Soft 2D nanoarchitectonics is not limited to the preparation of functional materials and the fabrication of device structures in two dimensions. Dynamic processes, such as self-assembly, molecular recognition, and molecular manipulation, are other attractive targets in soft 2D systems62. Unlike 3D media, restricted molecular motions within confined 2D spaces often result in well-defined orientation, ordering, selection, and efficiency in these processes. It is known that binding constants for molecular recognition are incredibly enhanced at the air–water interface compared with those observed in bulk aqueous media. For example, binding constant between guanidinium and phosphate at the 2D air–water interface are in the range of 106 and 107 M−1, while the corresponding constant is only 1.4 M−1 in the 3D aqueous phase63,64. According to theoretical simulations based on a quantum chemical approach, heterogenic dielectric features at the 2D interface of media significantly affect the nature of molecular interactions, which are fundamental aspects of supramolecular chemistry.

As they are not limited to confinement requirements and heterogenic dielectric features, dynamic interfaces have specific advantages in coupling between extremely different-sized events, such as centimeter- or meter-level macroscopic mechanical motions and nanometer-level molecular functions. Dynamic 2D media, such as air–water interfaces, have lateral sizes on the macroscale, but their thickness is confined within the nanoscale. Therefore, dynamic 2D interfaces are appropriate media for coupling macroscopic mechanical stimuli and molecular functions65. This intrinsic nature of dynamic 2D media enables us to accomplish incredible actions, such as control of molecular machines and tuning of molecular receptors, by hand-motion-like macroscopic mechanical motions66. For example, the molecular machine (steroid cyclophane) system exemplified in Fig. 10 is capable of catching and releasing a particular guest molecule upon macroscopic lateral compression and expansion of its monolayer formed at the air–water interface67,68. The control of molecular machines through nanotechnological actions can be accomplished by human-level actions, such as hand motions, which is defined as hand-operated nanotechnology.

Fig. 10 Catching and releasing a particular guest molecule upon macroscopic lateral compression and expansion of the monolayer of the molecular machine (steroid cyclophane) at the air–water interface Full size image

Controllable molecular motions are not limited to large apparent conformational changes, such as the cavity formation and opening described in the previous example. Slight structural tuning of molecular receptors can be achieved by macroscopic mechanical motions of soft 2D media. Two examples of molecular receptors are illustrated in Fig. 11: (A) cholesterol-armed cyclen69 and (B) cholesterol-substituted triazacyclononane70. In the former case, the helical structures of the molecular receptors, which contain four chiral cholesteryl residues, are influenced by changes in their packing states by external conditions, such as mechanical pressure. Upon embedding the cholesterol-armed cyclen receptors at the air–water interface, their guest accommodation space can be tuned by the application of lateral pressure to their monolayer, accompanied by a shift in their diastereomeric stability upon binding of chiral guests from the aqueous subphase. For example, the binding constant of d-valine to the cholesterol-armed cyclen monolayer exceeds that for the L isomer at lower surface pressure, showing D-preferential binding, but the binding constant to l-valine becomes larger than that to d-valine at increased surface pressure. The observed inversion of the enantiomeric selectivity toward amino acids can be achieved by tuning the receptor structures through macroscopic mechanical motions. This receptor tuning concept can be applied to realize the efficient differentiation between aqueous thymine and uracil derivatives by using mechanically adjustable cholesterol-substituted triazacyclononane receptors at the air–water interface. Under the selected conditions, the binding constant for uracil recognition becomes 60–70 times larger than that for thymine, although these nucleic acid bases, which have a structural difference of only one methyl group, cannot be distinguished by DNA or RNA.

Fig. 11: Slight structural tuning of molecular receptors by macroscopic mechanical motions in soft 2D media. a Chiral discrimination of amino acids by cholesterol-armed cyclen and b discrimination of uridine and thymine by cholesterol-substituted triazacyclononane Full size image

Molecular recognition in the above-mentioned examples utilized the fundamental structural flexibility of organic compounds. This way of thinking is different from well-known molecular recognition techniques that rely on information from single-crystalline structures and computational optimization. Figure 12 summarizes categories of molecular recognition modes in the history of supramolecular chemistry71,72. The most fundamental mode is based on a single stable state of a host–guest complex, as seen for molecular recognition with conventional artificial and biological receptors, such as crown ethers, cyclodextrins, and antibiotics (Fig. 12a). A switching mode was first demonstrated by Shinkai et al.73 in their pioneering work on photoswitchable azo-benzene hosts and expanded to include many kinds of molecular recognition systems. This switching mode creates multiple (two or three or four, etc.) stable states, and the recognition behavior can switch among these states (Fig. 12b). In contrast, the tuning concept explained above can be regarded as an emerging mode of molecular recognition (Fig. 12c). Through confining molecular receptors in soft 2D nanoarchitectures, the molecular states and energy states of molecules can be continuously shifted through macroscopic lateral mechanical motions. This mode imparts a countless number of receptor conformers as candidates for desired recognitions and functions. We can take the most desirable host structures from this continuous tuning process. This tuning mode is thus a novel mode of molecular recognition.

Fig. 12: Categories of molecular recognition modes in the history of supramolecular chemistry. a One stable state of a host–guest complex, b switching mode, and c tuning mode Full size image

The mechanical tuning of molecules in soft 2D architectures has been systematically investigated using amphiphilic binaphthyl compounds, because changes in the dihedral angle of the binaphthyl moiety can be easily monitored and theoretically simulated74. As illustrated in Fig. 13, the monolayer of the amphiphilic binaphthyl molecules is continuously compressed at the air–water interface and has been subjected to detailed structural analyses and theoretical calculations. At this soft 2D medium, the application of small mechanical energy (<1 kcal mol−1) is ensured, accompanied by a large variation in molecular area (>50%). The combination of several approaches, including experimental measurements of circular dichroism, thermodynamic energy calculations, single-molecule simulations, and molecular dynamics simulations, has revealed various facts concerning molecular tuning at the 2D interface of media. Mechanical energy can be proportionally converted to torsional energy in the binaphthyl molecule. The global average torsion angle of the binaphthyl molecule can be continuously shifted. Therefore, this molecular tuning is regarded as an analogous control of molecular conformation, possibly with pN-level forces.

Fig. 13 Mechanical tuning of amphiphilic binaphthyl compounds in soft 2D architectures Full size image

The modulation of molecular components induces changes in the molecular control from analog mode to digital mode75. When rather simple binaphthyl molecules are mixed in lipid matrices, a phase transition involving the crystallization/dissolution of quasi-stable binaphthyl crystals accompanied by the discontinuous digital opening of the binaphthyl moiety can be regulated by the application of a lateral mechanical force (Fig. 14). These changes are reversible and repeatable. These examples represent a step forward in the development of mechanical tools of molecular machines with continuous and reversible motion under an external force. In these attempts, kinetic and thermodynamic investigations as well as theoretical simulations are necessary to construct 2D systems to accurately control molecular machines.

Fig. 14 Phase transition by the crystallization/dissolution of quasi-stable binaphthyl crystals accompanied by the discontinuous digital opening of binaphthyl upon application of a lateral mechanical force Full size image

Very recently, Nakanishi and co-workers76 investigated the intramolecular motions of amphiphilic molecular rotors confined within two dimensions and further compared their behaviors with those in three dimensions (Fig. 15). The studied molecular rotors were 9-(2-carboxy-2-cyanovinyl)julolidine derivatives with fluorescence properties and twisted intramolecular charge-transfer capability. The suppression of their intramolecular rotation can be monitored by an increase in their fluorescence intensity. The in situ fluorescence measurement of the molecular rotor monolayer upon compression revealed that the intramolecular rotation was not suppressed even in condensed monolayers. In the 2D condensed phase with molecular alignment, the cross-section of the hydrophobic region of the molecular rotor ensures free rotation of the rotor. This molecular rotation was maintained in transferred LB films. In contrast, expanding the monolayers into three dimensions inhibits molecular rotation and promotes excimer formation. These examples indicate that well-considered molecular ordering is crucial to maintain free spaces for molecular motion to preserve molecular rotor motion in high-density states. Two-dimensional nanoarchitectonic design would be advantageous to operate molecular machines within condensed phases.