1 Introduction

The synthesis of progesterone for the first contraceptive pill by Ruseel Marker has been regarded as one of the five chemical discoveries that shaped the modern world [1,2,3,4]. Progesterone is the main active ingredient of oral contraceptive pills and a precursor to many steroid hormones such as cortisone, playing an essential role in the human life [5, 6]. Since Ruseel Marker discovered steroid sapogenins in Mexican yams could be turned into the hormone progesterone in a single step, the progesterone is still used today as a raw material for the production of many drugs, utilized in clinical treatment to save countless people from the suffering of various diseases [7,8,9,10,11]. The pharmacological activities of compounds depend on molecular structures, and in turn, specific steric structures may also bring attractive physical properties, such as piezoelectricity or ferroelectricity (necessary conditions for crystallisation in non-centrosymmetric or polar point groups) [12]. Ferroelectrics feature electrically switchable spontaneous polarization, which possess the ferroelectricity, piezoelectricity, pyroelectricity and nonlinear optical effects, leading to many valuable applications in data storage, energy conversion, ultrasonic sensing, and so on [13,14,15]. Although the research on contraceptive pill-related compounds has been around for decades, it has basically focused on their drug developments and chemical properties, with little regard for the physical properties related to ferroelectricity and piezoelectricity.

In this context, we are committed to developing the ferroelectricity in progesterone-based biomaterials for more biomedical and electronic values (Scheme 1). It should be mentioned that, unfortunately, the famous progesterone crystallizes in the P212121 space group, enabling the piezoelectricity but failing to meet the polar symmetry for ferroelectrics. Based on our continuous explorations on ferroelectrochemistry [16, 17], we discovered that replacing the carbonyl group of progesterone with a carboxyl group can be converted to 4-androsten-3-one-5-ene-17-carboxylic acid (17β-TCA), an important pharmaceutical intermediate used in the production of various steroid drugs. As a derivative of progesterone, the introduction of carboxyl groups brings about intermolecular hydrogen bonds in 17β-TCA, leading to an acentric and polar packing structure with P21 space group [18]. The hysteresis loop and the polarization switching of ferroelectric domains provide a solid evidence for the presence of ferroelectricity. It experiences a reversible structural phase transition at a high temperature of about 489 K and has a high melting point of 533 K, ensuring its wide temperature range to cope with high temperature working environments. To the best of our knowledge, this should be the first ferroelectric in steroid family, although organic ferroelectric crystals have been widely studied and have achieved great development and breakthroughs [19,20,21,22,23,24,25,26]. Given the unique advantages of environmental friendliness, low cost, high crystallinity, light weight, low acoustic impedance, and biocompatibility, 17β-TCA as an organic crystalline material would be a competitive candidate for biomedical, bio-electromechanics [27, 28], flexible electronics [29], and other applications.

Scheme 1.
scheme 1

The guiding ideology for developing the ferroelectricity of 17β-TCA

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2 Results and discussion

Single crystals of 17β-TCA were easily prepared by evaporating its ethanol solution at room temperature. The single-crystal structure determination reveals that 17β-TCA crystallizes in the monoclinic space group P21 at 293 K (Table S1), belonging to the polar point group 2 (C2). The asymmetric unit consists of one 17β-TCA molecule, in which two six-membered carbon rings (marked as B and C in Fig. 1a) adopt ‘chair’ conformations (Fig. 1b). Each 17β-TCA molecule links neighbor others through O–H···O hydrogen bonds, giving rise to an infinite head-to-tail one-dimensional hydrogen-bonded chain (Fig. S1). The adjacent chains are symmetrical about the 21 two-fold screw axis and the molecules are aligned along the b-axis, resulting in the spontaneous electric polarization along the b-axis direction (Fig. 1c). By contrast, the analog of 17β-TCA, progesterone, crystallized in the non-polar orthorhombic space group P212121 and does not have phase transition behavior, pointing out non-ferroelecticity (Fig. S2).

Fig. 1
figure 1

a Schematic diagram of molecular structure of 17β-TCA, consisting of three six-membered rings (Labeled as A, B and C) and one five-membered ring (Labeled as D). b A diagram of the stereo molecular structure in 17β-TCA crystal. c) The crystal packing diagram of 17β-TCA projected on the a-axis, the direction of the ferroelectric polarization is along the polar a-axis. H atoms were deleted from the diagram

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Differential scanning calorimetry (DSC) analysis revealed that 17β-TCA undergoes a reversible structural phase transition at about 489 K (Fig. 2a). Before the structural phase transition, crystal structural analysis indicates the 17β-TCA molecule is in a same ordered manner with the C–C and C–O bond distances in the normal range (Fig. S3). The crystal structure above 489 K is not successfully determined because of the weak X-ray diffractions at high temperature. The melting point of 533 K and the good thermal stability up to 608 K do indicate the high temperature phase (HTP, above 489 K) is stable (Fig. S4). Thus, variable temperature powder X-ray diffraction (PXRD) measurements were then carried out to get some structural information in the HTP. As shown in Fig. 2b, the PXRD patterns remain unchanged in the temperature range of 293–518 K, which means that the phase transition is an isostructural one, and the crystal of HTP has the same symmetry with that of low temperature phase (LTP, blow 489 K). The real part (ε′) of dielectric permittivity of 17β-TCA presents a remarkable anomaly near 489 K (Fig. 2c), further verifying the phase transition. We also employed the second harmonic generation (SHG) experiment to investigate crystal symmetry (Fig. 2d). Clear SHG signal can be observed in both LTP and HTP, in accordance with the polar packing structure.

Fig. 2
figure 2

Structural phase transition of 17β-TCA. a DSC curves. b Variable temperature PXRD patterns. Temperature-dependent c dielectric and d SHG properties

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In order to estimate the ferroelectric polarization of the crystal, we calculated the vector sum of the dipole moment of the molecule in the unit cell. As shown in Fig. S6b, the dipole moment of 17β-TCA molecule is about 3.1468 Debye. If all molecular dipoles contribute 100% to the total polarization, the polarization should be 2.39 μC/cm2. In fact, there is an obvious misalignment between the direction of molecular dipole moment and the crystallographic polar b-axis. The angle between the direction of the molecular dipole and the direction of the polar b-axis of the crystal is about 30 degrees. Therefore, we estimate the total polarization value to be about 2.07 μC/cm2. Furthermore, we employed Berry phase method to gain more accurate value of ferroelectric polarization, from which the polarization with 4.31 μC/cm2 along b-axis can be extracted [30]. While the polarization along a- and c-axis is zero, which is in good accordance with the symmetry requirement of space group P21. Note that the results from Berry phase calculation is much larger than that from vector sum of the dipole moment. This is because the molecules form intermolecular hydrogen bonds in the crystal, which pull the H atom on the carboxyl group towards the carbonyl group, thus making a positive contribution to polarization (Fig. S7). In addition, we have constructed several molecular structures containing different 'boat' and 'chair' conformations (Fig. S6c and S6e). Neither the magnitude nor the orientation of the dipoles differs much among them, demonstrating solid polarization stability in 17β-TCA crystal.

The macro ferroelectricity was directly verified by measuring the typical polarization–voltage (P–V) hysteresis loop (Fig. 3). Using the double-wave method, a standard P–V hysteresis loop was obtained from current density–voltage (J–V) curve, where two typically opposite peaks indicate two stable states with opposite polarizations. The well-shaped P–V hysteresis loop was measured with a Ps (spontaneous polarization) of 1.6 μC/cm2, suggesting the ferroelectricity of 17β-TCA. Additionally, the high melting point of 533 K and phase transition of 489 K enable the ferroelectricity has a broad working temperature, higher than that of other organic single-molecule ferroelectrics such as croconic acid (400 K) [31], (−)-camphanic acid (414 K) [32], and (R)-3-quinuclidinol and (S)-3-quinuclidinol (400 K) [33], which may find applications in future organic electronics.

Fig. 3
figure 3

P–V hysteresis loop of 17β-TCA measured on thin film sample via a double-wave method

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Fig. S8a-c show the lateral piezoresponse force microscopy (PFM) data and simultaneously acquired topography image on the 17β-TCA crystalline thin film (Fig. S10). We clearly observed the domain structure in the thin film, with obvious phase contrast and domain walls, indicating the existence of spontaneous polarization. The surface shows a smooth morphology, which has no crosstalk with the corresponding PFM signals.

The polarization switching of 17β-TCA was further detected by PFM as well. Firstly, an advanced PFM mode, namely switching spectroscopy PFM (SS-PFM), was adopted to investigate the variations of piezoelectric amplitude and phase sianals upon the application of a DC bias with a triangular waveform across the tip and sample. Fig. S8d and e exhibits the local PFM-based hysteresis on the 17β-TCA thin film, indicating the occurrence of polarization switching. By averaging the minima of the amplitude hysteresis loop, we can estimate that the coercive voltage for 1.5 μm thick film is about 79 V.

Besides the PFM switching loops, the PFM images before and after applying tip bias are also a typical probe for ferroelectric nature. Figure 4a and b shows the vertical PFM images overlaid on three-dimensional (3D) topography for the thin film at the initial state, presenting a uniform piezoresponse. A square area was scanned with a positive voltage of + 100 V. Then, a smaller region in the former square was scanned with a negative voltage of − 100 V. Figure 4c and d displays the PFM amplitude and phase images overlaid on 3D topography after writing the box-in-box pattern with reversed DC bias in the centre. Two regions with blue and red colors show almost a 180° phase difference, separated by clear domain walls shown in the amplitude image. These results confirm the switchable polarization and thus the ferroelectricity for 17β-TCA.

Fig. 4
figure 4

Domain switching measurements for the 17β-TCA thin film. Amplitude mapping (a, c) and phase mapping (b, d) of vertical PFM overlaid on 3D topography at initial state (a, b) and after applying tip voltage of ± 100 V in turn (c, d)

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We further performed the PFM technique [34, 35] to assess the piezoelectricity of 17β-TCA thin film. By sweeping the AC bias frequency, a clear resonant peak in the amplitude response of probe deflection is observed for both 17β-TCA thin film and poly(vinylidene fluoride) (PVDF) film, as shown in Fig. S9a and b, across which the phase response flips by 180° as expected from the simple harmonic oscillator (SHO) [36]. We then carried out first harmonic measurements on both 17β-TCA thin film and PVDF film, which excite and measure the response at the contact resonance, and thus indicate a linear response of the tip deflection. Such measurements have been carried out over a range of drive voltage up to 2 V, wherein it is clearly observed that the first harmonic response is linear to the applied bias, confirming the response comes from intrinsic piezoelectricity. The effective piezoelectric coefficient can be estimated from the slope. Here, the piezoelectricity of PVDF film was set as the benchmark, whose d33 was measured to be 28 pC/N via the “Berlincourt” method. Based on the slopes of the lines, the d33 of 17β-TCA thin film was calculated to be about 3.5 pC/N.

3 Conclusion

In summary, we demonstrate that 4-androsten-3-one-5-ene-17-carboxylic acid, a derivative of progesterone, is an organic single-component ferroelectric, which undergoes a reversible structural phase transition at a high temperature of 489 K. It shows clear ferroelectricity and ferroelectric-related properties, which can persist up to 533 K, giving a wide working temperature range. Combining the advantages of environmental friendliness, low cost, high crystallinity, light weight, and biocompatibility, one can expect the important combined effect of ferroelectricity and biomedical activity, promising to broaden the application fields beyond the traditional field of ferroelectrics.

[CCDC 2153383–2153386 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.]

The natural product 4-Androsten-3-one-5-ene-17-carboxylic acid, a derivative of progesterone, was discovered as an organic single-component ferroelectric material, which would inspire further studies of developing ferroelectricity in progesterone-related biomaterials for more biomedical and electronic values.