Amor a la Iglesia

Huisgen 1,3-dipolar cycloaddition between an azide and a terminal alkyne (CuAAC reaction) as a variety of the “click reaction” and is an invaluable tool for the modification of DNA and other biomolecules.60, 61 _{CuAAC chemistry has been used to}

couple a significant number of organic molecules to DNA.104 Prior to this work coupling had not been achieved using porphyrins. It is difficult to synthesise an azido functionalised DNA, however, alkyne nucleosides are commercially available. Therefore a number of novel azido functionalised porphyrins were synthesised for the use in CuAAC reactions. Although few examples of azido porphyrins are present in literature, it was possible to tune existing chemistry and apply it for the synthesis of the desired compounds (Figure 2.25). The azido porphyrins were classed in two categories depending on the type of azide synthesised: aliphatic and aromatic azides. After purification the presence of the azides was confirmed by observing the IR azide asymmetric stretches at ~2015 cm-1 for aromatic azides and 2095 cm-1 for aliphatic azides. N₃ MTPP MTPP N₃ N₃ MTPP Aromatic Aliphatic

Figure 2.25 Target compounds for use in CuAAC reactions (M = H2, NiII, CuII, ZnII, FeIII).

2.4.2.1 Synthesis of Aromatic Azides

The aromatic NiII azido porphyrin 41 was obtained in four steps from TPPps 3 and nitro benzaldehyde as shown in Figure 2.26. As discussed previously, the treatment of a DCM solution of 3 with 4-nitrobenzaldehyde and DBU, using a method adapted from Bonfantini et al.,78, 87 resulted in the rapid formation of a cis/trans mixture of 19. This was converted exclusively to the trans isomer by iodine treatment. Metallation of the nitro compound 19 with Ni(OAc)2·4H2O provided the NiII analogue 22 which was

achieved via diazotisation with H2SO4/NaNO2 in the dark followed by the addition of

NaN3.68, 69 The formation of the β-functionalised free base aromatic azide 42 was

achieved using a similar method to that described for the NiII _porphyrin.

N NH N HN PPh₃Cl TPP NO₂ OHC NO₂ NiTPP NH₂ TPP N₃ 3 i) v) vi) iii) NiTPP NO₂ TPP NH₂ NiTPP N₃ iv) 19 22 23 20 41 42 ii) 18

Figure 2.26 Synthesis of aromatic azides 41 and 42 for use in CuAAC reactions. Reagents and

conditions: i) DCM, DBU, RT, 30 min then I2, CHCl3, RT, 3 h, 85% ii) DCM, MeOH, Ni(OAc)2·4H2O,

overnight, reflux, 100% iii) THF, SnCl2.2H2O, HCl, RT, 24 h, Et3N, 78% iv) THF, H2O, NaNO2, H2SO4,

RT, 2 h then NaN3, RT, 20 min, 98% v) THF, SnCl2.2H2O, HCl, RT, 24 h, Et3N, 78% vi) THF, H2O,

The alkyne linked aromatic azide 45 (Figure 2.27) was successfully synthesised after numerous unsuccessful reactions. Attempts to form azide 45 from nitro 44 (via the corresponding aniline derivative) failed as the nitro precursor (44) could not be obtained using Horner-Emmons chemistry. Attempts to synthesise the nitro porphyrin 44 from the appropriate bromophosphonate 43 and TPPCHO (2) using modified Horner- Emmons chemistry resulted in the isolation of an intractable mixture of unknown compounds. Alternatively, it was possible to obtain the azide from the corresponding iodo derivative 32. The synthesis of the azide 45 was achieved in a 61% yield via the reaction of the iodo precursor 32 with NaN3, sodium ascorbate, N,N-DMEA and

Cu(ACN)4PF6 in dry DMSO. Alternative reaction conditions involving the bromo (40)

or iodo (32) functionalised porphyrins, as listed in Table 2.1, resulted in the quantitative isolation of the starting material. It is interesting that although iodo 32 could be converted to azide 45, reaction using the ethene equivalent of porphyrin 32 under identical reaction conditions only resulted in the isolation of the starting material.

TPP CHO NO2 P Br PhO OPh O TPP NO2 TPP NH₂ ZnTPP N₃

+

X

Figure 2.27 Synthesis of aromatic azide 45 for use in CuAAC reactions. Reagents and conditions: i)

THF, t-BuOK, RT, 3 h ii) DMSO, NaN3, sodium ascorbate, Cu(ACN)4PF6, N,N-DMEA, 70 °C, 48 h,

Table 2.1 Synthetic attempts for the synthesis of azide 45.

Starting material

Reagents Reaction Conditions Result

Bromo 40 NaN3, sodium ascorbate,

CuI, N,N-DMEA

DMSO, RT, overnight No reaction Bromo 40 NaN3, sodium ascorbate,

CuI, N,N-DMEA

DMSO, 70 °C, overnight No reaction Iodo 32 NaN3, sodium ascorbate,

CuI, N,N-DMEA

DMSO, 70 °C, overnight No reaction Bromo 40 NaN3, sodium ascorbate,

CuI, N,N-DMEA

DMSO: H2O (9:1),

microwave, 1 h, 100 °C

No reaction Iodo 32 NaN3, sodium ascorbate,

CuI, N,N-DMEA

DMSO: H2O (9:1),

microwave, 1 h, 100 °C

No reaction Iodo 32 NaN3, sodium ascorbate,

CuI, N,N-DMEA

DMSO: H2O (9:1),

70 °C, overnight No reaction Iodo 32 NaN3, sodium ascorbate,

CuI, N,N-DMEA

Toluene, 70 °C, overnight

No reaction Iodo 32 NaN3, L-proline, CuI,

NaOH

DMSO, 70 °C, overnight No reaction Iodo 32 nBuLi, tosyl azide THF, -78 °C to RT Unknown

products Iodo 32 NaN3, sodium ascorbate,

Cu(ACN)4PF6, N,N-DMEA

DMSO, 70 °C, 48 h 61 %

2.4.2.2 Synthesis of Aliphatic Azides

The desired aliphatic azides (Figure 2.28) were synthesised from aldehyde 47 and TPPps 3 in two steps via the Wittig reaction followed by metal insertion. Aldehyde 47 was obtained from para-tolunitrile in three steps using methods of Schlenoff et al.105 andBarbe et al.106 The aliphatic azide 48 was synthesised in an overall yield of 60% via a Wittig reaction between phosphonium salt 3 and aldehyde 47 followed by iodine isomerisation. The Wittig reaction must be performed using the azido aldehyde 47 as the bromo aldehyde 46 was found to self polymerise in the presence of DBU. Importantly, the aliphatic azide 48 was stable to the conditions used for the insertion of various metal ions (ZnII (49), NiII (50), and FeIII (51)). PtII insertion, which requires refluxing in benzonitrile, could not be obtained as decomposition of the azide occurred at the elevated temperatures.

TPP N3 NiTPP N3 OHC N3 ZnTPP N3 N NH N HN PPh3Cl OHC Br NC Br NC i) Polymer FeClTPP N3 46 47 3 48 49 50 51 ii) iii) iv) 46 ₄₇ v) vi) vii) viii)

Figure 2.28 Synthesis of aliphatic azides 48-51 for use in CuAAC reactions. Reagents and conditions: i)

CCl4, NBS, light, reflux, 2 h, 62% ii) toluene, DIBAL, 0 °C, 1 h then CHCl3, HCl, RT, 1 h, 72% iii)

Acetone, H2O, NaN3, reflux, overnight, 100% iv) DCM, DBU, RT, 20 min v) DCM, DBU, RT, 20 min

then CHCl3, I2, RT, overnight, 60% vi) DCM, MeOH, Zn(OAc)2·2H2O, RT, 1 h, 97% vii) CHCl3, MeOH,

Ni(OAc)2·4H2O, reflux, overnight, 99% viii) acetonitrile, CHCl3, FeCl2·4H2O, 70 °C, 5 h, then air, 70 °C,

overnight, 90%.

2.5 Conclusion

In summary, we have synthesised a number of β-pyrrolic functionalised porphyrin

precursors for the development of DNA-porphyrin supramolecular constructs. This includes the synthesis of lipophilic porphyrins for the construction of lipophilic DNAs, as well as building blocks required for pre- and post-synthetic Sonogashira and CuAAC reactions. The construction of these complexes will be discussed in Chapters 4-6.

Chapter 3

Synthesis of

β-Pyrrolic Ethynyl