The exhaustive reduction of formylporphyrins to methylporphyrins using dimethylformamide/water as reductant under microwave irradiation

Article abstract of DOI:10.1142/S1088424613501022

The reduction of meso-formyl derivatives of 5,15-diaryl- and 5,10,15-triphenylporphyrin (and their nickel(II) complexes) to the corresponding meso-methyl porphyrins is achieved in high yield by microwave heating of the substrate in dimethylformamide (DMF)

Full text of DOI:10.1142/S1088424613501022

Journal of Porphyrins and Phthalocyanines
J. Porphyrins Phthalocyanines 2013; 17: 1–9
DOI: 10.1142/S1088424613501022
Published at http://www.worldscinet.com/jpp/
The exhaustive reduction of formylporphyrins to
methylporphyrins using dimethylformamide/water as
reductant under microwave irradiation
Sarah J. Fletcher, Shannon R. Harper and Dennis P. Arnold*◊
School of Chemistry, Physics and Mechanical Engineering, Queensland University of Technology,
GPO Box 2434, Brisbane 4001, Australia
Received 13 August 2013
Accepted 12 September 2013
ABSTRACT: The reduction of meso-formyl derivatives of 5,15-diaryl- and 5,10,15-triphenylporphyrin
(and their nickel(II) complexes) to the corresponding meso-methyl porphyrins is achieved in high yield
by microwave heating of the substrate in dimethylformamide (DMF) in the presence of acids such as
trifluoroacetic acid, or even just with added water. The reactions are complete in less than 30 min at
250 °C. The reaction is strongly suppressed in very dry DMF in the absence of added acid. The meso-
hydroxymethyl porphyrins are also reduced to the methyl derivatives, suggesting the primary alcohols
may be intermediates in the exhaustive reduction. UV-visible spectra taken at intervals during reaction at
240 °C indicated that at least one other intermediate is present, but it was not identified. In d7-DMF, the
methylporphyrin isolated was mainly Por-CD2H, showing that both of the added hydrogens arise from
the solvent, and not from the added water or acid.
KEYWORDS: methylporphyrins, formylporphyrins, microwave, reduction, dimethylformamide.
Porphyrin scientists have been pursuing for many years
INTRODUCTION
the goal of understanding the electronic properties of
Functional group interconversions on the periphery
macrocyclic pigment molecules held in close proximity,
of porphyrins and metalloporphyrins are important
as a tool for mimicking the natural light-harvesting
for investigating in detail the effects of substituents
and photosynthetic pigments. Moreover, conjugated
on the electronic structures and spectra of porphyrins
diporphyrins have excited interest as possible highly
[1]. Porphyrins (and more generally, porphyrinoids)
efficient non-linear optical dyes [3].
are macrocyclic tetrapyrrole pigments of fundamental
Oneofthesystemsweweretargetingwasthediporphyrin
importance in biology, but they also provide an
unsurpassed platform for studies of electronic structures
imine H41a (Chart 1), a type of porphyrin dyad known
for only one previous analog, namely Zn21b, reported
of non-benzenoid aromatics, electronic absorption
by Anderson and co-workers in 2002 [4]. The formation
and emission spectra, and lately for supramolecular
of this imine by classical aldehyde/amine condensation
chemistry. Furthermore, the ability of porphyrinoids to
under protic acid catalysis is a frustratingly difficult
complex a huge variety of metal ions, either inside or on
reaction, and in our hands the conversions are invariably
the periphery of the macrocycle, adds another dimension
very low. Our preferred meso-substituted porphyrin is the
of synthetic opportunities. The present results arose
very convenient 5,10,15-triphenylporphyrin (H2TriPP)
from our quest to delineate interporphyrin interactions
(Scheme 1). We decided to try the reaction under
in diporphyrins linked by short covalent bridges [2].
microwave irradiation at elevated temperatures, initially
in toluene, then in N,N-dimethylformamide (DMF), in
the presence of trifluoroacetic acid (TFA). Subjecting
◊SPP full member in good standing
equimolar quantities of the aldehyde 2a and primary
aminoporphyrin 2b (Chart 2) to microwave irradiation at
*Correspondence to: Dennis P. Arnold, email: d.arnold@qut.
edu.au, fax: +61 7-3138-1804
Copyright © 2013 World Scientific Publishing Company

2
S.J. FLETCHER ET AL.
Ar
sign of the target imine H41a in the product mixture, this
curious finding prompted us to study this new reaction for
its intrinsic interest, and also as a possible useful addition
to the armoury of synthetic transformations around the
porphyrin periphery. Recently, we have succeeded in
preparing the imine dimer using Lewis acid catalysis; this
work will be reported elsewhere [5].
Ar
N
N
N
N
N
N
N
M
N
N
R
M
R
Ar
Ar
1a: Ar = R = Ph
1b: Ar = 3,5-tBu2C6H3; R = H
EXPERIMENTAL
Chart 1. The target imine dyad 1a (M = Ni, Zn, H2)
General
All solvents were AR grade, distilled on a rotary
evaporator to avoid high-boiling residues.
Column chromatography was performed
using LC60A 40–63 Micron DAVISIL silica
gel. Thin-layer chromatography (TLC) was
performed on Merck Silica Gel 60 F254 plates
and Grace UV254 plates. NMR experiments
were conducted on a Bruker Avance 400
spectrophotometer equipped with a QNP
probe or a Varian VR400 spectrophotometer
fitted with an Auto X probe, operating at 400
MHz for protons. Samples were prepared in
CDCl3, unless otherwise stated, with oven
dried glassware. Spectra were referenced
Ph
Ph
NH
N
NH
N
N
N
Ph
Ph
+
CHO
NH2
HN
HN
Ph
Ph
2b
2a
DMF
TFA
X
mw, 250 °C
Ph
Ph
Ph
NH
NH
N
N
N
1
to CHCl3 at 7.26 ppm for H and CDCl3 at
CH3
HN
Ph
N
Ph
N
77.0 ppm for 13C. Coupling constants are
reported in Hz. Deuterium NMR spectra
Ph
N
HN
HN
N
NH
of Ni4c (Chart 3) were recorded in CHCl3
2c
Ph
Ph
at 61.4 MHz on the Varian instrument,
using broadband proton decoupling, and
H21a
Ph
Scheme 1. Attempted synthesis of imine dyad H21a using microwave heating
CDCl3 as internal reference. Accurate mass
electrospray ionization (ESI) mass spectra
were recorded on a Kronos-G6520B QTOF
mass spectrometer using a flow rate of 0.4 mL/
Ph
Ph
Ni
min and MeOH as eluent. Source temperature
at 325 °C and capillary voltage at 4.0 kV were
employed. Solvent aspiration was accomplished
by nitrogen gas flowing at 5 L/min. Matrix-assisted
laser desorption/ionisation (MALDI) spectra were
obtained at The University of Queensland, Brisbane.
Analysis was performed with anApplied Biosystems
Voyager-DE STR BioSpectrometry workstation.
The instrument was operated in positive polarity
in reflectron mode for analysis. The samples were
spotted on a stainless steel sample plate in toluene
solutions using 2,5-dihydroxybenzoic acid as the
matrix. Data from 100 laser shots (337 nm laser)
were collected, signal-averaged, and processed
with the instrument manufacturer’s Data Explorer
software. UV-visible spectra were recorded in CHCl3
solutions on a Shimadzu UV-1800 spectrophotometer.
DMF was Merck AR grade, dried to constant water
content (but not “anhydrous”) by standing over 3Å
molecular sieves. To investigate the influence of water,
NH
N
N
N
N
N
N
X
X
Ph
Ph
HN
2a: X = CHO
2b: X = NH2
2c: X = CH3
2d: X = CH2OH
Ph
Ph
3a: X = CHO
3b: X = CH3
Chart 2. 5,10,15-triphenylporphyrin (TriPP) derivatives used in this
study
250 °C in DMF with 4 equivalents of TFA, led to 100%
conversion of the aldehyde, with no consumption of the
amine. However, TLC analysis of the product mixture
showed the formation of a very mobile red product, which
was easily separated and identified as the new porphyrin
derivative meso-methylH2TriPP 2c. Although there was no
Copyright © 2013 World Scientific Publishing Company
J. Porphyrins Phthalocyanines 2013; 17: 2–9

THE EXHAUSTIVE REDUCTION OF FORMYLPORPHYRINS TO METHYLPORPHYRINS
3
Ar
M
Et
Et
upon completion. The product was then extracted
with DCM (3 × 20 mL), dried over anhydrous
Na2SO4 and filtered through cotton wool prior to
solvent evaporation. The product was recrystallized
from DCM/pentane to yield burgundy, paper-like
crystals of Ni4d (58 mg, 75%). 1H NMR: dH, ppm
9.81 (1H, s, meso-H), 9.51, 9.12, 8.94, 8.93 (each
2H, d, J = 4.8 Hz, b-H), 7.88 (4H, br s, o-Ar-H),
7.76 (2H, br s, p-Ar-H), 6.63 (2H, d, J = 6.0,
CH2), 2.58 (1H, t, J = 6.0, OH), 1.50 (36H, s, tert-
butyl-H). UV-vis: lmax, nm (e, 103 M-1.cm-1) 410
(177), 524 (15.2), 554 (6.3). MS (MALDI): m/z
773.9 (calcd. for [M + H]+ 773.4), 756.8 (calcd. for
[M – OH + H]+ 756.4).
Et
Et
Et
X
N
N
N
N
N
N
N
N
X
M
Et
Ar = 3,5-tBu2C6H3
4a: X = CHO
4b: X = CH3
4c: X = CD2H
4d: X = CH2OH
4e: X = CH2N(CH3)2
Et
Ar
Et
5a: X = CHO
5b: X = CH3
5c: X = H
Chart 3. 5,15-Bis(di-t-butylphenyl)porphyrin (DAP) and octaethyl-
porphyrin (OEP) derivatives used in this study
5-Formyl-10,20-bis(3,5-di-t-butylphenyl)-
either Aldrich Sure-Seal™ or AR DMF distilled under
vacuum from CaH2 directly into the microwave vial were
used. TFA wasAjax LabChem “specially pure for peptide
work”.
porphyrin H24a. NiDAPCHO Ni4a (49 mg, 63
mmol) was dissolved in a mixture of H2SO4 and TFA (1:9,
5 mL) and stirred at room temperature for 15 min and
monitored by TLC (CHCl3 with a drop of TEA; micro-
work-up of TLC sample was performed to neutralize
prior to spotting on TLC plate) until the reaction was
complete. The solution was neutralized with saturated
sodium bicarbonate solution (50 mL) and transferred to a
separating funnel. DCM (3 × 20 mL) was used to extract
the product and the combined organic layers were washed
with deionized water (2 × 75 mL). The extract was then
dried over anhydrous Na2SO4 prior to the evaporation of
solvent. The product was purified by vacuum filtration
of a chloroform solution through a plug of silica gel;
evaporation to small volume and trituration with pentane
yielded fine, dark crystals of H2DAPCHO (H24a, 26 mg,
Preparation of porphyrin starting materials
The following porphyrin starting materials were prepared
by standard methods used in our laboratories and reported
previously: NiTriPPCHO (3a) [6], NiDAPCHO (Ni4a) [6],
NiOEPCHO (Ni5a) [7], H2OEPCHO (H25a) [8].
5-Formyl-10,15,20-triphenylporphyrin 2a. NiTriP-
PCHO (3a, 79 mg, 0.13 mmol) was dissolved in a mixture
of H2SO4 and TFA (1:9, 5 mL) and stirred at room
temperature. After 30 min the starting material was seen by
TLC to be consumed (CHCl3 with a drop of triethylamine;
micro-work-up of TLC samples was performed to
deprotonate the porphyrin dication prior to spotting on TLC
plate). The reaction mixture was neutralized with saturated
sodium bicarbonate (250 mL) and the product extracted
into dichloromethane (DCM). The organic layer was then
washed with water (3 × 100 mL), dried over anhydrous
Na2SO4, filtered and solvents removed. Recrystallization
1
58%). H NMR: dH, ppm 12.64 (s, 1H, CHO), 10.27 (s,
1H, meso-H), 10.10 (br d, 2H, b-H), 9.9.30 (d, 2H, J 4.4,
b-H), 9.13 (d, 2H, J 4.8, b-H), 8.96 (d, 2H, J 4.8, b-H),
8.10 (d, 4H, J = 2.0, o-Ar-H), 7.88 (t, 2H, J = 1.6, p-Ar-H),
1.59 (s, 36H, tert-butyl-H), -2.32 (2H, br s, inner N H).
These data agree with those published by Takanami et al.
[11], who prepared it by a different route. UV-vis: lmax
,
nm (e, 103 M-1.cm-1) 424 (205), 523 (12.7), 564 (10.7),
from CHCl3/MeOH gave dark purple crystals of 2a
1
(52 mg, 72%). H NMR: dH, ppm 12.50 (1H, s, CHO),
10.03 (2H, br d, b-H), 9.00 (2H, d, J 5.0, b-H), 8.78 (2H,
d, J 4.8, b-H), 8.71 (2H, d, J 4.7, b-H), 8.28–8.18 (6H, m,
o-Ph), 7.85–7.75 (9H, m, m,p-Ph), -1.97 (2H, bs, inner N
H). These data agree with those published by Dahms et al.
[9], who prepared it by a different route. The compound
was also reported by Ishkov et al., using selenous acid
oxidation of the methyl derivative, itself prepared by
cyclocondensation [10]; the chemical shift of the CHO
proton is apparently mis-reported as 11.14 ppm.
596 (7.6), 652 (9.3).
General procedure for microwave-heated reactions
of formylporphyrins
To a 2.0–5.0 mL microwave vial, a small stirrer bar
and porphyrin aldehyde (10–12 mmol) were added. DMF
(2 mL) and TFA or water were added to the vial, which
was then fitted with a septum. The solution was degassed
with N2 and sealed with the microwave vial cap. The
solution, which was a pink/red colour, was placed in the
microwave reactor for 30 min at 250 °C. It was cooled to
50 °C in the microwave and then removed. The brown/
red reaction mixture was diluted with DCM (20 mL)
in a separating funnel and washed with deionized water
(5 × 50 mL). The organic layer was dried over anhydrous
Na2SO4 and filtered through cotton wool into a 100 mL
round bottom flask, from which the solvent was
5-Hydroxymethyl-10,20-bis(3,5-di-t-butylphenyl)-
porphyrinatonickel(II) Ni4d. This was prepared by
reduction of the aldehyde Ni4a, according to the general
procedureofInhoffenetal.[8]NiDAPCHONi4b(100mg,
0.129 mmol), NaBH4 (196 mg, 5.19 mmol) and anhydrous
THF (20 mL) were added to a round bottomed flask and
stirred. The reaction progress was monitored by TLC and
the mixture was diluted with deionized water (50 mL)
Copyright © 2013 World Scientific Publishing Company
J. Porphyrins Phthalocyanines 2013; 17: 3–9

4
S.J. FLETCHER ET AL.
evaporated. The resulting residues were separated on
a silica gel column with hexane:chloroform (1:1). The
first eluted and major product, the methylporphyrin, was
recrystallised from DCM/methanol. For the small-scale
trial reactions, the product composition was assessed
semi-quantitatively by recording the 1H NMR spectrum
of the total crude product after removal of the DMF.
For the experiment with DMF-d7, the procedure was
modified slightly, as follows. NiDAPCHO (5 mmol)
was added to a 0.2–0.5 mL microwave vial with a small
stirrer bar. Water (1 mL) and d7-DMF (0.4 mL) were
added and the solution was degassed with N2. The vial
was placed in the microwave reactor for 2 h at 250 °C
with TLC assessment being conducted at 30, 60 and
120 min. The mixture was diluted with water (20 mL)
and extracted with DCM (3 × 10 mL). The combined
organic layers were washed with deionized water (3 × 20
mL) and dried over anhydrous Na2SO4. The solution was
filtered through cotton wool into a 50 mL round bottom
flask and the solvents evaporated. The products were
separated on a silica gel column with chloroform and 1H
NMR showed methylporphyrin to be the major product.
The 2H NMR spectrum of the sample was then recorded.
Data for new methylporphyrin derivatives isolated
from microwave reactions but for which typical yields
were not quantified, are as follows.
Preparative scale microwave synthesis of Ni4b
To a 2.0–5.0 mL microwave vial, a small stirrer bar
and NiDAPCHO (22.8 mg, 29.5 mmol) were added.
DMF (2 mL) and water (5 mL) were added to the vial,
which was then fitted with a septum. The solution was
degassed with N2 and sealed with the microwave vial cap.
The solution, which was a pink/red color, was placed in
the microwave reactor for 30 min at 250 °C. It was cooled
to 50 °C in the microwave and then removed, now brown/
red in color. The reaction mixture was diluted with DCM
(20 mL), placed in a separating funnel and washed with
deionized water (5 × 50 mL). The organic layer was dried
with anhydrous Na2SO4 and filtered through cotton wool
into a 100 mL round bottom flask, from which the solvent
was evaporated. The resulting residues were separated on
a silica gel column with hexane:chloroform (1:1). The
first eluted and major product, NiDAPCH3 (Ni4b, 14 mg,
18 mmol, 61%), was recrystallized from DCM/methanol
to yield fine, red/brown crystals.
Experiment to examine intermediates
NiDAPCHO Ni4a (30 mg, 39 mmol) was added to
a microwave vial (2.0–5.0 mL) with a small stirrer bar.
DMF (3 mL) was added, followed by water (7.5 mL,
0.42 mmol). The red-pink solution was degassed with
N2 and placed in the microwave reactor for 5 min at
240 °C. A 35 mL sample was taken and added to a 5 mL
volumetric flask. The flask was made up to the mark with
chloroform and the UV-vis spectrum was recorded. The
DMF solution was then degassed with N2 and placed in
the microwave for a further 5 min at 240 °C, after which
a sample was taken as described earlier. The process was
repeated until a total of eight samples had been taken and
the reaction appeared to have reached completion.
5-Methyl-10,15,20-triphenylporphyrinatonickel(II)
1
3b. H NMR: dH, ppm 9.36, 8.81 (each 2H, d, J = 4.8
Hz, b-H), 8.70 (s, 4H, b-H), 7.99–8.04 (6H, m, o-H
on 10,15,20-phenyl), 7.67–7.73 (9H, m, m, p-H on
10,15,20-phenyl), 4.29 (3H, s, CH3). UV-vis: lmax, nm (e,
103 M-1.cm-1) 416 (170), 530 (12.5). MS (MALDI): m/z
609.2 (calcd. for [M + H]+ 609.1).
5-Methyl-10,15,20-triphenylporphyrin2c. 1HNMR:
dH, ppm 9.54, 8.93, (each 2H, d, J = 4.8 Hz, b-H),
8.81 (4H, second order AB, b-H), 8.15–8.25 (6H, m,
o-H on 10,15,20-phenyl), 7.75–7.95 (9H, m, m, p-H
on 10,15,20-phenyl), 4.71 (3H, s, CH3), -2.67 (2H, br
s, NH). These data agree for the most part with those
reported by Ishkov et al. [10] MS (ESI): m/z 553.2440
(calcd. for[M + H]+ 553.2387), 575.2258 (calcd. for[M +
Na]+ 575.2206).
RESULTS AND DISCUSSION
After testing the reproducibility of the new observation
in the presence of the aminoporphyrin, we embarked on a
series of microwave reactions to investigate the conditions
that favor clean conversion to the methylporphyrin.
Reactants, catalysts/additives, time and temperature
were varied as shown by the entries in Table 1. As the
aminoporphyrin 2b was recovered unchanged from
experiment 1, the first control experiment was to omit
this reactant, and as expected, the reduction to methyl
porphyrin 2c was just as successful (entries 2 and 3).
Thenceforth, the amine was omitted. Entry 3 shows a
scale-up of the reaction to 68 mmol (42 mg), indicating
the success of this method for larger-scale preparative
use. We next changed the porphyrin substrate, to the
corresponding Ni(II) complex NiTriPPCHO 3a (entries
4, 5) including extending the heating time to 3 h to assess
the stability of the product 3b at 250 °C. These reactions
were also successful in achieving almost quantitative
formyl to methyl conversion.
5-Methyl-10,20-bis(3,5-di-t-butylphenyl)porphyrin
H24b. 1H NMR: dH, ppm 10.10 (s, 1H, meso-H), d 9.61,
9.28, 9.03, 9.02 (each 2H, d, J = 4.4 Hz, b-H), 4.78 (s,
3H, CH3), 1.58 (s, 36H, tert-butyl-H), -2.82 (s, 2H, NH).
UV-vis: lmax, nm (e, 103 M-1.cm-1) 416 (153), 512 (9.9),
547 (6.5), 586 (5.1), 643 (4.4). MS (ESI): m/z 701.4582,
(calcd. for[M + H]+ 701.4578).
5-Methyl-10,20-bis(3,5-di-t-butylphenyl)-
1
porphyrinatonickel(II) Ni4b. H NMR: dH, ppm 9.70
(s, 1H, meso-H), 9.38, 9.06, 8.88, 8.87 (each 2H, d, J =
4.8 Hz, b-H), 7.87 (d, 4H, J = 1.6, o-Ar-H), 7.74 (t, 2H,
J = 1.6, p-Ar-H), 4.32 (3H, s, CH3), 1.50 (s, 36H, tert-
butyl-H). UV-vis: lmax, nm (e, 103 M-1.cm-1) 409 (224),
525 (18.7). MS (MALDI): m/z 757.9, (calcd. for [M +
H]+ 757.4).
Copyright © 2013 World Scientific Publishing Company
J. Porphyrins Phthalocyanines 2013; 17: 4–9

THE EXHAUSTIVE REDUCTION OF FORMYLPORPHYRINS TO METHYLPORPHYRINS
5
Table 1. Summary of representative results of microwave heating of formylporphyrins in DMF under various conditionsa
Experiment Porphyrin substrate
Time, min
Additive
Resultb
40:60
Comment
+ H2TriPPNH2 2b ca. 1:1
1
2
H2TriPPCHO 2a
H2TriPPCHO 2a
H2TriPPCHO 2a
NiTriPPCHO 3a
NiTriPPCHO 3a
NiDAPCHO Ni4a
H2TriPPCHO 2a
NiDAPCHO Ni4a
NiDAPCHO Ni4a
NiDAPCHO Ni4a
NiDAPCHO Ni4a
60
60
60
60
180
60
60
60
60
30
30
TFA (5 mL)
TFA (5 mL)
TFA (5 mL)
TFA (5 mL)
TFA (5 mL)
TFA (5 mL)
H2O (2 mL)
H2O (2 mL)
H2O (5 mL)
H2O (5 mL)
H2O (5 mL)
0:100 unidentified minor products present
3
0:100 larger scale: 68 mmol porphyrin
4
75:25
0:100
0:100
—
—
—
5
6
7
0:100 unidentified minor product present
0:100
0:100 larger scale: 28 mmol porphyrin
0:100
8
—
9
10
11
—
0:100 23 mmol porphyrin; isolated recrystallized
yield Ni4b 63%
12
NiDAPCHO Ni4a
30
—
100:0
“super-dry DMF”: CaH2 distillation directly
into vial
13
14
15
NiDAPCHO Ni4a
NiDAPCHO Ni4a
NiDAPCHO Ni4a
30
30
H2O (50 mL)
D2O (2 mL)
H2O (1 mL)
0:100
100:0
—
“100%” D2O
120
0:100 0.4 mL d7-DMF; 5 mmol porphyrin; 4 × 30 min
with TLC checks; product NiDAPCHD2
16
17
18
19
20
NiDAPCH3 Ni4b
H2OEPCHO H25a
H2OEPCHO H25a
NiOEPCHO Ni5a
NiDAPCH2OH Ni4d
30
60
45
30
30
H2O (1 mL)
TFA (5 mL)
H2O (2 mL)
H2O (2 mL)
H2O (2 mL)
n/a
—
—
—
0.4 mL d7-DMF
major product H2OEP H25c
major product H2OEP H25c
major product NiOEP Ni5c
0:100c precipitate formed on cooling, minor product
Ni4e
21
22
23
NiDAPCH2OH Ni4d
NiDAPCH2OH Ni4d
NiDAPCHO Ni4a
20
60
—
H2O (5 mL)
60:40c
precipitate formed on cooling; Ni4e not
observed
TFA (7.5
mL)
0:100c unidentified minor products formed
H2O (7.5
mL)
0:100 240 °C, sampling of product mixture at 5 min
intervals with examination by UV-vis (see Fig. 3)
a
b
Standard conditions: 10–15 mmol porphyrin, 2 mL DMF. Result: ratio of unreacted formylporphyrin to methylporphyrin
product, estimated by integration of the methyl and aldehyde peaks in the 1H NMR spectrum of the crude reaction mixture; n/a =
not applicable as this was a control H/D exchange experiment. c Ratio Ni4d:Ni4b.
The method was extended to 5-formyl-10,20-bis(3,5-
di-t-butylphenyl)porphyrinatonickel(II) (NiDAPCHO)
Ni4a, and the corresponding methylporphyrin was
formed in high yield (entry 6). To study the effects of
the acid, the TFA was replaced with water for both 2a
and Ni4a, and the latter was also reacted in a larger
scale, with isolation and purification of the product Ni4b
in 61% recrystallized yield (entries 7–11). Under these
conditions, only 30 min was sufficient to consume the
aldehyde.
the methyl porphyrin Ni4b was not detected (entry 12).
The reaction was found to tolerate ten times the amount
of water (entry 13). On the other hand, use of 2 mL of
nominally “100% deuterated” water gave no Ni4b after
the time indicated, perhaps indicating a strong deuterium
isotope effect (entry 14).
To investigate the source of the reducing Hs in this
reaction, we then employed d7-DMF, scaled down in
volume (entry 15), and checked the reaction progress
by heating for four 30 min periods, with sampling and
TLC analysis. The reaction progressed normally, but
more slowly. The methylporphyrin Ni4b was isolated
The need for the presence of water and/or acid(s) was
assessed by using DMF that was vacuum distilled from
CaH2 directly into the microwave vial before sealing
and subjecting Ni4a to the usual conditions. However,
1
2
as usual, and the product was examined by H and H
NMR spectroscopy; the former indicated deuteration to
Copyright © 2013 World Scientific Publishing Company
J. Porphyrins Phthalocyanines 2013; 17: 5–9

6
S.J. FLETCHER ET AL.
lower temperature of 240 °C, and the vial was cooled,
removed from the microwave reactor, and sampled at
intervals, beginning with 5 min (entry 23). Aliquots were
removed and diluted to a fixed volume with CHCl3, before
examination by UV-vis spectroscopy. Standards of Ni4a,
Ni4b and Ni4d were recorded quantitatively at similar
concentrations, and these spectra are plotted in Fig. 2.
The results of the sampled run are shown in Fig. 3. It is
Fig. 1. The 2H NMR spectrum of NiDAPCD2H (Ni4c) from the
microwave-heated reaction of Ni4a in d7-DMF at 250 °C
the extent of ca. 1.75 deuterium atoms per porphyrin, i.e.
the product was mostly NiDAP-CD2H Ni4c. Attempted
examination at higher resolution showed the broadening
expected due to H–D coupling, but clear separation was
not achieved. The 2H NMR spectrum is shown in Fig. 1,
and it shows that there was no concomitant deuteration
of the porphyrin or aryl positions. A control experiment
with the Ni4b in d7-DMF showed no exchange occurred
over the normal time period of the process (entry 16).
Finally, we also tried the OEP (H2OEP = 2,3,7,8,12,-
13,17,18-octaethylporphyrin) aldehydes, both free base
and Ni(II) complex. The starting materials H25a and
Ni5a were consumed over periods of 30–60 min, but no
methyl products H25b and Ni5b were detected. NMR
spectra showed the only products were the corresponding
deformylated porphyrins H25c and Ni5c (entries 17–19).
Considering the mechanism of the exhaustive
reduction, a possible intermediate is the primary
alcohol, e.g. Ni4d. This compound was prepared readily
by reduction of the aldehyde Ni4a with NaBH4 in
THF, and was then substituted for the aldehyde in our
usual conditions (entries 20–22). The results were a
little inconsistent: in two of the runs, a red precipitate
appeared on cooling. After the first experiment, the solid
was collected and NMR spectroscopy showed it to be
a mixture of the methylporphyrin Ni4b and the meso-
dimethylaminomethyl (DMAM) porphyrin Ni4e, in
a ratio of 5:1. The latter was identified by comparison
with the spectrum of a sample prepared previously in our
laboratory by the route of Ponomarev and co-workers
[12]. However, in the two subsequent runs, only very
small amounts of this product were observed, along with
a variety of other, unidentified porphyrins, all in very
small quantities compared with the major product, the
methylporphyrin Ni4b. So the hydroxymethylporphyrin
could be an intermediate in the reduction, but the role
(if any) of the DMAM porphyrin is still unclear.
Fig. 2. The UV-visible spectra of NiDAPCHO (Ni4a, solid),
NiDAPCH3 (Ni4b, dashed), and NiDAPCH2OH (Ni4d, dotted)
Fig. 3. The UV-visible spectra recorded after sampling at
the intervals shown, during the microwave heating of Ni4a at
240 °C in DMF
To assess whether intermediates could be identified
during the reaction time, a run was conducted at the
Copyright © 2013 World Scientific Publishing Company
J. Porphyrins Phthalocyanines 2013; 17: 6–9

THE EXHAUSTIVE REDUCTION OF FORMYLPORPHYRINS TO METHYLPORPHYRINS
7
Ar
M
H+ cat.
O
O
Me
N
+ H2O
Me
H
+
H
N
H
O
H
N
Me
N
N
N
N
Me
= Ar
R
O
C
O–
H
OH
Ar
H
Me
+
H
C
H
N
C
Me
Me
N
Ar
Me
O
Ar
Ar
Me
Me
H
O
H
O
H
O
H
Me
Me
Me
Me
H
+ H2O
O
C
O
N
C
N
C
+
H
H
Ar
Ar
H+
cat.
ArCHO + 2HCONMe2 + H2O
ArCH3 + 2CO2 + 2NHMe2
H
H
H
Me
O
O
+
H
N
C
+
N
C
+
H
H
Me
H
O–
H
O
Me
Ar
Ar
Me
H
+
H
O
H
H
H
H
+
O
N
C
+
C
C
O
+
N
Me
H
O–
Me
Me
Ar
H
Ar
Me
H+ cat.
ArCH2NMe2 + HCONMe2 + H2O
ArCH3 + CO2 + 2NHMe2
O
C
H
O
Ar
O
H
C
O
C
O
+
Ar
H
H
H
+
O
H
O
H
H
O
C
O
H+ cat.
C
O
C
H
+
H2O
H
Ar
H
O
H
Ar
C
H
H
O
O
H
H
H
H
O
O
+
C
Ar
C
Ar
H
H
Scheme 2. Possible mechanisms for the reductions of formyl-, dimethylaminomethyl- and hydroxymethylporphyrins to
methylporphyrins in DMF in the presence of water and an acid catalyst
apparent that at least one intermediate is present, as no
isosbestic point remained through the run. Moreover there
was an initial rise in absorbance in the region of the band
maximum of the formyl starting material. Furthermore,
at around 15 min, the absorbance near 600 nm
has fallen dramatically, but absorbance near 550 nm is
prominent. This is the region where the hydroxymethyl
Ni4d absorbs, but equally, this could indicate the presence
of the DMAM porphyrin Ni4e. Later in the run, when
almost all Ni4a is consumed, the profile is largely the same
as that of the final product Ni4b. The results are by no
means definitive, as the absorbance apparent near 550 nm
is higher than would be expected if only Ni4d were present.
Because of the impossibility of sampling totally in situ,
and the non-specific nature of the analytical method, we
conclude only that more than one intermediate is involved.
meso-Methylporphyrins have been prepared previously
by a variety of reductive methods, usually from the
Copyright © 2013 World Scientific Publishing Company
J. Porphyrins Phthalocyanines 2013; 17: 7–9

8
S.J. FLETCHER ET AL.
corresponding meso-formyl derivatives [7, 13–15], or
occasionally by other means, such as the cleavage of
meso-triphenylphosphinomethyloctaalkylporphyrins
[16]. Both metalated and free base methylporphyrins
have been prepared for octaalkylporphyrins, but the
derivatives of 5,15-diaryl- or 5,10,15-triarylporphyrins,
which are the more commonly used frameworks in
recent years, were not reported until 1993 [17]. Since
then, almost all reports of such structures have involved
synthesis of 5-mono- or 5,15-dimethylporphyrins by
cyclocondensations, and only the metal-mediated
synthesis of Therien and co-workers [17], and the
Pd-catalyzed methylation of meso-bromoporphyrins
using potassium organotrifluoroborates by Senge and
co-workers [18], have used pre-formed porphyrins to
which the methyl substituents were then attached. Since
5,15-diaryl- or 5,10,15-triarylporphyrins with a huge
variety of possible aryl groups are readily available, a
simple route to meso-methylporphyrins should be useful.
The question of the detailed mechanism of this CHO
to CH3 exhaustive reduction is a complex one. It is clear
from our experiments that DMF is providing the reducing
Hs (as shown by the deuteration results), and either
free acid(s) or water or both are involved, presumably
in catalytic roles. We note that using specially dried
DMF completely curtails the reduction. DMF has been
reported frequently as a reductant [19], especially as an
adjunct in the preparation of metal nanoparticles, but as
far as we are aware, not for the exact conversion we have
studied. There is a multitude of methods in the literature
for this reduction in non-porphyrinic substrates (e.g. the
Clemmensen orWolff–Kischner reactions, amongst many
more modern methods) [20], but we have not uncovered
this precise use of a DMF/catalyst or DMF/water system
for CHO to CH3 conversion. It is certainly possible
that the primary alcohol is an obligate intermediate, as
suggested by entries 20–22 and the UV-visible spectra
recorded in our sampled run (entry 23). This reaction
bears some resembance to the Leuckart–Wallach suite of
reactions, whereby aldehydes and ketones are converted
to dialkylaminomethyl derivatives using amine sources
(including DMF) and reducing equivalents in the form
of formate sources [21]. In very few of the numerous
references to this reaction type, the corresponding
carbinols were isolated and/or observed during the
reactions [22].
this reaction are continuing, but meanwhile the present
results represent a new resource in the armamentarium of
porphyrin chemists.
Acknowledgements
We thank Queensland University of Technology and
the Science and Engineering Faculty for a Strategic
Masters Scholarship for SRH and the School of
Chemistry, Physics and Mechanical Engineering for a
grant to support SJF.
Supporting information
1H NMR spectra (CDCl3) of previously unreported
porphyrins are given in the supplementary material. This
material is available free of charge via the Internet at
http://www.worldscinet.com/jpp/jpp.shtml.
REFERENCES
1. See, for example: a) Sergeeva NN, Senge MO and
Ryan A. In Handbook of Porphyrin Science, Vol.
3, Kadish KM, Smith KM and Guilard R. (Eds.)
World Scientific: 2010; pp 325–366. b) Fields KB,
Ruppel JV, Snyder NL and Zhang XP. In Handbook
of Porphyrin Science, Vol. 3, Kadish KM, Smith
KM and Guilard R. (Eds.) World Scientific: 2010;
pp 367–428. c) Horn S, Dahms K and Senge MO.
J. Porphyrins Phthalocyanines 2008; 12: 1053–1077.
d) Senge MO and Richter J. J. Porphyrins Phthalo-
cyanines 2004; 8: 934–953.
2. Arnold DP, Goh MS, Harper SR and McMurtrie JC.
In Handbook of Porphyrin Science, Vol. ??, Kadish
KM, Smith KM and Guilard R. (Eds.) World Scien-
tific: 2014; in press.
3. Senge MO, Fazekas M, Notaras EGA, Blau WJ,
Zawadzka M, Locos OB and Mhuircheartaigh
EMN. Adv. Mater. 2007; 19: 2737–2774.
4. Screen TEO, Blake IM, Rees LH, Clegg W, Borwick
SJ and Anderson HL. J. Chem. Soc., Perkin Trans. 1
2002: 320–329.
5. Harper SR, Pfrunder MC, McMurtrie JC andArnold
DP. In preparation.
6. Locos OB and Arnold DP. Org. Biomol. Chem.
2006; 4: 902–916.
7. Arnold D, Johnson AW and Winter M. J. Chem.
Soc., Perkin Trans. 1 1977: 1643–1647.
Numerous mechanisms for the CHO to CH2OH/
CH2NMe2 transformation and their subsequent conver-
sion to CH3, perhaps involving free radicals (as recently
suggested for some DMF reactions [23]), or the
PorCH2OC(O)H ester, are conceivable. At this stage, the
details are not clear, but one plausible ionic mechanism is
presented in Scheme 2. We have recently discovered that
with simple arylaldehydes, the dimethylaminomethyl
product is exclusively formed under some conditions,
which represents a new version of the Leuckart–
Wallach-type reaction of carbonyls [24]. Our studies of
8. Inhoffen HH, Fuhrhop J-H, Voigt H and Brickmann
jr. H. Liebigs Ann. Chem. 1966; 695: 133–143.
9. Dahms K, Senge MO and Bakar MB. Eur. J. Org.
Chem. 2007: 3833–3848.
10. Ishkov YuV, Zhilina ZI and Krivushko VA. Russ. J.
Org. Chem. 1997; 33: 1346–1350.
11. Takanami T, Wakita A, Sawaizumi A, Iso K,
Onodera H and Suda K. Org. Lett. 2008; 10; 685–687.
Copyright © 2013 World Scientific Publishing Company
J. Porphyrins Phthalocyanines 2013; 17: 8–9

THE EXHAUSTIVE REDUCTION OF FORMYLPORPHYRINS TO METHYLPORPHYRINS
9
12. Ponomarev GV, Yashunsky DV and Arnold DP. In
d) Kamiya I, Tsunoyama T and Sakurai H. Chem.
Lett. 2007; 36: 646–647. e) Pastoriza-Santos I and
Liz–Marzán LM. Langmuir 2002; 18: 2888–2894.
f) Yu JY, Schreiner S and Vaska L. Inorg. Chim.
Acta 1990; 170: 145–147.
Recent Research Developments in Pure and Applied
Chemistry, Vol. 2, Pandalai SG. (Ed.) Transworld
Research Network: 1998; pp 199–215.
13. Smith KM, Bisset GMF and Bushell MJ. Bioorg.
Chem. 1980; 9: 1–26.
14. Smith KM and Bisset GMF. J. Chem. Soc. Perkin 1.
1981: 2625–2630.
20. Smith MB. March’s Advanced Organic Chem-
istry: Reactions, Mechanisms, and Structure, John
Wiley & Sons Inc.: Hoboken, 2007.
15. Jiang X, Nurco DJ and Smith KM. Chem. Commun.
1996: 1759–1760.
16. Yashunsky DV, Ponomarev GV and Arnold DP.
Tetrahedron Lett. 1996; 37: 7147–7150.
17. DiMagno SG, Lin VS-Y and Therien MJ. J. Org.
Chem. 1993; 58: 5983–5993.
18. Horn S, Cundell B and Senge MO. Tetrahedron
Lett. 2009; 50: 2562–2565.
19. See, for example: a) Muzart J. Tetrahedron 2009;
65: 8313–8323. b) Dhital RN, Kamonsatikul C,
Somsook E, Bobuating K, Ehara M, Karanjit S and
Sakurai H. J. Am. Chem. Soc. 2012; 134: 20250–
20253. c) Sakurai H, Kamiya I and Kitahara
H. Pure Appl. Chem. 2010; 82: 2005–2016.
21. For a recent example, see Barba F, Recio J and
Batanero B. Tetrahedron Lett. 2013; 54: 1835–1838.
22. a) Awachie PI and Agwada VC. Tetrahedron 1990;
46: 1899–1910. b) Agwada VC and Awachie PI.
Tetrahedron Lett. 1982; 23: 779–780.
23. a) Li H, Xie J, Xue Q, Cheng Y and Zhu C.
Tetrahedron Lett. 2012; 53: 6479–6482. b) Kumar
PS, Kumar GS, Kumar RA, Reddy NV and Reddy
KR. Eur. J. Org. Chem. 2013: 1218–1222. c) Zhao
Q, Miao T, Zhang X, Zhou W and Wang L. Org.
Biomol. Chem. 2013; 11: 1867–1873.
24. Fletcher SJ and Arnold DP. Unpublished results.
Copyright © 2013 World Scientific Publishing Company
J. Porphyrins Phthalocyanines 2013; 17: 9–9