New 1,1’-Ferrocene Bis(sulfonyl) Reagents

Abstract

Several new 1,1′-bis(sulfonyl)ferrocenes designed for the synthesis of sulfonamide linked biological conjugates have been prepared. 1,1′-Bis(sulfonylbromide)ferrocene can be produced from the corresponding sulfonylchloride via a bis(sulfonylhydrazide) intermediate. Bis(sulfonyl-N-hydroxybenzotriazole)ferrocene can also be synthesized from the sulfonyl chloride, and reaction of glycine methyl ester with the sulfonyl chloride affords a [3]ferrocenophane complex. All new compounds have been structurally characterized by X-ray crystallography.

Graphical Abstract

New 1,1′-bis(sulfonyl)ferrocenes designed for the synthesis of sulfonamide linked biological conjugates have been prepared. 1,1′-Bis(sulfonylbromide)ferrocene can be produced from the corresponding sulfonylchloride via a bis(sulfonylhydrazide) intermediate. Bis(sulfonyl-N-OBt)ferrocene can be synthesized from the sulfonyl chloride, and reaction of glycine methyl ester with the sulfonyl chloride affords a [3]ferrocenophane complex.

Introduction

The linking of organometallic units with molecules of biological relevance, including biological macromolecules, has been receiving increasing attention over the past three decades.^[1–5] One area of particular activity is amide bond formation between two amino acids or peptides to separate rings of ferrocene.^[6–8] The most commonly studied systems is based on 1,1′-ferrocene dicarboxylic acid; 1′-aminoferrocene-1-carboxylic acid and ferrocene-1,1′-diamine have been studied as well.^[9,10] By producing 1,1′-bis(substituted) ferrocene complexes, unusual hydrogen bonding interactions between the amino acid groups can be achieved. The method of amide bond formation to generate bis(substituted) species has led to a wealth of new compounds and information on their hydrogen bonded structures.

Recently, we have started to explore bis(sulfonamide) based conjugates to examine differences from the amide based complexes.^[11] In this communication, we examine alternative methods to 1,1′-ferrocene bis(sulfonamides) derived from 1,1′-bis(sulfonylchloride)ferrocene, including the bis(sulfonylhydrazide), bis(sulfonylbromide) and bis(sufonylhydroxybenzatriazole) modified ferrocenes. Additionally, we observed that reaction with glycine methyl ester results in a new bio-organometallic ferrocenophane. All of these compounds, which are shown in Scheme 1, can be readily prepared from easily synthesized starting materials, and can be used as precursors for generating biologically relevant conjugate complexes.

Scheme 1.

Reactions referred to in this paper.

Results and Discussion

1,1′-Bis(sulfonylchloride) ferrocene 1 can be readily generated in three steps from ferrocene via reaction with chlorosulfonic acid, isolation as the ammonium salt, and then reaction with PCl₅.^[12] Previously, we have shown that 1 can be used to generate both mono- and bis(sulfonamide) derivatives.^[11] The sulfonyl chloride is useful in that it exhibits selectivity in reactivity with amines under wet (i.e. non-dried) conditions, however reactions with amines frequently requires higher temperatures or extended reaction times. In order to make more rapidly reacting reagents, we decided to prepare the bis(sulfonylbromide) analog of 1. Sulfonyl bromides have been prepared for aryl compounds,^[13,14] but not for ferrocenes. We used the same synthetic methodology for aryl sulfonyl bromides, preparing bis 1,1′-(sulfonylhydrazide)ferrocene 2 via reaction of 1 with hydrazine. We fully characterized compound 2, including via X-ray crystallography, as shown in Figure 1. The structure of 2 shows a nearly eclipsed conformation of cyclopentadienyl rings, with an angle of ~72° between the -SO₂NHNH₂ groups on the cyclopentadienyl groups. The bond lengths of the sulfonylhydrazide unit are as expected for this functional group,^[15–17] with an S-N bond length averaging ~1.64 Å and an average N-N bond length of ~1.41 Å. In the solid state, we observe intermolecular hydrogen bonding between the SO₂ units and the NHNH₂ groups (S-N distances ranging between ~2.86 and ~3.03 Å) as well as between hydrazine functional groups in the solid (N-N distance of ~3.01 Å). 1,1′-Bis-(sulfonylbromide)ferrocene 3 can be produced from 2 via reaction with elemental bromine and purified via column chromatography. Compound 3 was also structurally characterized (Figure 1) and this complex is structurally similar to compound 1, but with the expected longer S-Br bond length of 2.2066(8) Å. Notably, this is the first reported crystal structure of a sulfonyl bromide compound. As in 1, the compound adopts an anti conformation with the two sulfonyl bromide groups at an angle of 180° and the bromides are each pointing away from the ferrocene. We observed that compound 3 reacts avidly with primary amines under room temperature conditions to produce the corresponding 1,1′-bis(sulfonamide) ferrocene compounds.

Figure 1.

The molecular structures of 2 (top left), 3 (top right) and 4 (bottom) with 50% thermal ellipsoids. Hydrogen atoms have been omitted for clarity.

An alternative method for the formation of amide bonds is to use hydroxybenzotriazole, HOBt, as the leaving group.^[18–23] This unit has been successfully used for the activation of carbonyl functionalized ferrocenes for the formation of amino acid conjugates.^[22,24] HOBt has been used occasionally to activate sulfonic acid derivatives^[25,26] and we hypothesized that a similarly structured sulfonyl group would allow for the rapid generation of ferrocene bis(sulfonamides). Thus, we prepared compound 4, 1,1′-bis(sulfonyl-N-hydroxybenzotriazole)ferrocene, which is produced from the reaction of compound 1 with 1-hydroxybenzotriazole hydrate. The resultant product can be purified via silica gel chromatography, and we were able to fully characterize compound 4 including via X-ray crystallography (Figure 1). The ferrocene adopts a staggered anti conformation, with the -SO₂OBt groups arranged at 180° to each other in the solid. The plane of the OBt unit is tilted by ~38° from the plane of the cyclopentadienyl group. As in the 1,1′-bis(sulfonylbromide)ferrocene described above, compound 4 also reacts avidly with amines to produce the corresponding bis-1,1′ (sulfonamide)ferrocene compounds

As we were investigating the amino acid chemistry of compound 1, we observed an unusual reaction with glycine methyl ester. For most primary amines, we observe either the formation of mono or bi-functionalized ferrocene sulfonamides.^[11] However in the case of glycine methyl ester, we observed the formation of a [3]ferrocenophane, compound 5. Ferrocenophanes have been reported using a variety of bridging groups to link the two cyclopentadienyl rings.^[27–32] We were able to fully characterize this compound, including via single crystal X-ray methods, as shown in Figure 2. As can be seen in the structure, the amine terminus of the glycine bridges the two cyclopentadienyl rings via -SO₂N(R)SO2-linkages, resulting in a three atom connection. Due to the number of atoms involved in the bridge and the length of both the S-C and S-N bonds, there is little strain in this ferrocenophane, and the Cp rings have a dihedral angle of 11.6°. The structure of previuosly reported 2-benzylidene [3]ferrocenophane-1,3-dione exhibited a ~14° dihedral angle between Cp rings^[31] while Hirao observed larger tilt angles around ~16° in the imide-bridged [3]ferrocenophane compounds.^[30,32] The S-N bonds measure 1.6807(13) and 1.6854(12) Å and the S-N-S bond angle is 121.37(7)°. The remaining two angles about the nitrogen atom measure 118.43(10) and 118.74(10)°, and therefore the geometry about this atom is almost a perfect trigonal plane. We are continuing to develop this new “bioorganometallic” ferrecenophane as a reagent for the modification of amines via amide bond formation at the carboxylic acid functional group of the glycine.

Figure 2.

The molecular structure of 5 with 50% thermal ellipsoids. Hydrogen atoms have been omitted for clarity.

Conclusions

In summary, we have prepared three new ferrocene derivatives designed for conjugation with biological compounds. These complement the 1,1′-bis-(sulfonylchloride)ferrocene route to making bis(sulfonamide) derivatives and add to the toolbox of organometallic units that can be modified with compounds such as amino acids. Additionally, we observed that reaction of 1,1′-bis(sulfonylchloride)ferrocene and glycine methyl ester affords a new bioorganometallic ferrocenophane. We are continuing our investigations into methods for the covalent attachment of ferrocenes and other organometallic units onto molecules of biological interest.