Lactonization of α -Ferrocenyl Ketocarboxylic Acids via Nucleophilic Attack of Carbonyl Oxygen

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Introduction
After the discovery of ferrocene in 1951 [1], research has been focused on understanding the role of the ferrocenyl moiety in stabilizing the positive charge at its alpha position.The stability of α-ferrocenyl carbenium ions has been established based on the enhanced rates of solvolysis of ferrocenyl substrates with the SN1 mechanism.For example, ferrocenylmethyl acetate solvolysis in 80% aqueous acetone at 30 °C is 6.7 times faster than triphenylmethyl acetate [2].Various research groups have studied the existence of α-ferrocenylcarbenium ions using the chemical shift values of protons and carbons at the carbocationic centers in NMR [3][4][5][6][7][8].The ability of the ferrocenyl moiety to stabilize the positive charge at its α-position has generated further interest in understanding the basic nature of the oxygen atom in acylferrocenes.Protonation of oxygen in acylferrocenes influences their reactivity, particularly in electrophilc aromatic substitution reactions.The electronic effects induced by protonation at the oxygen atom can also significantly alter the electron density of ferrocene moiety, impacting the overall electronic properties of the molecule.Both experimental [9][10][11] and computational [12] studies have shown that carbonyl oxygen is the most basic site in acyl-or formylferrocene.The higher basicity of the carbonyl oxygen in acylferrocenes than that of aryl ketones and aldehydes has been attributed to the cooperative interaction of the proton with both oxygen and the iron center [9].
Understanding the basic nature of the carbonyl oxygen lying alpha to the ferrocenyl moiety, we wished to explore the nucleophilicity of carbonyl oxygen in acylferrocenes, since nucleophilicity correlates with basicity [13,14].We realized that the α-ferrocenyl ketocarboxylic acid could offer both electrophilic and nucleophilic centers if the carboxy carbon was converted into a better electrophilic center.Moreover, separating ketone and carboxylic acid functions with two or three carbon atoms can give thermodynamically stable five-or six-membered rings by an intramolecular nucleophilic attack.We were also interested in studying the effect of breaking conjugation between the carbonyl group and the cyclopentadienyl ring on the reaction outcomes.The study on the nucleophilicity of carbonyl oxygen in acylferrocenes can help understand the competition between cyclopentadienyl carbons and carbonyl oxygen if the molecule contains an electrophilic center.Herein, we report the following two pathways of lactone formation: 1. an intramolecular nucleophilic attack of carbonyl oxygen on the carboxy carbon in the presence of trifluoroacetic anhydride; 2. nucleophilic substitution of the hydroxy group in α-hydroxy carboxylic acids by carboxylic oxygen under acidic conditions.

General Procedures
All experiments were performed under nitrogen using standard Schlenk line techniques.All reagents and solvents were purchased from commercial suppliers.Ferrocene, succinic anhydride, magnesium sulfate (Alfa Aesar, Ward Hill, MA, USA), glutaric anhydride (TCI America, Portland, OR, USA), sodium borohydride, phthalic anhydride, aluminum chloride (Acros Organic, Waltham, MA, USA), and trifluoroacetic anhydride (Oakwood Chemicals, Estill, SC, USA) were used as received. 1H NMR (400 MHz), 19 F NMR (376 MHz), and 13 C NMR (100.6 MHz) spectra were recorded on a JEOL-400 ESZ spectrometer, Peabody, MA, USA at room temperature.The spectra were referenced to the residual protonated solvent ( 1 H) or the solvent signal ( 13 C). 19F NMR spectra were referenced to the external reference of the spectrometer.IR spectra were recorded on a Bruker Alpha-E FTIR spectrometer, Billerica, MA, USA using a diamond crystal ATR accessory in a range between 400 and 4000 cm −1 .ESI-MS were recorded on Agilent 6470 LC/TQ, Santa Clara, CA using a 1260 infinity II HPLC system.Melting points were taken on a Dynalon™ Afon™ DMP100, Rochester, NY, USA Melting Point Device and were uncorrected.
X-ray diffraction data were measured at T = 90 K on a Bruker Kappa Apex-II diffractometer equipped with a microfocus CuKα source (λ = 1.54184Å) for 2a′ or a sealed-tube MoKα source (λ = 0.71073 Å) for 2b and 3b.Structures were solved using SHELXT [15] and refined using SHELXL, 2017/1 [16].Hydrogen atoms were visible in difference maps, placed in idealized positions during refinement, and treated as riding.The crystal of 2a′ was an inversion twin, and the BASF parameter was refined to 0.481 (16).Because the two independent molecules in 2a′ were related by an approximate inversion center at 0.484, ½, ¾, restraints were necessary to prevent C atoms from becoming non-positive definite.The crystal and refinement data are presented in Table 1.

Synthesis and Structural Elucidation of Compounds 2a, 2a′, 1b-5b and Proposed Mechanisms of Their Formation
As shown in Scheme 1, the Friedel−Crafts acylation of ferrocene with succinic anhydride, glutaric anhydride, and phthalic anhydride in the presence of AlCl3 using dichloroethane as solvent gave 3-(ferrocenoyl)propionic acid, 1a, 4-(ferrocenoyl)butyric acid, 2a, and 2-(ferrocenoyl)benzoic acid, 3a, respectively.Unlike 1a and 3a, the synthesis of 2a yielded a neutral byproduct that displayed the presence of an unsubstituted cyclopentadienyl ring, two types of methylene protons (in a 1:2 integration ratio), and two sets of substituted cyclopentadienyl protons (in a 1:1 integration ratio) (Figure S1).FTIR (1664 cm −1 ) and 13 C NMR (204 ppm) (Figure S2) indicated the presence of ketone function in the molecule.ESI-MS analysis of the product showed a strong signal at m/z 469 (Figure S3) corresponding to two ferrocenyl moieties, two ketones, and three methylene groups in the molecule.The single-crystal X-ray structure of the product unambiguously indicated the formation of 1,3-diferrocenoylpropane, 2a′.Although the compound 2a′ was synthesized from the reaction of ferrocene and glutaryl chloride [21,22], to our knowledge, the formation of such a binuclear product by Friedel−Crafts acylation of ferrocene with glutaric anhydride has not been previously reported.
Since the primary goal of this study was to investigate the nucleophilicity of the carbonyl group next to the ferrocenyl moiety, we treated 3-(ferrocenoyl)propionic acid, 1a with trifluoroacetic anhydride (Scheme 2).On adding trifluoroacetic anhydride (TFAA), the compound immediately changed its color from red to deep purple.We separated the product by silica gel column chromatography using DCM as eluent.The 1 H NMR analysis of the product shows only four signals with an integration ratio of 2:2:2:5 (Figure S5), indicating the loss of two methylene protons compared to the starting keto-carboxylic acid, 1a.The FTIR showed two strong signals at 1825 cm −1 and 1726 cm −1 , indicating the presence of two carbonyl groups in the molecule.A high-energy IR band (1825 cm −1 ) was consistent with a trifluoroacetyl group in the molecule, which was further confirmed by two quartets at 116.9 ( 1 J = 290.4Hz) ppm and 172.8 ( 2 J = 34.5 Hz) ppm in 13 C NMR and a singlet at −76.5 ppm in 19 F NMR (Figures S6 and S7).ESI-MS analysis of the product showed a signal at m/z 365.0, but determining the structure of the compound was still a challenge.Finally, the compound yielded dark purple crystals when it was crystallized by slow vapor diffusion of hexane into its solution in dichloromethane under nitrogen.Although a complete structure refinement by X-ray crystallography was not possible due to the tiny size of the crystals and their twinning, the analysis was sufficient to identify the compound.The preliminary crystallographic results showed the formation of an α, β-unsaturated cyclic lactone with a trifluoroacetyl group attached to the β-position of the ring (Figure S8).To understand the chemistry further, we treated 4-(ferrocenoyl)butyric acid, 2a, with TFAA in DCM (Scheme 2).As expected, the reaction yielded the desired product 2b in 49% isolated yield after chromatographic separation.The spectroscopic data (Figures S9-S11) of the product were in agreement with the formation of the lactone in a similar way to the formation of 1b.The single-crystal X-ray analysis of the product unambiguously confirmed the formation of 6-ferrocenyl-5-trifluoroacetyl-3,4-dihydropyran-2-one (Figure 2).The compound crystallizes in the monoclinic space group P21/n with a single molecule in its asymmetric unit.The bond length between C11 and C12 is 1.3599 (5) Å, confirming a double bond between α and β carbons.The six-membered lactone ring has a half-boat conformation with the Cremer and Pople [24] puckering parameters QT = 0.4736(5) Å, θ = 117.34(6)°,and φ = 30.74(6)°.The two Cp rings in the molecule acquire roughly eclipsed conformation with an average torsional angle C-Cg1-Cg2-C of 11.61°.The Cp rings of the ferrocenyl moiety are almost parallel, with the dihedral angle between their planes being 2.73°.
The mechanism of intramolecular cyclization of the keto-carboxylic acid 1a to form an α, β-unsaturated lactone 1b can be proposed as shown in Scheme 3. The reaction between the carboxylic acid and trifluoroacetic anhydride gives a mixed anhydride (I) on which the trifluoroacetate group acts as an excellent leaving group.The carbonyl oxygen of the ketone makes a nucleophilic attack on the carboxy carbon to form a tetrahedral intermediate (II).Such an unusual nucleophilic attack of carbonyl oxygen might be possible due to the electron-donating effects of the ferrocenyl moiety at its alpha position.The tetrahedral intermediate loses trifluoroacetate, forming a resonance-stabilized carbocation (III).The stability of such carbenium ions is attributed to the electron-releasing effects of the ferrocenyl moiety as well as the nearby lone pair of electrons on the oxygen atom.The carbocation loses a proton from the β-position to create a double bond in conjugation with the cyclopentadienyl moiety (IV).The double bond attacks TFAA to give another resonance-stabilized carbocation with a trifluoroacetate group in the ring (V).The inductive effects of the trifluoroacetyl group and a positive charge at the adjacent position both facilitate the loss of protons to give the final product (1b).The proposed mechanism involves the formation of 5-ferrocenyl-2(3H)-furanone, IV as an intermediate product from the β-elimination of carbocation III.We were interested in exploring the reaction outcomes in the absence of hydrogen at the β-position of ferrocenyl moiety.For this purpose, we treated 2-(ferrocenoyl)benzoic acid, 3a, with trifluoroacetic anhydride in DCM.On adding TFAA, the compound changed color from dark red to amber at first and then to green.This color change was attributed to the formation of ferrocenium ions [25,26].During aerobic workup, the reaction product changed to a lighter red color.The 1 H NMR analysis of the product indicated the formation of two isomers in a ca.1:1 ratio.We separated the isomeric mixture by taking advantage of their different solubilities in diethyl ether.The substituted cyclopentadienyl rings of both isomers showed four multiplets, indicating the formation of a chiral center at the alpha position of the ferrocenyl moiety.A single signal in 1 H or 13 C NMR for the unsubstituted cyclopentadienyl ring for both isomers indicated the presence of either a mirror plane or a rotational axis of symmetry in the molecule (Figures S12-S15).The ether-insoluble isomer was crystallized from chloroform by vapor diffusion of diethyl ether.The single-crystal X-ray analysis of the product revealed the formation of meso isomer of dimeric lactone, 3,3′-diferrocenyl-3,3′-diphthalide (Figure 3).The compound crystallized in the monoclinic space group P21/c with the molecule lying on an inversion center.The lactone rings bent inward, making a dihedral angle of 48.42° with the cyclopentadienyl ring.The two Cp rings adopted a nearly eclipsed conformation with a C-Cp1-Cp2-C dihedral angle of 2.18°.The C-C bond connecting the two monomers was 1.5751(12) Å.The ether-soluble also contained the same number of signals in NMR as the meso isomer.Therefore, the stereochemistry of the product, by analogy, was assigned to be racemic (R, S).The meso isomer decomposed above 250 °C while the racemic one melted at 124 °C.The isomeric mixture of the complex 3b was reported by Nesmeyanov et al. with limited characterization data [27].(Å) for the complex: Fe1-C1 2.0494(8), Fe1-C2 2.0576(8), Fe1-C3 2.0567(8), Fe1-C4 2.0500(9), Fe1-C5 2.0491(8), Fe1-C6 2.0502(8), Fe1-C7 2.0587(8), Fe1-C8 2.0542(8), Fe1-C9 2.0475(7) Fe1-C10 2.0405(7), O1-C14 1.3711(9), O1-C11 1.4578(8), O1-C14 1.3711(9), O2-C14 1.2084(9), Fe-Cp (centroid, substituted) 1.650, Fe-Cp (centroid, unsubstituted) The formation of the dimerized lactone from 3a in the presence of TFAA further supports our hypothesis of intramolecular nucleophilic attack of carbonyl oxygen on the carboxylic carbon.As shown in Scheme 4, the nucleophilic attack of the carbonyl oxygen on the carboxy carbon, followed by a loss of the leaving group (vide supra), forms the αferrocenylcarbenium ion (VII).The carbenium ion undergoes internal oxidation−reduction (valence tautomerization) whereby the non-bonding electron from the d2g set of iron is transferred to the positively charged carbon atom, giving a radical cation (VIII) [28].The two radical cations undergo coupling to give a dication dimer (IX).The intermolecular oxidation−reduction between the dimer and ferrocene derivative in the solution produces the neutral dimer 3b.Similar reaction mechanisms have been proposed earlier by Cais and others [25,[29][30][31][32][33] to explain the formation of dimerized products obtained from the solvolysis of α-ferrocenylcarbinols under acidic conditions.We attempted to isolate and characterize all the reaction products and their byproducts to validate the proposed mechanism.We could not isolate more than 48% of the dimeric products in our multiple synthetic efforts.We observed the formation of a black intractable residue, possibly due to the decomposition of cationic intermediates caused by the sacrificial oxidation of ferrocene derivatives.Careful separation of the reaction products by column chromatography indicated the formation of monoferrocenyl dimerized lactone as a byproduct of the reaction as evidenced by only one unsubstituted cyclopentadienyl group and 17 other chemically unique protons in 1 H NMR(Figure S16).We added two equivalents of ferrocene in the reaction mixture to prevent the loss of the starting compound during reductive dimerization of the radical cation VIII.Under these conditions, the yield of 3b increased to 85% and no decomposition product was detected.We assume that ferrocene preferentially oxidizes to provide the electron to the carbenium ion.
To obtain a better insight into the participation of the ferrocenyl moiety in activating the carbonyl oxygen for a nucleophilic attack, we decided to reduce the ketone to secondary alcohol and treat the hydroxycarboxylic acid with TFAA.The compound changed from red to yellow when compounds 1a and 2a were treated with NaBH4 in NaOH(aq).The product remained soluble in NaOH, indicating the presence of the carboxylic acid group in the molecule.However, when the solutions were acidified using HCl, both compounds gave orange precipitates no longer soluble in aqueous NaOH (Scheme 5).The neutral product showed a strong signal at 1758 cm −1 (4b) and 1727 cm −1 (5b) in IR and a doublet of doublet corresponding to one proton at 5.31 ppm (4b) and 5.16 (5b) in 1 H NMR, indicating the formation of lactones (Figures S17-S20).The lactone 5b was crystallized from a diethyl ether and hexane mixture by slow evaporation.A single-crystal X-ray analysis of the product showed the formation of the desired product (Figure S21); however, its complete refinement was difficult due to weak scattering and crystal twinning.
, and the torsional angle C-Cg1-Cg2-C in four ferrocenyl moieties ranges from 1.21° to 21.42°.In the crystal, the compound displays weak intermolecular π•••π interactions between two Cp rings, C-H•••π interactions between Cp-H and the centroid of Cp, and C-H•••O interactions between Cp-H and the carbonyl oxygen of two adjacent molecules (Figure S4).

Figure 3 .
Figure 3. ORTEP diagram of solid-state structure showing the atom-numbering scheme of compound 3b.Displacement ellipsoids are drawn at the 50% probability level.Selected bond lengths

Scheme 4 .
Scheme 4. Proposed mechanism of the formation of dimerized lactone.

Table 1 .
Crystal data and refinement parameters.