB-MS: m/z obsd. 612.2184, calcd.

612.2166 ([M]⁺, M = C₃₅H₄₁BrN₂OSi). Anal. calcd. for

Zn(II)-3-Bromo-17,18-dihydro-10-mesityl-18,18-

dimethylporphyrin (ZnC-22). Following a streamlined

procedure [17], a solution of Western half 19 (153 mg,

0.569 mmol) and Eastern half 20 (210 mg, 0.569 mmol)

in distilled CH₂Cl₂was treated with a solution of

p-TsOH·H₂O(541mg, 2.85mmol)inanhydrousmethanol

(6 mL) under argon. The resulting red reaction mixture

was stirred at room temperature for 40 min. A sample

J. Porphyrins Phthalocyanines 2015; 19: 19–26

20

D. RA ET AL.

of 2,2,6,6-tetramethylpiperidine (1.2 mL, 7.11 mmol)

was added. The reaction mixture was concentrated. The

resulting solid was dissolved in CH₃CN (56.9 mL) and

subsequently treated with 2,2,6,6-tetramethylpiperidine

(2.4 mL, 14 mmol), Zn(OAc)₂(1.62 g, 8.81 mmol), and

AgOTf (446 mg, 1.74 mmol). The resulting suspension

wasreﬂuxedfor14hexposedtoair.Thecrudemixturewas

ﬁltered through a pad of silica (CH₂Cl₂). The ﬁltrate was

chromatographed [silica, hexanes/CH₂Cl₂(2:1 → 1:1 →

(silica, CH₂Cl₂) to give a green solid (40.5 mg, 95%): ¹H

NMR (300 MHz, CDCl₃) d 1.86 (s, 6H), 2.02 (s, 6H),

2.59 (s, 3H), 2.64 (s, 3H), 4.47 (s, 2H), 7.21 (bs, 2H), 8.06

(s, 1H), 8.32 (d, J = 4.2 Hz, 1H), 8.36 (s, 1H), 8.47 (d, J =

4.2 Hz, 1H), 8.56 (d, J = 4.2 Hz, 1H), 8.58 (s, 1H), 8.72

(d, J = 4.2 Hz, 1H), 9.25 (s, 1H). MALDI-MS: m/z obsd.

566.5. ESI-MS: m/z obsd. 566.1472, calcd. 566.1477

([M]⁺, M = C₃₂H₃₀N₄SZn). UV-vis (toluene): l_abs, nm 410,

616 nm; l_em, nm (l_ex= 410 nm, toluene) 621, 666.

1

1:2)] to afford a green solid (119 mg, 34%): H NMR

Zn(II)-17,18-dihydro-10-mesityl-3-methoxy-18,18-

dimethylporphyrin (ZnC-25). Modifying the procedure

used to synthesize ZnC-24 [73], a mixture of ZnC-22

(10. mg, 0.017 mmol), Pd₂(dba)₃(3.1 mg, 0.0034 mmol,

20 mol%), Xantphos (2.1 mg, 0.0041 mmol, 20 mol%),

and sodium methoxide (2.7 mg, 0.051 mmol) was dried

in a Schlenk ﬂask for 1 h. Degassed xylenes (1.6 mL)

was added, and the mixture was purged with argon.

The reaction mixture was heated to reﬂux for 24 h.

After cooling to room temperature, the reaction mixture

was treated with CH₂Cl₂and water. The organic layer

was separated, dried (Na₂SO₄), and concentrated. The

resulting residue was chromatographed [silica, hexanes/

CH₂Cl₂(1:1→1:2)] to give a green solid (1.5 mg, 16%):

¹H NMR (300 MHz, CDCl₃) d 1.85 (s, 6H), 1.98 (s, 6H),

2.58 (s, 3H), 4.41 (s, 2H), 4.53 (s, 3H), 7.19 (s, 2H), 7.74

(s, 1H), 8.26 (d, J = 3.9 Hz, 1H), 8.29 (s, 1H), 8.44 (d, J =

3.9 Hz, 1H), 8.46 (d, J = 3.9 Hz, 1H), 8.50 (s, 1H), 8.66

(d, J = 3.9 Hz, 1H), 9.51 (s, 1H). MALDI-MS: m/z obsd.

551.0. ESI-MS: m/z obsd. 550.1707, calcd. 550.1706

([M]⁺, M = C₃₃H₃₀N₄OZn). UV-vis (toluene): l_abs, nm

404, 603; l_em, nm (l_ex= 410 nm, toluene) 606, 656.

3,13-Dibromo-17,18-dihydro-18,18-dimethyl-10-(4-

methylphenyl)porphyrin (C-29). Following a reported

procedure [13, 21], a mixture of Eastern half 21 (0.284 g,

0.674 mmol) andWestern half 19 (0.202 g, 0.750 mmol) in

CH₂Cl₂(20mL)wastreatedwithasolutionofp-TsOH·H₂O

(0.640 g, 3.37 mmol) in MeOH (5 mL). The resulting

mixture was stirred at room temperature for 30 min.

A sample of 2,2,4,4-tetramethylpiperidine (3.21 mL,

18.9 mmol) was added, and the resulting mixture was

concentrated. The resulting brown solid was suspended

in acetonitrile (67 mL), and samples of Zn(OAc)₂(1.86 g,

10.1 mmol), 2,2,4,4-tetramethylpiperidine (3.25 mL,

19.1 mmol), and AgOTf (0.520 g, 2.00 mmol) were

added. The resulting mixture was reﬂuxed for 18 h. The

mixture was concentrated and ﬁltered through silica using

hexanes/CH₂Cl₂as an eluent. Fractions containing chlorin

were collected, concentrated, dissolved in CH₂Cl₂(20

mL), and treated with TFA (0.400 mL, 5.23 mmol). The

resulting mixture was stirred for 4 h and quenched by the

addition of saturated aqueous NaHCO₃. The organic layer

was separated, washed (water and brine), dried (Na₂SO₄),

and concentrated. Column chromatography (silica,

hexanes/CH₂Cl₂) afforded a green solid (47 mg, 12%):

¹H NMR (400 MHz, CDCl₃) d -2.02 (bs, 1H), -1.64 (bs,

1H), 2.04 (s, 6H), 2.69 (s, 3H), 4.64 (s, 2H), 7.54 (d, J =

7.8 Hz, 2H), 7.99 (d, J = 7.8 Hz, 2H), 8.60 (d, J = 4.4 Hz,

(300 MHz, CDCl₃) d 1.84 (s, 6H), 2.01 (s, 6H), 2.59

(s, 3H), 4.50 (s, 2H), 7.22 (s, 2H), 8.30 (d, J = 3.4 Hz,

1H), 8.49 (s, 1H), 8.53 (d, J = 3.9 Hz, 1H), 8.60 (d,

J = 4.5 Hz, 1H), 8.67 (s, 1H), 8.78 (s, 1H), 8.87 (d, J =

3.9 Hz, 1H), 9.73 (s, 1H). LD-MS: m/z obsd. 599.8.

ESI-MS: m/z obsd. 598.0710, calcd. 598.0705 ([M]⁺,

M = C₃₁H₂₇BrN₄Zn). UV-vis: l_abs, nm 410, 614; l_em, nm

(l_ex= 410 nm) 617, 647.

Zn(II)-17,18-dihydro-3-(N,N-dimethylamino)-10-

mesityl-18,18-dimethylporphyrin (ZnC-23). Follow-

ing a procedure for amination of aryl bromides [72]

with slight modiﬁcation, a mixture of ZnC-22 (10. mg,

0.017 mmol), Pd(OAc)₂(1.5 mg, 0.0068 mmol,

40 mol%), (tert-butyl)₃PHBF₄(1.9 mg, 0.0068 mmol,

40mol%),and sodiumtert-butoxide(4.9mg,0.051mmol,

3 equiv) was dried in a Schlenk ﬂask for 1 h. Degassed

toluene (1.6 mL) and dimethylamine (85 mL, 2.0 M

in toluene, 0.17 mmol, 10 equiv) were added, and the

mixture was purged with argon. The reaction mixture

was heated to reﬂux for 48 h. After cooling to room

temperature, the reaction mixture was treated with

CH₂Cl₂and water. The organic layer was separated, dried

(Na₂SO₄), and concentrated. The resulting residue was

chromatographed [silica, hexanes/CH₂Cl₂(1:1 → 1:2)],

followed by a second column (silica, CH₂Cl₂with 1%

TEA) to give a green solid (4.6 mg, 49%, 95% purity):

¹H NMR (300 MHz, CDCl₃) d 1.87 (s, 6H), 1.95 (s, 6H),

2.58 (s, 3H), 3.61 (s, 6H), 4.36 (s, 2H), 7.19 (s, 2H), 7.69

(s, 1H), 8.18 (s, 1H), 8.22 (d, J = 4.1 Hz, 1H), 8.39 (m,

3H), 8.61 (d, J = 4.1 Hz, 1H), 9.49 (s, 1H). MALDI-MS:

m/z obsd. 563.1. ESI-MS: m/z obsd. 564.2097, calcd.

564.2100 ([M + H]⁺, M = C₃₃H₃₃N₅Zn). UV-vis

(toluene): l_abs, nm 410, 612; l_em, nm (l_ex= 410 nm,

toluene) 617, 664.

Zn(II)-17,18-dihydro-10-mesityl-18,18-dimethyl-3-

methylthioporphyrin (ZnC-24). Following a procedure

for aryl thioether formation [73], a mixture of ZnC-22

(45.1mg,0.0750mmol),Pd₂(dba)₃(13.7mg,0.0150mmol,

20 mol%), Xantphos (8.7 mg, 0.015 mmol, 20 mol%),

and sodium thiomethoxide (15.8 mg, 0.225 mmol, 3 equiv

relative to ZnC-22) was dried in a Schlenk ﬂask for 1 h.

Degassed xylenes (1.5 mL) was added, and the mixture

was purged with argon. The reaction mixture was heated

to reﬂux for 24 h. After cooling to room temperature,

the reaction mixture was treated with CH₂Cl₂and water.

The organic layer was separated, dried (Na₂SO₄), and

concentrated. The resulting residue was chromatographed

J. Porphyrins Phthalocyanines 2015; 19: 20–26

PROGRESS TOWARDS SYNTHETIC CHLORINS WITH GRADED POLARITY, CONJUGATABLE SUBSTITUENTS

21

1H), 8.76 (s, 1H), 8.83 (s, 1H), 8.94 (d, J = 4.4 Hz, 1H),

8.95 (s, 1H), 9.11 (s, 1H), 9.87 (s, 1H). ¹³C NMR (100

MHz, CDCl₃): d, ppm 21.6, 31.1, 46.5, 52.0, 94.4, 95.3,

105.8, 113.4, 118.5, 122.1, 124.4, 127.9, 129.3, 132.3,

132.7, 132.9, 134.1, 134.6, 137.2, 137.8, 138.0, 140.1,

151.0, 153.2, 163.3, 175.7. ESI-MS: m/z obsd. 587.0450,

calcd. 587.0440 ([M + H]⁺, M = C₂₉H₂₄N₄Br₂). (The same

reaction on a 2.5 mmol scale provided 11% yield.)

128.7, 128.8, 129.1, 130.3, 132.0, 132.2, 132.9, 133.1,

134.1, 134.8, 135.4, 137.7, 138.3, 140.15, 140.22, 151.8,

153.7, 163.8, 176.0. LD-MS: m/z obsd. 631.6, calcd.

631.3 ([M + H]⁺, M = C₄₅H₃₄N₄).

17,18-Dihydro-18,18-dimethyl-10-(4-methyl-

phenyl)-3,13-bis[2-(4-(2-phenylethynyl)phenyl)-

ethynyl]porphyrin (C-32). Following Procedure A,

a mixture of C-29 (24.0 mg, 40.8 mmol), 4-ethynyl-1-

(2-phenylethynyl)benzene (41 mg, 0.20 mmol), and

Pd(PPh₃)₂Cl₂(5.6 mg, 8.0 mmol) in DMF/TEA (4 mL)

was allowed to react overnight. Final workup entailed

column chromatography [silica, hexanes/CH₂Cl₂(2:1)]

to afford a purple-brown solid (27.2 mg, 80%). The

resulting product contained a trace amount of blue-

ﬂuorescent material (most probably a trace amount of

4-ethynyl-1-(2-phenylethynyl)benzene or homocoupled

byproduct thereof). For ﬂuorescence studies a sample of

product (~20 mg) was dissolved in CHCl₃/MeOH (6 mL,

5:1) and treated with Zn(OAc)₂·2H₂O (0.180 g, 0.820

mmol). The resulting mixture was stirred for 4 h, diluted

with CH₂Cl₂, washed (aqueous NaHCO₃and brine), dried

(Na₂SO₃), and concentrated. Column chromatography

[silica, hexanes/CH₂Cl₂(1:1)] afforded a green solid.

The resulting solid was dissolved in CH₂Cl₂(20 mL) and

treated with TFA (0.4 mL). The resulting mixture was

stirred for 4 h, diluted with CH₂Cl₂, treated with aqueous

NaHCO₃and subsequently stirred for 5 min. The organic

layer was separated, washed (water and brine), dried

(Na₂SO₄), and concentrated. Column chromatography

[silica, hexanes/CH₂Cl₂(2:1)] afforded spectroscopically

pure product (10.5 mg): ¹H NMR (400 MHz, CDCl₃): d,

ppm -1.84 (bs, 1H), -1.40 (bs, 1H), 2.07 (s, 6H), 2.70 (s,

3H), 4.67 (s, 2H), 7.38–7.42 (m, 6H), 7.56 (d, J = 7.8 Hz,

2H), 7.59–7.62 (m, 4H), 7.66 (d, J = 8.4 Hz, 2H), 7.69 (d,

J = 8.4 Hz, 2H), 7.83 (d, J = 8.4 Hz, 2H), 7.93 (d, J =

8.4 Hz, 2H), 8.04 (d, J = 7.8 Hz, 2H), 8.64 (d, J = 4.3 Hz,

1H), 8.80 (s, 1H), 8.94 (s, 1H), 8.98 (d, J = 4.3 Hz,

1H), 9.01 (s, 1H), 9.27 (s, 1H), 9.99 (s, 1H). ¹³C NMR

(100 MHz, CDCl₃): d, ppm 21.7, 31.2, 46.6, 52.2, 86.2,

86.5, 89.3, 91.7, 91.8, 94.9, 95.6, 96.6, 97.7, 100.0,

105.4, 117.5, 122.4, 122.6, 123.1, 123.2, 123.4, 123.6,

123.9, 125.1, 127.9, 128.6, 128.7, 130.4, 131.8, 131.9,

132.0, 132.1, 133.0, 133.2, 134.2, 134.9, 135.4, 137.7,

138.2, 140.17, 140.20, 151.9, 153.8, 163.8, 176.0.

ESI-MS: m/z obsd. 831.3441, calcd. 831.3482 ([M + H]⁺,

M = C₆₁H₄₂N₄).

General procedures for Sonogashira reaction

with chlorin C-29. Procedure A. Samples of C-29, the

appropriate ethyne derivative, and Pd(PPh₃)₂Cl₂were

placed in a Schlenk ﬂask, whereupon solvent (DMF/TEA,

1:1) was added. The reaction mixture was degassed by

freeze-pump-thaw (three cycles), after which the reaction

ﬂask was ﬁlled with nitrogen and placed in preheated oil

bath. The reaction mixture was stirred at 80–85°C with

monitoring of the reaction by absorption spectroscopy and

TLC [silica, hexanes/CH₂Cl₂(2:1)]. Upon consumption

of all starting material, the reaction mixture was allowed

to cool to room temperature, diluted with ethyl acetate,

washed (water, brine), dried (Na₂SO₄), and concentrated.

Subsequent puriﬁcation is described for each instantiation

below. Procedure B. Samples of C-29, the appropriate

ethyne derivative, and tri-o-tolylphosphine were placed in

a Schlenk ﬂask, whereupon solvent (toluene/TEA, 5:1) was

added. The reaction mixture was degassed by freeze-pump-

thaw (two cycles), and then a sample of Pd₂(dba)₃was

added. The reaction mixture was degassed again by freeze-

pump-thaw (three cycles), after which the reaction ﬂask

was ﬁlled with nitrogen and placed in a pre-heated oil bath.

(When TMS-ethyne was used, the addition of TMS-ethyne

was done after the ﬁnal freeze-pump-thaw cycle given the

low boiling point of this ethyne.) The reaction mixture was

stirred at 60°C with monitoring of the reaction progress

by absorption spectroscopy and TLC. If a signiﬁcant

amount of the starting material was present after ~4–5 h,

another batch of Pd₂(dba)₃and tri-o-tolylphosphine was

added under nitrogen. Upon consumption of all starting

material, the reaction mixture was allowed to cool to

room temperature and was then concentrated. Subsequent

puriﬁcation is described for each instantiation below.

17,18-Dihydro-18,18-dimethyl-10-(4-methyl-

phenyl)-3,13-bis(2-phenylethynyl)porphyrin (C-31).

Following Procedure A, a mixture of C-29 (24.0 mg,

40.8 mmol), phenylethyne (20 mL, 200 mmol), and

Pd(PPh₃)₂Cl₂(5.6 mg, 8.0 mmol) in DMF/TEA (4 mL)

was allowed to react overnight. Final workup entailed

column chromatography [silica, hexanes/CH₂Cl₂(2:1)]

to afford a purple-brown solid (23.4 mg, 91%): ¹H NMR

(400 MHz, CDCl₃): d, ppm -1.85 (bs, 1H), -1.43 (bs, 1H),

2.06 (s, 6H), 2.69 (s, 3H), 4.66 (s, 2H), 7.45–7.59 (m,

8H), 7.86–7.88 (m, 2H), 7.97–7.99 (m, 2H), 8.02 (d, J =

7.9 Hz, 2H), 8.64 (d, J = 4.3 Hz, 1H), 8.80 (s, 1H), 8.92

(s, 1H), 8.96 (d, J = 4.3 Hz, 1H), 9.02 (s, 1H), 9.29 (s,

1H), 10.03 (s, 1H). ¹³C NMR (100 MHz, CDCl₃): d, ppm

21.6, 31.2, 46.5, 52.2, 84.3, 84.6, 94.8, 95.5, 96.8, 98.0,

105.4, 117.8, 122.4, 122.7, 123.5, 123.6, 125.0, 127.9,

17,18-Dihydro-3,13-bis[2-(4-(2-(4-methoxy-

carbonylphenyl)ethynyl)phenyl)ethynyl]-18,18-

dimethyl-10-(4-methylphenyl)porphyrin (C-33).

Following Procedure A, a mixture of C-29 (24.0 mg,

40.8 mmol), methyl 4-[2-(4-ethynylphenyl)ethynyl]

benzoate(52 mg, 0.20 mmol), and Pd(PPh₃)₂Cl₂(5.6 mg,

8.0 mmol) in DMF/TEA (4 mL) was allowed to react

overnight. Final workup entailed column chromatography

(silica, CH₂Cl₂) to afford a purple-brown solid (16.1 mg,

1

42%): H NMR (400 MHz, CDCl₃): d, ppm -1.84 (bs,

1H), -1.40 (bs, 1H), 2.07 (s, 6H), 2.70 (s, 3H), 3.96 (s,

J. Porphyrins Phthalocyanines 2015; 19: 21–26

22

D. RA ET AL.

6H), 4.67 (s, 2H), 7.66 (d, J = 7.8 Hz, 2H), 7.63–7.68

(three overlapped doublets, 6H), 7.71 (d, J = 8.3 Hz, 2H),

7.84 (d, J = 8.2 Hz, 2H), 7.95 (d, J = 8.2 Hz, 2H), 8.03 (d,

J = 7.8 Hz, 2H), 8.05 (d, J = 8.3 Hz, 2H), 8.07 (d, J = 8.3

Hz, 2H), 8.64 (d, J = 4.4 Hz, 1H), 8.81 (s, 1H), 8.94 (s,

1H), 8.98 (d, J = 4.4 Hz, 1H), 9.02 (s, 1H), 9.27 (s, 1H),

9.99 (s, 1H). LD-MS: m/z obsd. 947.5, calcd. 947.4 ([M +

H]⁺, M = C₆₅H₄₆N₄O₄).

¹³C NMR spectrum showed a low signal-to-noise ratio, in

which case identiﬁcation of several low-intensity signals

in the aromatic region was ambiguous). LD-MS: m/z

obsd. 686.4, calcd. 686.3 ([M]⁺, M = C₄₇H₃₄N₄O₂).

17,18-Dihydro-18,18-dimethyl-10-(4-methylphenyl)-

3,13-bis[2-(4-(N,N-dimethylamino)phenyl)ethynyl]

porphyrin (C-36). Following Procedure B, a mixture

of C-29 (20.0 mg, 34.0 mmol), 4-(N,N-dimethylamino)

phenylethyne (14.8 mg, 102 mmol), Pd₂(dba)₃(6.2 mg,

6.7 mmol), and P(o-tol)₃(13.4 mg, 44.1 mmol) in toluene/

TEA (6.8 mL) was allowed to react overnight. Final workup

entailed column chromatography (silica, CH₂Cl₂) to provide

a semi-pure product, which was washed with MeOH (with

sonication, twice) to afford a purple solid (15.0 mg, 61%):

¹H NMR (400 MHz, CDCl₃): d, ppm -1.87 (bs, 1H), -1.44

(bs, 1H), 2.05 (s, 6H), 2.86 (s, 3H), 3.08 (s, 6H), 3.11 (s,

6H), 4.64 (s, 2H), 6.81 (d, J = 8.9 Hz, 2H), 6.85 (d, J = 8.8

Hz, 2H), 7.53 (d, J = 7.8 Hz, 2H), 7.74 (d, J = 8.8 Hz, 2H),

7.85 (d, J = 8.9 Hz, 2H), 8.02 (d, J = 7.8 Hz, 2H), 8.62 (d,

J = 4.3 Hz, 1H), 8.76 (s, 1H), 8.85 (s, 1H), 8.93 (s, 1H), 8.96

(d, J = 4.3 Hz, 1H), 9.28 (s, 1H), 10.02 (s, 1H). ESI-MS: m/z

obsd. 717.3692, calcd. 717.3700 ([M + H]⁺, M = C₄₉H₄₄N₆).

1 7 , 1 8 - D i h y d r o - 1 8 , 1 8 - d i m e t h y l - 1 0 - ( 4 -

methylphenyl)-3,13-bis[2-(phenanthren-9-yl)

ethynyl]porphyrin (C-37). Following Procedure A,

a mixture of C-29 (19.7 mg, 33.5 mmol), 9-ethynyl-

phenanthrene (16.2 mg, 80.2 mmol), and Pd(PPh₃)₂Cl₂

(4.7 mg, 6.7 mmol) in DMF/TEA (2.3 mL) was allowed

to react overnight. Final workup entailed column

chromatography [silica, hexanes/CH₂Cl₂(3:2)] to afford

a violet-brown solid (7.4 mg, 27%): ¹H NMR (400 MHz,

CDCl₃): d, ppm -1.77 (bs, 1H), -1.35 (bs, 1H), 2.10 (s,

6H), 2.72 (s, 3H), 4.71 (s, 2H), 7.60 (d, J = 7.8 Hz, 2H),

7.66–7.79 (m, 4H), 7.81–7.94 (m, 4H), 7.99–8.02 (m,

1H), 8.04–8.06 (m, 1H), 8.09 (d, J = 7.8 Hz, 2H), 8.41

(s, 1H), 8.52 (s, 1H), 8.68 (d, J = 4.3 Hz, 1H), 8.74–8.75

(m, 2H), 8.77–8.79 (m, 1H), 8.81–8.83 (m, 1H), 8.85 (s,

1H), 8.96–8.98 (m, 1H), 9.02 (d, J = 4.3 Hz, 1H), 9.05 (s,

1H), 9.05–9.07 (m, 1H), 9.14 (s, 1H), 9.45 (s, 1H), 10.16

(s, 1H). ¹³C NMR (100 MHz, CDCl₃): d, ppm 21.7, 31.3,

45.6, 52.2, 88.8, 89.1, 95.0, 95.2, 95.7, 96.4, 105.5 117.9,

119.9, 120.0, 122.5, 122.8, 122.9, 123.1, 123.2, 125.2,

127.2, 127.3, 127.4, 127.48, 127.54, 127.8, 127.9, 128.9,

129.0, 130.3, 130.4, 130.5, 130.6, 130.7, 131.4, 131.5,

132.4, 132.8, 133.0, 133.2, 134.2, 135.0, 135.5, 137.7,

138.3, 140.3, 140.4, 151.9, 153.8, 163.9, 176.1. LD-MS:

m/z obsd. 830.6, calcd. 830.3 ([M]⁺, M = C₆₁H₄₂N₄).

17,18-Dihydro-18,18-dimethyl-3,13-bis(3-N,N-

dimethylamino-1-propyn-1-yl)-10-(4-methylphenyl)-

porphyrin (C-38). Following Procedure A, a mixture of

C-29(24.0mg,40.8mmol),N,N-dimethylpropargylamine

(21 mL, 0.20 mmol), and Pd(PPh₃)₂Cl₂(5.6 mg, 8.0 mmol)

in DMF/TEA (4 mL) was allowed to react overnight.

Final workup entailed column chromatography [silica,

CH₂Cl₂/MeOH (25:1)] to afford a violet-brown solid

17,18-Dihydro-3,13-bis[2-(4-methoxycarbonylphenyl)

ethynyl]-18,18-dimethyl-10-(4-methylphenyl)-porphyrin

(C-34). Following Procedure A, a mixture of C-29

(45.5 mg, 77.3 mmol), 4-methoxycarbonylphenylethyne

(37.1 mg, 232 mmol), and Pd(PPh₃)₂Cl₂(10.7 mg,

15.2 mmol) in DMF/TEA (4.9 mL) was allowed to react

overnight. Final workup entailed column chromatography

[silica, hexanes CH₂Cl₂(1:1)] to afford a purple-brown

1

solid (25.1 mg, 43%): H NMR (400 MHz, CDCl₃): d,

ppm -1.83 (bs, 1H), -1.40 (bs, 1H), 2.07 (s, 6H), 2.70 (s,

3H), 3.99 (s, 6H), 4.67 (s, 2H), 7.56 (d, J = 7.8 Hz, 2H),

7.90 (d, J = 8.3 Hz, 2H), 8.00 (d, J = 8.3 Hz, 2H), 8.03

(d, J = 7.8 Hz, 2H), 8.17 (d, J = 8.3 Hz, 2H), 8.20 (d, J =

8.3 Hz, 2H), 8.64 (d, J = 4.3 Hz, 1H), 8.81 (s, 1H), 8.95

(s, 1H), 8.98 (d, J = 4.3 Hz, 1H), 9.03 (s, 1H), 9.26 (s,

1H), 9.98 (s, 1H). ESI-MS: m/z obsd. 747.2963, calcd.

747.2965 ([M + H]⁺, M = C₄₉H₃₈N₄O₄).

17,18-Dihydro-3,13-bis[2-(4-formylphenyl)

ethynyl]-18,18-dimethyl-10-(4-methylphenyl)

porphyrin (C-35). Following Procedure B, a mixture

of C-29 (22.3 mg, 39.8 mmol), 4-formylphenylethyne

(12.7 mg, 99.5 mmol), Pd₂(dba)₃(7.1 mg, 7.7 mmol),

and P(o-tol)₃(15.4 mg, 50.6 mmol) in toluene/TEA

(3.9 mL) was allowed to react overnight. TLC analysis

showed complete consumption of starting material, and

formation of one major product accompanied by a smaller

amount of byproducts. Final workup entailed column

chromatography (silica, CH₂Cl₂) to provide a semi-pure

product, for which ¹H NMR spectroscopy showed a small

amount of impurities in the aromatic region (probably

dba remnants, and/or a product of homocoupling of

4-formylphenylethyne). Further puriﬁcation by column

chromatography [silica, hexanes/CH₂Cl₂(1:2), twice]

afforded a pure product as a purple-brown solid, but with

a signiﬁcant loss in yield (4.4 mg, 16%; no effort was

made to optimize the reaction conditions to improve the

1

yield): H NMR (400 MHz, CDCl₃): d, ppm -1.79 (bs,

1H), -1.36 (bs, 1H), 2.08 (s, 6H), 2.70 (s, 3H), 4.68 (s,

2H), 7.56 (d, J = 7.7 Hz, 2H), 7.98-8.12 (m, 10H), 8.64

(d, J = 4.3 Hz, 1H), 8.82 (s, 1H), 8.97 (s, 1H), 8.98 (d,

overlapped with a singlet, 1H), 9.06 (s, 1H), 9.27 (s, 1H),

9.99 (s, 1H), 10.11 (s, 1H), 10.17 (s, 1H). ¹³C NMR (100

MHz, CDCl₃): d, ppm 21.7, 31.2, 46.6, 52.2, 88.2, 88.8,

95.2, 95.6, 96.0, 97.0, 105.3, 116.9, 121.8, 122.9, 125.4,

125.7, 127.9, 128.4, 129.2, 129.6, 129.8, 129.98, 129.99,

130.00, 130.91, 132.4, 132.6, 133.3, 134.1, 134.9, 135.5,

135.7, 136.0, 137.9, 138.0, 140.2, 148.0, 152.1, 153.9,

163.9, 176.2, 191.6 (only one signal from the formyl

carbon was visible; due to the low quantity of sample, the

1

(21.4 mg, 88%): H NMR (400 MHz, CDCl₃): d, ppm

-1.99 (bs, 1H), -1.58 (bs, 2H), 2.04 (s, 6H), 2.64 (s, 6H),

J. Porphyrins Phthalocyanines 2015; 19: 22–26

PROGRESS TOWARDS SYNTHETIC CHLORINS WITH GRADED POLARITY, CONJUGATABLE SUBSTITUENTS

23

2.68 (s, 3H), 2.70 (s, 6H), 3.89 (s, 2H), 3.97 (s, 2H), 4.62

(s, 2H), 7.53 (d, J = 7.8 Hz, 2H), 8.00 (d, J = 7.8 Hz,

2H), 8.60 (d, J = 4.3 Hz, 1H), 8.77 (s, 1H), 8.83 (s, 1H),

8.94 (d, overlapped with singlet, 1H), 8.94 (s, 1H), 9.21

(s, 1H), 9.95 (s, 1H). LD-MS: m/z obsd. 593.0. ESI-MS:

m/z obsd. 593.3406, calcd. 593.3387 ([M + H]⁺, M =

C₃₉H₄₀N₆). The most prominent peak in the LD-MS

spectrum was m/z = 637, which corresponds to [M +

N(CH₃)₂]⁺.

was collected using q/2q scan mode. Three standard

reﬂections were measured every 4800 s of X-ray expo-

sure time. Scaling the data was accomplished using

a 5-point smoothed curved routine ﬁt to the intensity

check reﬂections. The intensity data were corrected for

Lorentz and polarization effects. An empirical absorption

correction was applied using psi scan data. The data were

reduced using routines from the NRCVAX set of programs

[84]. The structure was solved using SIR92 [85]. All non-

hydrogen atoms were reﬁned anisotropically. Hydrogen

atom positions were introduced at calculated positions,

and were allowed to ride on the parent carbon or nitrogen

atom. The hydrogen atom displacement parameters

were also allowed to ride according to the following

expression: U(H) = U_eq({C|N}) + 0.01. The calculated

structure factors were ﬁt to the data using full matrix

least-squares based on F. The calculated structure factors

included corrections for anomalous dispersion from the

usual tabulation [86]. A secondary extinction correction

was included in the ﬁnal cycles of reﬁnement.

17,18-Dihydro-18,18-dimethyl-10-(4-methylphenyl)-

3,13-bis[2-(trimethylsilyl)ethynyl]porphyrin (C-39).

Following Procedure B, a mixture of C-29 (45.5 mg,

77.3 mmol), trimethylsilylethyne (17 mL, 0.12 mmol),

Pd₂(dba)₃(14.2 mg, 15.5 mmol), and P(o-tol)₃(28.3 mg,

93.0 mmol) in toluene/TEA (30.7 mL) was reacted for

5 h. Another batch of trimethylsilylethyne (17 mL, 0.12

mmol), Pd₂(dba)₃(14.2 mg, 15.5 mmol), and P(o-tol)₃

(28.3 mg, 93.0 mmol) was added, whereupon the reaction

mixture was allowed to react overnight. Final workup

entailed column chromatography [silica, hexanes/CH₂Cl₂

1

(4:1)] to provide a purple solid (21.2 mg, 44%): H

NMR (400 MHz, CDCl₃): d, ppm -1.93 (bs, 1H), -1.50

(bs, 1H), 0.54 (s, 9H), 0.61 (s, 9H), 2.06 (s, 6H), 2.70 (s,

3H), 4.67 (s, 2H), 7.55 (d, J = 7.9 Hz, 2H), 8.02 (d, J =

7.9 Hz, 2H), 8.64 (d, J = 4.3 Hz, 1H), 8.78 (s, 1H), 8.91

(s, 1H), 8.98 (d, J = 4.3 Hz, 1H), 8.99 (s, 1H), 9.23 (s,

1H), 9.95 (s, 1H). ¹³C NMR (100 MHz, CDCl₃): d, ppm

0.40, 0.43, 21.6, 31.2, 46.5, 52.2, 94.9, 95.6, 99.4, 99.9,

102.4, 103.9, 105.4, 117.6, 122.5, 122.6, 125.8, 127.8,

131.0, 132.9, 133.2, 134.1, 134.5, 135.6, 137.7, 138.2,

139.9, 140.4, 151.8, 153.7, 163.8, 176.0. ESI-MS:

m/z obsd. 623.3027, calcd. 623.3021 ([M + H]⁺, M =

C₃₉H₄₂N₄Si₂).

OUTLOOK

The ability to create stable chlorins with features of

graded polarity, conjugatable substituents, or wavelength

tunability provides the foundation for pursuit of diverse

applications. While each feature alone can be attained in

a fairly straightforward manner, combinations of two or

all three features present challenges:

·

Chlorinswithhydrophobic,hydrophilic,oramphiphilic

properties are readily obtained.

Hydrophobic chlorins with one or more conjugatable

substituents also are readily obtained, as demonstrated

by the synthesis of two such chlorins here as well as

by the recent work of others [26, 87, 88].

3,13-Diethynyl-17,18-dihydro-18,18-dimethyl-10-

(4-methylphenyl)porphyrin (C-40). A solution of C-29

(11 mg, 18 mmol) in THF/MeOH (2 mL, 1:1) was treated

with K₂CO₃(7.5 mg, 54 mmol). The resulting mixture was

stirred at room temperature for 2 h. The reaction mixture

was diluted with CH₂Cl₂, washed (water, brine), dried

(Na₂SO₄), and concentrated. Column chromatography

[silica, hexanes/CH₂Cl₂(3:2)] provided a brownish-violet

·

Onehydrophilic,bioconjugatablechlorinwasprepared

herein; the chlorin contains facially encumbering

phosphonate groups and a carboxylic acid tether.

The introduction of auxochromes, chieﬂy at the

3,13-positions, enables the long-wavelength Q_yband

to be tuned from 603 nm to 715 nm [21, 77]. Attempts

to employ a previously unexamined set of potential

auxochromes (methoxy, dimethylamino, methylthio,

phenanthryl, p-substituted phenyl, and oligomeric

ethynylphenyl substituents) led to valuable data

concerning structure vs. spectral properties but did

not enlarge the spectral window for wavelength

tuning with chlorins.

1

solid (6.8 mg, 79%): H NMR (400 MHz, CDCl₃): d,

ppm -1.97 (bs, 1H), -1.54 (bs, 1H), 2.04 (s, 6H), 2.68 (s,

3H), 3.88 (s, 1H), 4.03 (s, 1H), 4.63 (s, 2H), 7.53 (d, J =

7.7 Hz, 2H), 7.99 (d, J = 7.7 Hz, 2H), 8.62 (d, J = 4.3 Hz,

1H), 8.79 (s, 1H), 8.91 (s, 1H), 8.94 (d, J = 4.3 Hz, 1H),

9.02 (s, 1H), 9.23 (s, 1H), 9.96 (s, 1H). LD-MS: m/z obsd.

487.8, calcd. 478.2 ([M]⁺, M = C₃₃H₂₆N₄).

X-ray structure determination for 1,3,3-trimethyl-

7-(4-iodophenyl)-2,3,4,5-tetrahydrodipyrrin N¹⁰-

oxide (11). The sample, mounted on the end of a glass ﬁber

using 5-min epoxy, was transferred to the diffractometer.

All X-ray measurements were made on an Enraf-Nonius

CAD4 diffractometer at room temperature. The unit cell

dimensions were determined by a symmetry-constrained

ﬁt of 25 well centered reﬂections and their Friedel pairs

with theta 31° < 2(q) < 36°. A unique quadrant of data

·

The combination of hydrophobic and wavelength

tunability presents little challenge, as the chlorin is

intrinsically neutral with no polar substituents, and

hence is hydrophobic.

The combination of bioconjugatable and wavelength

tunability also presents little challenge, as

a

biconjugatable group can be introduced at the 5- or

10-position via the Eastern half, leaving the 3- and

J. Porphyrins Phthalocyanines 2015; 19: 23–26

24

D. RA ET AL.

13-positions open for introduction of auxochromes

for wavelength tuning.

under number CCDC-1029006. Copies can be obtained

on request, free of charge, via www.ccdc.cam.ac.uk/

data_request/cif or from the Cambridge Crystallographic

Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK

(fax: +44 1223-336-033 or email: data_request@ccdc.

cam.ac.uk).

·

The combination of hydrophilic with wavelength

tunability presents a rather unmet challenge, which

largely stems from the absence of synthetically

versatile and benign groups that impart hydrophilicity.

The facially encumbering aryl-bis(phosphonate)

group described herein illustrates a viable design,

yet whether this approach can be extended alone

to encompass wavelength tunability (or together

with wavelength tunability without compromising

bioconjugatability) remains unclear.

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Article Doi

Progress towards synthetic chlorins with graded polarity, conjugatable substituents, and wavelength tunability

DOI: 10.1142/S1088424615500042

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Article abstract of DOI:10.1142/S1088424615500042

Full text of DOI:10.1142/S1088424615500042

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