Probing Noncovalent Interactions: 

From Molecular Spectroscopy to Applications

Our research group is presently working on various noncovalent interactions (NCI) and their applications. These NCIs include hydrogen bonds (H‑bond) with sulfur and selenium and carbon, Carbon bond (C‑bond) and Carbo‑hydrogen bond (CH‑bond). The objective is to investigate these interactions at the molecular level by using a combination of spectroscopy and quantum chemistry. The fundamental insights gained from molecular spectroscopy are used for applications such as in the stability, storage and enzymatic activity of biomolecules and catalysis. The group actively involves in building scientific instruments and designing software for data acquisition and analysis. A brief description of our research activity is summarized below.

(A) Spectroscopy and Dynamics of Molecules and Clusters 

Hydrogen Bonds (H-bonds) play important roles in imparting functionality to the basic molecules of life by stabilizing their structures and directing their interactions. Extensive research has focused on H-bonds involving electronegative atoms like nitrogen, oxygen, and halogens, exploring their impact on chemical reactions, catalysis, and biological processes. However, the involvement of less electronegative atoms like sulfur and selenium in H-bond formation introduces the concept of "noncanonical" H-bonds. Initially perceived as weak, these interactions have gained significant recognition due to advancements in experimental techniques, such as gas-phase laser spectroscopy and solution NMR spectroscopy, as well as theoretical predictions. 

Our research delves into the versatility of sulfur and selenium-centered H-bonds (S/SeCHBs), investigating their diverse applications across various fields, including chemical reactions, optoelectronics, and structural biology. We have demonstrated the significance and strength of these H-bonds in both natural and modified biomolecules. Precise experimental data, particularly from gas-phase laser spectroscopy, has been instrumental in revising the initial perceptions regarding the strength of S/SeCHBs. Thus, molecular beam experiments, though difficult to perform on smaller model thio- or seleno-substituted Molecules, etc. (amides, nucleobases, drug molecules), are inevitable to gather elementary knowledge and convincing concepts on S/SeCHBs that can be extended from a small four-atom sulfanyl dimer to a large 14 kDa iron–sulfur protein, ferredoxin. Furthermore, S/SeCHBs offer unique opportunities for molecular engineering, enabling the design of intricate molecular frameworks and supramolecular assemblies.

The applications of S/SeCHBs extend beyond their role in biomolecules. They offer promising avenues in synthetic chemistry, such as tuning reaction selectivity and inducing novel phenomena like dual phosphorescence and chemiluminescence. Our investigations into the dispersive nature of hydrogen bonds between metal hydrides and sulfur or selenium as acceptors are expected to advance our understanding of proton and hydride transfer mechanisms. The spectroscopic data are useful for the development of improved force fields.  Through molecular spectroscopy, we gain new insights ion the hydrogen bonds involving sulfur and selenium. These insights pave the way for advancements in crystal engineering, enabling more sophisticated photo- and biophysical studies utilizing various spectroscopic methods. Furthermore, they hold immense potential for the development of cutting-edge technologies, including next-generation field-effect transistors, high-performance batteries, superconductors, and organic thin-film transistors, among many other multifunctional materials that will shape the future.


NCIs involving carbon (either as an electron acceptor or donor) are very sparse. For example, the weak C-H···O interaction where carbon acts as an H-bond donor is well studied. However, in proteins, the occurrence, strength, and importance of carbon bonds (C‑bonds) between an electron-rich carbonyl-oxygen acceptor and an electron-deficient sp3-hybridized carbon ϭ-hole donor through n→ϭ* electron delocalization are yet to be perceived. A bidirectional noncovalent interaction (NCI) without π- and/ or lone pair(s) of electrons has never been reckoned until the recent report, which confirms that this type of NCI can be possible with the involvement of only s-electrons and this newly discovered NCI can be coined as Carbo‑Hydrogen bond (CH‑bond) based on its resemblances with both C-bond and H‑bond, and the logic behind the name of "dihydrogen bond" or Ci:::H Hydrogen bond. The molecules containing inverted carbon atoms (Ci) and Ci-Ci ϭ-bond are capable of forming CH‑bond with main group hydrides through ϭCi‑Ci→ϭ*X-H (H‑bond) and ϭX-H→ϭ*Ci‑Ci (C‑bond) orbital interactions.  We are interested to explore carbon-centered noncovalent interactions that were ignored or not discovered over the years. 


The major constraint in studying such dimers bonded through the above mentioned NCIs is that dimerization energy or binding energy for them is too weak. These weakly bound dimers can easily be dissociated with the thermal energy available at NTP. The collision between the monomers and dimers, dimers and solvent molecules leads to dissociation of the dimers, which restricts investing such dimers in solution at ambient temperature and pressure. It needs a special molecular spectroscopy technique called "Supersonic Jet Spectroscopy," which is used to study the structure and dynamics of molecules and molecular clusters that have been cooled to about 10-15 K (far below their boiling points) but remain in the gas phase. Cooling the internal degrees of freedom (molecular rotations and vibrations) through the isenthalpic expansion of the molecular jet with a speed higher than the speed of sound in a vacuum produces a highly resolved and simplified mass and conformer selective electronic and vibrational spectra.


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(B) Instrumentation 


Beyond utilizing established techniques like fluorescence spectroscopy, TCSPC, fluorescence upconversion, NMR, EPR, ESI-MS, ECD, and ITC, our research group actively engages in the design and construction of custom-built scientific instruments tailored to our specific research needs. This approach allows us to address unique experimental requirements that cannot be met by commercially available systems. We also develop accompanying software, often using LabVIEW, for data acquisition and analysis from these custom-built instruments. A brief description of a few of the instruments is provided below.


Supersonic Jet Spectroscopy is a powerful technique employed to investigate the structure and dynamics of molecules and molecular clusters. In this method, molecules are cooled to extremely low temperatures, typically around 10-15 K, while remaining in the gas phase. This significant cooling, far below their boiling points, minimizes molecular motion and vibrational energy, leading to several key advantages:

To implement this technique, a dedicated spectrometer has been designed and built in-house by NISER PhD and MSc students. This custom-built instrument requires a suite of specialized components, including Nd-YAG pumped dye lasers, an IR OPO, molecular beam chambers, high-voltage power supplies, delay generators, high-speed rotary and turbo pumps, and sensitive detectors such as MCPs, channeltrons, and PMTs.

Beyond the scientific gains, this project provides invaluable training opportunities for students, enabling them to gain hands-on experience in designing and building sophisticated scientific instrumentation.


Vibrational Circular Dichroism (VCD) Spectroscopy is a valuable tool for determining the absolute configuration of chiral molecules without the requirement of a UV-Vis chromophore. VCD is a powerful technique for investigating the self-aggregation of chiral molecules (homocomplexes) and their noncovalent interactions with other molecules (heterocomplexes) due to its unique sensitivity to conformational landscapes. However, at room temperature, VCD spectra of flexible molecules can become broad due to the presence of multiple conformations and complexes.

To overcome this limitation, matrix isolation (MI) can be combined with VCD spectroscopy (MI-VCD). In this technique, molecules are trapped within a cold noble gas matrix (typically at temperatures around 10-30 K), significantly reducing conformational flexibility and eliminating solvent interactions. This low-temperature environment results in much narrower IR and VCD spectra compared to solution-phase measurements, facilitating detailed spectral assignments and the analysis of conformational distributions.

The sharp spectral features obtained through MI-VCD can be effectively utilized for chiral recognition, investigating chirality transfer in noncovalently bonded complexes.


Polaritonic Chemistry and Vibrational Strong Coupling (VSC) are relatively nascent research domain in chemistry. This phenomenon arises due to the strong interaction between quantized excitations in molecules and quantized photon states confined within optical cavities.

Molecular polaritons, formed through the coupling of electronic, vibrational, and rovibrational transitions with photon modes, have garnered significant experimental attention. These hybrid light-matter states emerge from the strong coupling between photons (ranging from UV to IR) and molecular excitations, such as electronic or vibrational transitions.

VSC specifically describes the strong interaction between an infrared photon and a vibrational mode of a molecule, where the rate of energy exchange between them surpasses any dissipative processes within the system. This strong coupling leads to the disappearance of the initial vibrational state and its subsequent splitting into two new eigenstates, often referred to as vibro-polaritonic or hybrid light-matter states.

While VSC in solution phase has provided valuable insights into fundamental chemical processes, including reaction mechanisms, rates, solvent polarity, and enantioselectivity, experimental investigations of VSC in the gas phase remain scarce. This scarcity primarily stems from the significant challenges associated with designing and constructing suitable gas cells, flow cells, and Fabry-Pérot cavities for observing VSC in the gas phase.

However, gas-phase VSC offers distinct advantages. Our research plan focuses on exploring cavity coupling of gas-phase molecules within a Fabry-Pérot cavity, specifically investigating the coherent control of molecular vibrational and rotational modes by laser light. This experimental approach will enable the exploration of spectrsocopy and reaction dynamics in the gas phase, free from the influence of solvents.


Frequency-domain Terahertz (THz) Spectroscopy is uniquely suited for investigating low-energy phenomena, such as molecular rotations, intermolecular vibrations, and phonon resonances. The terahertz (THz) region of the electromagnetic spectrum, spanning frequencies from 0.1 to 10 THz (wavelengths from 30 µm to 3 mm; wavenumber from 3.33 cm−1 to 103 cm−1), lies between the microwave and infrared regions. This region was historically referred to as the "terahertz gap" due to the significant challenges associated with generating and detecting radiation within this frequency range. However, recent advancements in THz technology have enabled researchers to effectively explore this previously inaccessible region.

THz spectroscopy provides invaluable insights into the structural and dynamic properties of diverse materials, including semiconductors, polymers, and biomolecules. Key applications include elucidating molecular interactions, characterizing phonon modes, and probing hydration dynamics. The non-destructive nature of THz radiation enables its penetration through materials such as plastics and clothing, making it an indispensable tool for applications ranging from imaging and security screening to materials testing.

Our research focuses on investigating the influence of intermolecular vibrations on the structure and function of hydrogen-bonded and halogen-bonded molecular clusters, cocrystals, and biological water. As research continues to explore the applications of THz technology in pharmaceutical analysis, its role in enhancing the detection and understanding of cocrystals is expected to significantly expand, offering promising avenues for improving drug formulation and efficacy.

Understanding the optical properties of materials in the THz region, including the refractive index and dielectric function, is essential for a wide range of applications. One of our objectives is to develop a robust and convenient methodology for accurately extracting both the real and imaginary components of the complex refractive index and dielectric function in the THz region.


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(C) Applications


Fundamental insights derived from diverse spectroscopic studies guide our research in several applied research areas, including: (i) the design of suitable fluorescence probes for investigating energy transfer processes, such as Förster Resonance Energy Transfer (FRET), in biomolecules; (ii) the selection of appropriate ionic liquids to enhance the stability and storage of biomolecules, including DNA, RNA, and proteins; and (iii) the optimization of enzymatic activity and the improvement of drug solubility in aqueous media.

Our research encompasses several key areas:

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