**1. Introduction—Historical Backgrounds, Knowledge, Then, and Now**

*1.1. What Is the Life?—Open System, Negative Entropy, Non-Equilibrium Thermodynamics*

Humankind has been thinking about life for a long time; where did life come from? Where will life go? Does life exist on earth only? So far, many scientists have postulated several scenarios throughout the primordial eons to address these curious questions. Regarding the first life on earth, the origin of biomolecular handedness remains an unanswered question in the scientific community [1–41].

In 1944, Erwin Schrödinger, one of the leading quantum physicists in his day, wrote an essay book titled *What is Life? With Mind and Matter and Autobiographical Sketches* [1]. Entropy inevitably increases only in a closed system-like universe as the consequence of the second law of thermodynamics. Living matters, thus, cannot elude conventional physics laws, but should involve other physics laws. To avoid a thermodynamic equilibrium by a spontaneous decay, living matters have to acquire and maintain negative entropy in an open system. Because living organisms exist as metastable states, metabolism that is a biological term of maintaining negative entropy is needed through all processes of eating, drinking, breathing, and, in case of plants, assimilating. To my knowledge, the two key concepts are rarely stated in most chemistry textbooks and not lectured in schools and colleges, although Schrödinger was the first to invoke an importance of these concepts. The chemistry textbooks and lectures teach us positive entropy, close system, enthalpydriven chemical reaction, and Arrhenius plot, but do not involve quantum tunneling, resonance, hierarchy from elemental particles, atoms, and molecules, four fundamental forces in nature, parity violation in weak nuclear force, the origin of homochirality, and the origin of life.

In 2002, Soffer et al. stated mathematically that non-equilibrium thermodynamics and equilibrium thermodynamics, respectively, correspond to the excited-state and the groundstate solutions of a Schrödinger wave equation [39]. In 2017, by referring to Schrödinger's notes, Ornes descried the core concept, concerning how non-equilibrium thermodynamics are connected to the mystery of life and other fields [40]. Non-equilibrium biological systems play key roles in gene transcription, diffusion in cytoplasm, transporting substances between cells with molecular motors, and cell signaling. Moreover, non-equilibrium phenomena are commonly recognized in the fields of fluid dynamics, plasma physics, meteorology, and astrophysics.

Likewise, an issue of left–right preference in the biomolecular handedness in the ground and excited states should involve these key concepts. When an equal probability of a simple chiral molecule, such as L- and D-alanine is considered, two possible states exist, corresponding to an increase in entropy. Living organisms only comprising optically active ingredients on Earth are possible to exist under open-flow conditions of energy and chemical resources because the metastable life requires low-entropy foods with chirality, and harvests solar/thermal energy [1,10,17]. If life existed on earth in the past, one of the greatest mysteries is whether stereogenic centers and/or stereogenic bonds in Hadean and Precambrian eons are identical to those of the on-going life on earth or are the extraterrestrial origin [22–38]. A conclusive answer to the question appears difficult because any fossil records of biomolecules and biopolymers associated with their handedness were decomposed. The snowball earth hypothesis, however, claims that prokaryotes inhabited the Precambrian eon for ~2 billion years [27,28]. Researchers in archaeological bacteriology have accepted that lighter 12C-containing stuffs are enriched in living organisms for their entire lifetimes. Indeed, the fact that 13C in 13C-/12C-isotopic ratio is significantly depleted would be evidence that the methanogenic microbes existed in the Archaean eon 3.5–3.8 billion years ago, associated with evolution of geodynamo of Earth, although Earth was born 4.54 billion years ago already [33–36].

Characterization of isotopic ratios and L-D ratios is powerful to discuss the origin of amino acids and carboxylic acids on Earth whether it is extraterrestrial origin or terrestrial origin. In 1987, Epstein et al. invoked that amino acids and carboxylic acids extracted from the Murchison meteorite were extraterrestrial in origin from isotopic ratios of D in D/H and 15N in 15N/14N [37]. In 1997, Engel and Macko supported the extraterrestrial origin of amino acids and carboxylic acids in the meteorite from the analysis of the isotopic ratios and L-D ratios of alanine and glutamic acids [38].

Regarding the origin of biological homochirality associated with the first life on Earth, several scenarios are postulated. For example, the possible scenarios are classified to: (i) extraterrestrial and terrestrial origins; (ii) the by-chance and the necessity mechanisms; (iii) physical force origins and chemical substance origins. Importantly, all chemical processes and reactions should obey the physics laws regardless of extraterrestrial and terrestrial origins and chance-and-necessity mechanisms. The only exception would be that these physics laws, and chemistry, cannot apply to black holes.

#### *1.2. Physical Advantage Factors for Left–Right Asymmetry*

Goldanskii et al. comprehensively reviewed that 13 physical advantage factors called *g*\* can cause a left–right preference to address the homochirality question at molecular and polymeric levels [42–44]. The *g*\*-values defined in physics may be a half of the Kuhn's anisotropy or Kuhn's dissymmetry ratio, *g*-values, defined in chemistry. The capabilities of chiral physical forces can access primitive molecules, followed by polymerization processes, which enable the homochiral world on terrestrial and extraterrestrial conditions. The global

advantage factors are universal, deterministic for the biomolecular handedness, while the local advantage factors are mirror-symmetric, hence, provide the by-chance mechanism. Among the advantage factors, the *g*\* of circularly polarized (CP) light source is considerably high on the order of 10<sup>−</sup>4–10−2.

On the other hand, the *g*\* for handed *β*−-electron is extremely small, only 10−9– 10−11, while the values of *g*\* for: (i) static magnetic field with linearly polarized light, known as the Faraday effect; (ii) Coriolis force (rotation) with static electric filed and static magnetic field; and (iii) Coriolis force with static magnetic field and gravitational field are on the order of 10−4. Coriolis force with gravitational force is a mirror symmetric chiral force, corresponding to the vectoral hydrodynamic flowing, often called swirling flow and vortex flow. Handed weak neutral current provides the smallest *g*\* on the order of 10−17. Static magnetic field, static electric filed (so-called Stark effect), and gravitational field alone do not induce the left–right preference. CP-light, Coriolis force, static electric filed, static magnetic field, and gravitational field are parity-conserving mirror-symmetrical physical forces, while a weak neutral current and *β*−-electron are parity-violating handed physical sources.

In 1953, Frank treated, mathematically, the first seminal bifurcation model account for a spontaneous mirror symmetry breaking in terms of evolution of biological homochirality [45]. For visibility and clarity, Goldanskii et al. illustrated two bifurcation models connecting to double-well and single-well potential curves [42–44]; a mirror-symmetric bifurcation model with a mirror-symmetric double-well potential curve and a non-mirrorsymmetric bifurcation model with a non-mirror-symmetric double-well potential curve. Based on these bifurcation models associated with the *g*\* values discussed above, Goldanskii et al. showed two scenarios, allowing us to well recognize both the bi-chance and necessity mechanisms for the spontaneous mirror symmetry breaking. Knowing the fluctuation behaviors around these bi-furcation points with those *g*\* values, namely, a phase transition characteristics from the single-well to the double-well or from the double-well to the single-well is the key to rationally design the left–right preference, followed by the homochirality systems [7,8,46].

#### 1.2.1. Circularly Polarized Light Source

Historically, in 1874, LeBel, and in 1894, van't Hoff, proposed independently a possibility of absolute asymmetric synthesis (AAS) using *r*- and *l*-CP light as chiral physical source [46–49]. A half century after their predictions, in 1929, Kuhn and Broun experimentally realized their conjectures as photodestruction mode AAS [46]. Their pioneering work prompted allowed many researchers to investigate AAS for a century because expensive chiral chemical substances are no longer needed [47–50]. However, most researchers have long believed that *l*-CP light produces left-hand (or right-hand) molecules preferentially and vice versa because the product chirality is determined solely by the hand of CP light. The AAC with *r*- and *l*-CP light covers absolute asymmetric photosynthesis, photodestruction, and photoresolution modes [47–49]. Generating left–right preference endowed with CP-light was coined photochirogenesis by Yoshihisa Inoue as the key concept of CP light–matter interactions in 1996 [7,8,51].

In the 1970s, Calvin et al. reported an anomaly of an excitation wavelength dependent CP light-driven photosynthesis mode AAS recognized as a switching product chirality of [8]-helicene in homogeneous toluene solution [52]. In 2014, Meinert et al. reported the wavelength-dependent CP light-driven photodestruction mode AAS revealing switching chirality when *rac*-alanine film was decomposed upon irradiation of two vacuum-UV light sources (184 and 200 nm) [53]. A recent development of wavelength-dependent CP light driven photoresolution mode AAS employed by us will be given in Section 4.5 [54–56].

#### 1.2.2. Static Electric Field

According to recent works, with static electric fields, so-called Stark effects, in the absence of magnetic field, Auzinsh et al. reported chirogenesis as emission modes on the order of *g* = 0.20 (10% for circularity) at <sup>7</sup>*D*3/2 state and *g* = 0.15 (7.5% for circularity) at <sup>9</sup>*D*3/2 state of parity-violating, paramagnetic Cs vapor placed between two mirrored electrodes [57]. On the other hand, Datta et al. indicated an occurrence of lowering molecular symmetry of achiral diamagnetic aromatic molecules by a computer simulation. Coronene, a 6-fold highly symmetric molecule, undergoes *D*6h→*C*<sup>2</sup> distortions via vibrational instability upon application of sufficiently intense static external electric field [58]. The electric field induced structural distortion is understood as resulting from excess charge accumulation of planar rings circumvented by symmetry lowering. Contrarily, tribenzopyrene, a contorted polyaromatic compound due to a repulsion by two pairs of syn H-atoms, undergoes, spontaneously, *C*2v→*C*<sup>2</sup> distortions in the absence of the electric field. Coronene, tribenzopyrene, and other fused aromatics are assumed to be the representative polycyclic aromatic hydrocarbons, so-called PAHs, which are abundant in the universe [59]. Because *C*2-symmetric molecules are chiral, a naive question remains to be elucidated experimentally, whether *C*2-coronene and *C*2-tribenzopyrene exist as racemic mixtures or single enantiomers in connection with the homochirality question in the universe. Collision-free, gas-phase circularly polarized luminescence (CPL) spectroscopy may allow us to provide an answer to this question.

#### 1.2.3. Static Magnetic Field

With the origin of biological chirality in mind, Pasteur was the first to attempt a chemical process called enantioselection, showing whether left-handed or right-handed molecules are produced under magnetic field, but failed because the magnetic field is a pseudo-vector that cannot be coupled with molecular chirality [60]. In 1994, Zadel et al. published an astonishing paper titled *Enantioselective Reactions in a Static Magnetic Field* [61]. Several research teams attempted to reproduce these results immediately, but failed [62,63], because, prior to the experiments, in the solutions, under 2.1 Tesla of static magnetic field (NMR instrument) in the paper, all reaction solutions were in advance design and manipulated [64]. Static magnetic field on the order of 2 Tesla does not induce any detectable enantioselective reaction in a fluidic solution under non-restricted Brownian molecular motions. Uniform static magnetic fields do not induce molecular chirality because of the time-odd, axial vector [60,65]

Naaman and Wadeck reviewed theory and experiments of chiral-induced spin selectivity (CISS), where ordered films of chiral molecules on surfaces can act as electron spin filters [66]. By applying the idea of CISS, in 2018 and 2019, Naaman and his international team succeeded in enantiospecific crystallization of three L-/D-amino acids and thiolated L-/D-alanine-based helical oligomers at the magnetized surface with a gold-coated ferromagnet cobalt film [67,68]. Enantioselectivity is determined by north-up and south-up geometry of the magnet and the nature of chiral substances. An attractive force between electrons in the substrate and in the molecules is on the order of several tens of kJ mol−<sup>1</sup> when a molecule surface distance is 0.1–0.2 nm [68]. Brownian motion of floppy molecules is considerably restricted at the molecule surface interface, followed by a great suppression of the molecular motions during crystallization at the surface. Since a magnetic field is a short-distance force compared to the electric field, a proximity effect of the molecule at the magnetized surface should be considered.

In 1955, Akabori proposed the polyglycine hypothesis—foreproteine as the origin of protein homochirality on Earth [22]. The hypothesis involves three steps: (i) formation of aminoacetonitrile from formaldehyde, ammonia, and hydrogen cyanide, which were ubiquitous in primordial Earth; (ii) polymerization of aminoacetonitrile at a solid surface, such as a Kaolinite that is a two-dimensional aluminosilicate Al4Si4O4(OH)4, followed by hydrolysis to yield polyglycine and ammonia; (iii) introduction of side chains to polyglycine. The experimental results showed that: (i) methylene groups of polyglycine are adsorbed on Kaolinite; and (ii) glycyl residues are converted to serine and threonine residues reacted with formaldehyde and acetaldehyde, respectively. Although achiral glycine has two equal C-H bonds, the two C-H bonds at each residue of helical oligoglycine and polyglycine

are no longer equal. The two C-H bonds at each glycine residue of the helix may reveal different reactivity toward chemical species. Akabori conjectured that the origin of all L-selectivity in amino acids of proteins results from the by-chance mechanism because there is no chirality in Kaolinite. The hypothesis, followed by experiments, were reported just before the groundbreaking fever in 1956–1958 that the parity in the *β*-decay process of 60Co is violated, though a left–right equality of enantiomers was a concrete common sense in chemistry in those days [69–76].

Knowing the magnetic minerals and the first geodynamo on Earth is an important clue how Earth's core, atmosphere, biomolecular chirality, and life evolved [33–36]. In 2015, Tarduno et al. claimed that, by analyzing inside of zircon crystals, which were indestructible for nearly 4.4 billion years, in Western Australia, Earth's magnetic field had evolved already from more than 4 billion years ago [33]. Likewise, from the oldest rocks in South Africa, Earth's magnetic evolved around 3.5 billion years ago [34]. Moreover, a recent work indicates that, from magnetic minerals in ancient Greenlandic rocks, Earth's magnetic field arose at least 3.7 billion years ago [35,36], enabling to magnetically shield primitive life and chiral substances evolved on Earth.

The CISS theory [66], along with the experimental results [67,68] proven by Naaman et al., encourages to test whether: (i) helical oligoglycine and polyglycine are adsorbed vertically at the magnetized surface; (ii) the two C-H bonds at each residue reveal a different chemical reactivity toward several chemical species in the absence and presence of UV-light around 190–220 nm; and (iii) enantioselectivity is determined solely by north-up and south-up geometry.

In 2019, Stevenson and Davis proposed a possibility of magnetophoresis that radical species of D- and L-substances are separable and sortable under an ultrastrong magnetic field gradient of >4.4 × 109 Tesla [77]. Such an ultrastrong magnetic field and gradient can no longer obey the standard Maxwell equations. Paramagnetic chiral molecular species in the universe may be passing through in the vicinity of magnetar, which are newborn neutron stars spinning very fast that generate the ultrastrong magnetic field. Kouveliotou et al. think that more than 100 million magnetars are wandering through the interstellar universe and trillions of organic paramagnetic materials are imbedded in cold molecular clouds [78]. The ultrastrong magnetic field causes vacuum birefringence, photon splitting, scattering suppression, and distortion of atoms [78]. Although magnetic field gradients are widely utilized in NMR imaging, so-called MRI, the feasibility of the ultrastrong magnetic field gradient is challenging.

#### 1.2.4. Hydrodynamic Flowing as a Model of Coriolis Force with Gravitational Force

When artificial molecular chromophores and luminophores are dispersed in the fluidic medium, hydrodynamic swirling flowing clockwise (CW) and counterclockwise (CCW) are experimentally testable models to validate the origin of the gravitational field's left–right preference [79–83]. The vectoral hydrodynamic flowing is often called as swirling flow and/or vortex flow. The unidirectional hydrodynamic flowing in the CW or CCW direction imparts the left–right preference at the molecular and supramolecular levels. The left–right preference in the northern hemisphere may be opposite to that in the southern hemisphere due to parity-conserving physical force on Earth.

In 1993, Ohno et al. reported chirogenesis of circular dichroism (CD)-active *J*-aggregates from achiral free-base porphyrin derivative in acidic water solution by mechanically swirling in CW and CCW directions [79]. They observed two clear couplet-like CD bands around 410–450 nm due to Soret band and 480–500 nm due to Q-band. The couplet-like CD band profiles were inverted by choosing the CW or CCW direction during the propagation of *J*-aggregate. Very weak non-couplet CD band around 480 nm, however, was recognized under a stagnant condition. Obviously, the hydrodynamic flowing appears responsible for the chirogenesis, but a statistical analysis was not performed yet. It is unclear whether this event occurs using the specific porphyrin derivative at a specific laboratory.

In 2001, Ribó et al. confirmed, by the statistical analysis from nearly a hundred of independent experiments that macroscopic swirling forces in the CW and CCW directions indeed generate homochiral aggregates from water soluble achiral porphyrin derivatives that slightly differ from the porphyrin above [80]. The hydrodynamic flowing indeed acted as a trigger of the spontaneous homochiral *l*-or-*r* aggregation [81].

Although water-soluble porphyrin derivatives carrying multiple phenyl rings at mesopositions are directly connected to biomolecular substances, the idea of hydrodynamic flowing is applicable to chain-like synthetic polymers and several chromophore/luminophore during their association processes that feel the handed force of the hydrodynamic flowing, regardless of the northern and the southern hemispheres on Earth and other exoplanets. The author assumes that, since unsubstituted free-base porphyrin framework is very floppy, these porphyrin derivatives substituted with tetraaryl groups at meso-positions may adopt dynamically twisting two structures, between left and right, in a fluidic solution at ambient temperature.

In line with the bifurcation scenario, in 2011, Okano et al. succeeded in chirogenesis from achiral rhodamine B as a red luminescent molecular probe doped to a water-soluble sol-gel polymer, revealed by CPL spectroscopy [82]. Based on a statistic analysis, the sign in CPL signals at 580 nm was controlled by the CW/CCW motions of hydrodynamic flowing in a cuvette. The critical temperature (*T*c) for gelation was controlled by tuning the concentration of the polymer in aqueous solution. The polymer solution was in a sol state with a low viscosity, while stirring above the *T*c, while the solution below the *T*<sup>c</sup> spontaneously underwent a non-flowing gel state in a very high viscosity.

In 2018, by mimicking submarine rock micropores at primordial Earth, Liu and collaborators designed a sophisticated microfluidic chirogenesis system [83]. The fluidic system was composed of ten pairs of inclined microchambers to efficiently generate pairs of CW and CCW microvortices using achiral 3-fold molecular symmetric aromatic molecules that possessed supramolecular gelation capability. By a statistical analysis based on 56 totally independent experiments, they ascertained that the microfluidic chirogenesis system works very efficiently by simulating a behavior of hydrodynamic flowing in the microchamber. They re-confirmed that the microfluidic system is viable for a very rapid chirogenesis within 1 ms of the water-soluble porphyrin derivative. These results should shed light on the origin of the biomolecular homochirality; how oceanic vortices play a critical role in protein folding and self-organization in primordial Earth.

#### 1.2.5. Static Magnetic Field with Polarized Light

Static magnetic field with linearly polarized light and static magnetic field with unpolarized light, which are called magneto-optical effects, including Faraday and polar Kerr effects, are possible to be chiral physical sources, enable to induce mirror symmetrical, left–right imbalance in the ground and photoexcited states. The left–right chiroptical preference from achiral substances in the ground and photoexcited states is determined by north-up and south-up magnetic fields to propagation of incident light, called magnetic circular dichroism (MCD) [84–87] and magnetic circularly polarized luminescence (MCPL) [88–91], respectively. The phenomena are closely connected to Zeeman splitting of degenerate molecular orbitals. Recently, Imai, Fujiki, and coworkers verified mirror symmetrical MCPL characteristics from diamagnetic achiral organic and racemic lanthanide luminophores. These luminophores radiate *l*- and *r*-CP light upon unpolarized light at north-up and south-up Faraday geometry [92–94]. However, it is obscure whether mirror symmetrical MCPL arises from Zeeman splitting of degenerate molecular orbitals in the ground states or in the photoexcited states because a comparison with the corresponding MCD spectra is not elucidated yet. Nevertheless, in analogy with the first report of Raman scattering in 1928 [95], the MCPL characteristics teach that the handed light emission under external magnetic field is becoming a new type of secondary radiation sources, *l-* and *r*-CP light, in the absence of any chemical chirality, when achiral luminophores are, by-chance, placed on magnetized substances (even on ubiquitous), but a weak geomagnetic field of

~3 × <sup>10</sup>−<sup>5</sup> T. In that case, the magnetic fields should satisfy north-up and south-up Faraday geometries. A magnetic field-caused CP light source from achiral luminophores may be ubiquitous in the universe, and was therefore the source of circularly polarized radiation as seeds of molecular chirality in the past (and now all over universe).

Rikken and Raupach designed a static magnetic field-driven photoresolution molecular system using racemic K3CrIII(oxalate)3 complex in water upon irradiation of Ti:sapphire laser at 696 nm [96]. They demonstrated an occurrence of mirror-symmetrical photoresolution from the complex, in which a preferential chirality is determined by north-up and south-up Faraday geometries. Recently, Sharma calculated (based on the MCD effect) that unpolarized ultraviolet sunlight, so-called UV-C region, combined with atmospheric paramagnetic oxygen diluted with carbon dioxide can possibly trigger an initial enantiomeric excess (ee) to determine the biomolecular handedness under the geomagnetic force in Archaean Earth [97]. Notably, when the UV-C light destructs several biomolecular constituents, a preferential chirality between purine and pyrimidine nucleosides depends on a partial pressure of carbon dioxide. However, a preference in the product chirality of amino acids is always L-form. Thus, a static magnetic field with unpolarized light becomes one candidate for efficient photodestruction, and photoresolution modes in racemic amino acids and nucleosides in water disregard of terrestrial and interstellar conditions.

#### 1.2.6. Longitudinally Polarized Left-Handed *β*-Electron and Right-Handed *β*-Positron

In 1956, Lee and Yang theoretically indicated a possibility of parity-violation in certain nuclear reactions. In 1957, Wu et al. experimentally confirmed the parity-violation in the reaction 60Co→60Ni + *<sup>e</sup>*<sup>−</sup> + anti-ν<sup>e</sup> using *<sup>β</sup>*−-decay of radioisotope 60Co. Likewise, a parityviolation in *<sup>β</sup>*+-decay process that the 58Co→58Fe + *<sup>e</sup>*<sup>+</sup> <sup>+</sup> <sup>ν</sup><sup>e</sup> was confirmed, while positron and anti-ν<sup>e</sup> were antimatters of electron and νe, respectively [69–76]. The parity-violation relies on a weak charged current of the radioisotopes. In 1958, Goldhaber et al. determined that helicity of massless electron neutrino is left-handed from the resonance scattering experiment of <sup>γ</sup>-ray at 960 keV that an excited nucleus 63Sm152 (1− state) spontaneously radiates a handed γ-ray to relax a ground state nucleus 62Sm152 (0+ state) [74].

In 1959, this discovery prompted Vester and Ulbricht to propose so-called Vester– Ulbricht (V–U) hypothesis: parity-violating, spin-polarized left-handed *β*-electron causes circularly polarized bremsstrahlung that preferentially decomposes D-amino acids and left-handed DNA precursors, thus remaining *l*-amino acids and right-handed DNA on Earth [98,99]. In 1984, Bonner reported the failure of the V–U hypothesis—that several racemic amino acids cause radioracemization when polarized *β*-electron Bremsstrahlen from radioisotopes 90Sr-90Y, 14C, and 32P is applied [100].

In 1982 and 1984, Zitzewitz et al. utilized low-energy, right-handed *β*-positron in place of left-handed *β*-electron, and reported a weak asymmetry of leucine while cystine and tryptophan had little V–U effects [101,102]. In 2014, Dreiling and Gay confirmed successfully that the V–U hypothesis is valid, based on the detection of a preferential L-D decomposition of racemic 3-bromocamphor [103]. In 2018, Dreiling et al. confirmed volatile ester derivatives of DL-amino acids and DL-sugar molecules with low-energy *β*-electron and *β*-positron may be suited to verify the V–U hypothesis.
