synthesis of meso-substituted porphyrins mariusz tasior
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Synthesis of meso-substituted porphyrins
Mariusz Tasior
Rothemund method – in 1935...
Rothemund, P., J. Am. Chem. Soc. 1935, 57, 2010.
HN
CH3CHOconditions
N HN
NH N
H3C
CH3
CH3
CH3
conditions: 140°C, 24hr, pyridine, followed by slow cooling
sealed tube was employed to avoid loss of the volatile aldehydes
Rothemund method – in 1935...
First report about effects of metals in pyrrole-aldehyde condensation: Ball, R. H. et al. J. Am. Chem. Soc. 1946, 68, 2278.
HN
RCHOconditions
N HN
NH N
R
R
R
R
conditions = 90 - 220°C, 24 - 48hr, solvent: MeOH, pyridine
high concentration of starting materials (0.5M), no oxidant
R = H, CH3, C4H9, C6H5 etc
yields: porphine was isolated in 0.9% yield, TMP 1% yield, products were contaminated with 10-20% of chlorin
improved procedure for TPP published in 1941 (7.5-9% yield)
Some general considerations...HN
CHO
conditions
HO
HN NH HN NH HN
HN
Some general considerations...
NH HN
NH HN
NH HN
NH HN
OHN HN
NH N
high dilution oxidant !!!
Adler method
Adler, A.D.; Longo, F. R.; Shergalis, W., J. Am. Chem. Soc. 1964, 86, 3145.
HN conditions
N HN
NH N
Ph
Ph
Ph
Ph
conditions: acetic acid or benzene + chloroacetic acid, Dean-Stark trap, air, reflux, 36hr, or propionic acid (bp 141°C), reflux, 30 min.
lower yield in presence of metal salts
yields: TPP was isolated in 30-40% yield, products were contaminated with 2-10% of chlorin which can be easly removed by treatment with DDQ in refluxing toluene.
CHO
Air!!! Reagents concentration 0.02M!!!
Scope of Adler method
low yields <10%, some anomalus products are observed (o-acetoxybenzaldehyde)
CHO
R
CHO
OH
CHO
OAc
some functional groups must be protected
D2O TPP-d8OO
OHN relux
1h, no air
benzaldehyde
air
Scope of Adler method
HN conditions
N HN
NH N
R
R
R
R
CHORLi
HN
OH
R
HN
RCHNconditions
N HN
NH N
R
R
R
R
Mixed-aldehyde condensation
N HN
NH N
A
A
A
A
N HN
NH N
A
A
B
A
N HN
NH N
A
A
B
B
N HN
NH N
B
B
B
B
N HN
NH N
A
B
B
B
N HN
NH N
A
B
A
B
6.25% 25% 25%
12.5%25%6.25%
Mixed-aldehyde condensation
N HN
NH N
4.5% yield
O
O
CHO HO
pyrrole, tolualdehyde, propionic acid
Dont event think about condensation of 3 aldehydes, few examples in the literature, 0.7% max
Leznoff, C. C.; Svirskaya, P.I, Angew. Chem. In. Ed. 1978, 12, 947.
Lindsey method 1979-...
Lindsey, J. S., Hsu, H. C., Schreiman, I. C. Tetrahedron Lett. 1986, 27, 4969.Lindsey, J. S., Schreiman, I. C., Hsu, H. C., Kearney, P. C., Marguerettaz, A. M.
Tetrahedron Lett. 1986, 27, 4969.Acid cocatalysis, salt effect: Lindsey et al. JPP, 2001, 5, 681
HN
RCHOconditions
N HN
NH N
R
R
R
R
conditions: catalyst - TFA or BF3-etherate, DCM, rt, 30-60 minlow concentration of starting materials (0.01M), addition of DDQ or p-chloranil in the second step
Reaction is vey sensitive to changes in reagents and catalyst concentrationDDQ reacts 5500 times more rapidly than p-chloranil in the dehydrogenation of 1,2-dihydronaphthalene
yields: up to 50%
Ethanol as cocatalyst in TMP synthesis
Scope of Lindsey methodmight be a problem
N
CHO
CHO
OH
CHO
OAc
some functional groups must be protected
O
O
CHO competitive Michael addition
CHO
Comparison of synthetic methodsRothemund Adler Lindsey
Solvent Pyridine Propionic acid
Acetic acid
RCOOH+benzene
DCM
Chloroform
Temperature 140-220ºC 141ºC 25ºC
Catalyst - Same as solvent TFA
BF3-etherate
Clays, other acids
Concentration 0.4-3.6M 0.3-0.1M 0.1-0.001M
Reaction time 24-48hr 1hr 1hr
Workup Separate crystals Filter crystals Chromatography
Yield <10% ~20% ~ 40%
Scope very narrow modest broad
Routes to specific classes of meso-substituted porphyrins
N HN
NH N
TMS CHO
TMS
TMS
TMS
TMS
1. pyrrole, BF3-etherate2. DDQ, 14%
N HN
NH N
C12H25O CHOCo2(CO)8, THF
C12H25O
(CO)3Co
Co(CO)3
CHO
OC12H25
OC12H25
OC12H25
C12H25O
1. pyrrole, BF3-etherate
2. DDQ
3. Fe(ClO4)3, MeOH
Trans-A2B2-porphyrins
HN
1. TFAN HN
NH N
A A
NH
2. p-chloranilA
B
B
aldehyde + pyrrole
MgBr2 or InCl3
CHOB
For dipyrromethane synthesis: Lindsey, J. S. et al. Org. Process Res. Dev. 2003, 7, 799.For condensation conidtions and scrambling: Lindsey, J. S. et al. J. Org. Chem. 1999, 8, 2864
Scrambling
NH HN
NH HN
B
A
A
H+
NH+ HN
NH HN
B
A
A
H
NH
NH
HN
HN
A
B A
NH +HN
NH HN
B
A
A
Porphyrins bearing up to 4 different meso substituents
NH
EtMgBr, THF
HN
A
NSB
O
NH HN
A
OB
1. EtMgBr, THF
2. CROCl
NH HN
A
OB
OC
NaBH4, MeOH
NH HN
A
OHB
HOC
NH
1. TFA, DCM
HN
D
NH HN
A
OHB
HOC
N HN
NH N2. DDQ
B
A
C
D
Thank you...