Ultrahigh-Vacuum Tip-Enhanced Raman Spectroscopy.

Molecule-surface interactions and processes are at the heart of many technologies, including heterogeneous catalysis, organic photovoltaics, and nanoelectronics, yet they are rarely well understood at the molecular level. Given the inhomogeneous nature of surfaces, molecular properties often vary among individual surface sites, information that is lost in ensemble-averaged techniques. In order to access such site-resolved behavior, a technique must possess lateral resolution comparable to the size of surface sites under study, analytical power capable of examining chemical properties, and single-molecule sensitivity. Tip-enhanced Raman spectroscopy (TERS), wherein light is confined and amplified at the apex of a nanoscale plasmonic probe, meets these criteria. In ultrahigh vacuum (UHV), TERS can be performed in pristine environments, allowing for molecular-resolution imaging, low-temperature operation, minimized tip and molecular degradation, and improved stability in the presence of ultrafast irradiation. The aim of this review is to give an overview of TERS experiments performed in UHV environments and to discuss how recent reports will guide future endeavors. The advances made in the field thus far demonstrate the utility of TERS as an approach to interrogate single-molecule properties, reactions, and dynamics with spatial resolution below 1 nm.

Single-Molecule Chemistry with Surface- and Tip-Enhanced Raman Spectroscopy.

Single-molecule (SM) surface-enhanced Raman spectroscopy (SERS) and tip-enhanced Raman spectroscopy (TERS) have emerged as analytical techniques for characterizing molecular systems in nanoscale environments. SERS and TERS use plasmonically enhanced Raman scattering to characterize the chemical information on single molecules. Additionally, TERS can image single molecules with subnanometer spatial resolution. In this review, we cover the development and history of SERS and TERS, including the concept of SERS hot spots and the plasmonic nanostructures necessary for SM detection, the past and current methodologies for verifying SMSERS, and investigations into understanding the signal heterogeneities observed with SMSERS. Moving on to TERS, we cover tip fabrication and the physical origins of the subnanometer spatial resolution. Then, we highlight recent advances of SMSERS and TERS in fields such as electrochemistry, catalysis, and SM electronics, which all benefit from the vibrational characterization of single molecules. SMSERS and TERS provide new insights on molecular behavior that would otherwise be obscured in an ensemble-averaged measurement.

Photoinduced Plasmon-Driven Chemistry in trans-1,2-Bis(4-pyridyl)ethylene Gold Nanosphere Oligomers.

Continuous wave (CW) pump-probe surface-enhanced Raman spectroscopy (SERS) is used to examine a range of plasmon-driven chemical behavior in the molecular SERS signal of trans-1,2-bis(4-pyridyl)ethylene (BPE) adsorbed on individual Au nanosphere oligomers (viz., dimers, trimers, tetramers, etc.). Well-defined new transient modes are caused by high fluence CW pumping at 532 nm and are monitored on the seconds time scale using a low intensity CW probe field at 785 nm. Comparison of time-dependent density functional theory (TD-DFT) calculations with the experimental data leads to the conclusion that three independent chemical processes are operative: (1) plasmon-driven electron transfer to form the BPE anion radical; (2) BPE hopping between two adsorption sites; and (3) trans-to- cis-BPE isomerization. Resonance Raman and electron paramagnetic resonance (EPR) spectroscopy measurements provide further substantiation for the observation of an anion radical species formed via a plasmon-driven electron transfer reaction. Applications of these findings will greatly impact the design of novel plasmonic devices with the future ability to harness new and efficient energetic pathways for both chemical transformation and photocatalysis at the nanoscale level.

Expanding applications of SERS through versatile nanomaterials engineering.

Surface-enhanced Raman scattering (SERS) spectroscopy has evolved into a cross-disciplinary analytical technique by unveiling relevant chemical, biological, material, and structural information. The focus of this review is on two critical properties for successfully expanding applications of SERS spectroscopy: quality of the plasmonic substrate and molecule localization to the substrate. In this review, we discuss recent work on quantifying SERS distance dependence, key factors for substrate characterization and performance evaluation, expansion of SERS applications through substrate development for UV plasmonics and short-distance capture strategies for optimizing analyte-surface structures. After surveying the recent developments of these seemingly disparate fields, we suggest new research directions that may originate from a synergistic blend of all the herein discussed topics. Finally, we discuss major challenges and open questions related to the application of SERS for understanding of chemical processes at the nanoscale, with special interest on in situ catalysts and biosensing.

Identification of Dimeric Methylalumina Surface Species during Atomic Layer Deposition Using Operando Surface-Enhanced Raman Spectroscopy.

Operando surface-enhanced Raman spectroscopy (SERS) was used to successfully identify hitherto unknown dimeric methylalumina surface species during atomic layer deposition (ALD) on a silver surface. Vibrational modes associated with the bridging moieties of both trimethylaluminum (TMA) and dimethylaluminum chloride (DMACl) surface species were found during ALD. The appropriate monomer vibrational modes were found to be absent as a result of the selective nature of SERS. Density functional theory (DFT) calculations were also performed to locate and identify the expected vibrational modes. An operando localized surface plasmon resonance (LSPR) spectrometer was utilized to account for changes in SER signal as a function of the number of ALD cycles. DMACl surface species were unable to be measured after multiple ALD cycles as a result of a loss in SERS enhancement and shift in LSPR. This work highlights how operando optical spectroscopy by SERS and LSPR scattering are useful for probing the identity and structure of the surface species involved in ALD and, ultimately, catalytic reactions on these support materials.

Observation of Single Molecule Plasmon-Driven Electron Transfer in Isotopically Edited 4,4'-Bipyridine Gold Nanosphere Oligomers.

We clarify mechanistic questions regarding plasmon-driven chemistry and nanoscale photocatalysis within optically confined near-field plasmonic systems. Using surface-enhanced Raman scattering (SERS), we directly monitor the photoinduced reaction dynamics of 4,4'-bipyridine molecules, localized in plasmonic hot spots within individual gold nanosphere oligomers. Our experiment generates surface electrons from the gold nanoparticle using an intense off-molecular resonance continuous wave pump field, and detects radical anion products via SERS. This is done by adopting a dual-wavelength spectroscopic approach. Empirical evidence of plasmon-driven electron transfer is provided for the first time by direct detection of the 4,4'-bipyridine radical anion species localized in the plasmonic hot spots of individual gold nanosphere oligomers, corroborated by open-shell density functional theory calculations. An isotopologue approach using both protonated and deuterated 4,4'-bipyridine molecules demonstrates the single molecule response of plasmon-driven electron transfer occurring in single nanosphere oligomer systems with a 3% yield, a phenomenon unobserved in ensemble measurements under analogous experimental conditions. This mechanism has broad applicability to using nanoscale chemical reactors for surface redox reactions on the subnanometer scale.

Quantitative Determination of the Differential Raman Scattering Cross Sections of Glucose by Femtosecond Stimulated Raman Scattering.

Femtosecond stimulated Raman spectroscopy (FSRS) is a vibrational spectroscopy technique that has been used in a wide variety of applications: from transient vibrational signature tracking to amplifying weak normal Raman scattering signals. Presented here is an application of FSRS to quantify the differential Raman scattering cross sections (DRSCs) of glucose. In using FSRS to determine the DRSCs of multiple glucose vibrational modes, we demonstrate the applicability of both stimulated Raman loss (SRL) spectroscopy and stimulated Raman gain (SRG) FSRS. Using the two analogous FSRS techniques, SRG and SRL, we determine that the DRSCs of glucose excited at 514.5 nm range from a low of 5.0 ± 1.1 × 10-30 to a high of 8.9 ± 0.9 × 10-30 cm2 molecule-1 sr-1. This work establishes both the compatibility of SRL for measuring DRSCs and values for the DRSC of multiple vibrational modes of glucose.

Native Electron Capture Dissociation Maps to Iron-Binding Channels in Horse Spleen Ferritin.

Native electron capture dissociation (NECD) is a process during which proteins undergo fragmentation similar to that from radical dissociation methods, but without the addition of exogenous electrons. However, after three initial reports of NECD from the cytochrome c dimer complex, no further evidence of the effect has been published. Here, we report NECD behavior from horse spleen ferritin, a ∼490 kDa protein complex ∼20-fold larger than the previously studied cytochrome c dimer. Application of front-end infrared excitation (FIRE) in conjunction with low- and high-m/z quadrupole isolation and collisionally activated dissociation (CAD) provides new insights into the NECD mechanism. Additionally, activation of the intact complex in either the electrospray droplet or the gas phase produced c-type fragment ions. Similar to the previously reported results on cytochrome c, these fragment ions form near residues known to interact with iron atoms in solution. By mapping the location of backbone cleavages associated with c-type ions onto the crystal structure, we are able to characterize two distinct iron binding channels that facilitate iron ion transport into the core of the complex. The resulting pathways are in good agreement with previously reported results for iron binding sites in mammalian ferritin.

Spiers Memorial Lecture. Surface-enhanced Raman spectroscopy: from single particle/molecule spectroscopy to ångstrom-scale spatial resolution and femtosecond time resolution.

Four decades on, surface-enhanced Raman spectroscopy (SERS) continues to be a vibrant field of research that is growing (approximately) exponentially in scope and applicability while pushing at the ultimate limits of sensitivity, spatial resolution, and time resolution. This introductory paper discusses some aspects related to all four of the themes for this Faraday Discussion. First, the wavelength-scanned SERS excitation spectroscopy (WS-SERES) of single nanosphere oligomers (viz., dimers, trimers, etc.), the distance dependence of SERS, the magnitude of the chemical enhancement mechanism, and the progress toward developing surface-enhanced femtosecond stimulated Raman spectroscopy (SE-FSRS) are discussed. Second, our efforts to develop a continuous, minimally invasive, in vivo glucose sensor based on SERS are highlighted. Third, some aspects of our recent work in single molecule SERS and the translation of that effort to ångstrom-scale spatial resolution in ultrahigh vacuum tip-enhanced Raman spectroscopy (UHV-TERS) and single molecule electrochemistry using electrochemical (EC)-TERS will be presented. Finally, we provide an overview of analytical SERS with our viewpoints on SERS substrates, approaches to address the analyte generality problem (i.e. target molecules that do not spontaneously adsorb and/or have Raman cross sections <10-29 cm2 sr-1), SERS for catalysis, and deep UV-SERS.

Ultrafast and nonlinear surface-enhanced Raman spectroscopy.

Ultrafast surface-enhanced Raman spectroscopy (SERS) has the potential to study molecular dynamics near plasmonic surfaces to better understand plasmon-mediated chemical reactions such as plasmonically-enhanced photocatalytic or photovoltaic processes. This review discusses the combination of ultrafast Raman spectroscopic techniques with plasmonic substrates for high temporal resolution, high sensitivity, and high spatial resolution vibrational spectroscopy. First, we introduce background information relevant to ultrafast SERS: the mechanisms of surface enhancement in Raman scattering, the characterization of plasmonic materials with ultrafast techniques, and early complementary techniques to study molecule-plasmon interactions. We then discuss recent advances in surface-enhanced Raman spectroscopies with ultrafast pulses with a focus on the study of molecule-plasmon coupling and molecular dynamics with high sensitivity. We also highlight the challenges faced by this field by the potential damage caused by concentrated, highly energetic pulsed fields in plasmonic hotspots, and finally the potential for future ultrafast SERS studies.

High-Resolution Distance Dependence Study of Surface-Enhanced Raman Scattering Enabled by Atomic Layer Deposition.

We present a high-resolution distance dependence study of surface-enhanced Raman scattering (SERS) enabled by atomic layer deposition (ALD) at 55 and 100 °C. ALD is used to deposit monolayers of Al2O3 on bare silver film over nanospheres (AgFONs) and AgFONs functionalized with self-assembled monolayers. Operando SERS is used to measure the intensities of the Al-CH3 and C-H stretches from trimethylaluminum (TMA) as a function of distance from the AgFON surface. This study clearly demonstrates that SERS on AgFON substrates displays both a short- and long-range nanometer scale distance dependence. Excellent agreement is obtained between these experiments and theory that incorporates both short-range and long-range terms. This is a high-resolution operando SERS distance dependence study performed in one integrated experiment using ALD Al2O3 as the spacer layer and Raman label simultaneously. The long-range SERS distance dependence should make it possible to detect chemisorbed surface species located as far as ∼3 nm from the AgFON substrate and will provide new insight into the surface chemistry of ALD and catalytic reactions.

Understanding the vibrational mode-specific polarization effects in femtosecond Raman-induced Kerr-effect spectroscopy.

Optically heterodyne-detected femtosecond Raman-induced Kerr-effect spectroscopy (OHD-FRIKES) was observed in neat cyclohexane. In this Letter, an examination of the effect of the Raman pump ellipticity on the multiplex OHD-FRIKES spectra is discussed. The Raman pump ellipticity scanned OHD-FRIKES results reproduce anomalous observables from previous OHD-FRIKES experiments and suggest new methods of tracking transient vibrational mode polarization in complex systems.

Coupled wave equations theory of surface-enhanced femtosecond stimulated Raman scattering.

We present a coupled wave semiclassical theory to describe plasmonic enhancement effects in surface-enhanced femtosecond stimulated Raman scattering (SE-FSRS). A key result is that the plasmon enhanced fields which drive the vibrational equation of motion for each normal mode results in dispersive lineshapes in the SE-FSRS spectrum. This result, which reproduces experimental lineshapes, demonstrates that plasmon-enhanced stimulated Raman methods provide unique sensitivity to a plasmonic response. Our derived SE-FSRS theory shows a plasmonic enhancement of |gpu|(2)ImχR(ω)gst (2)/ImχR(ω), where |gpu|(2) is the absolute square of the plasmonic enhancement from the Raman pump, χR(ω) is the Raman susceptibility, and gst is the plasmonic enhancement of the Stokes field in SE-FSRS. We conclude with a discussion on potential future experimental and theoretical directions for the field of plasmonically enhanced coherent Raman scattering.

Lowest triplet (n, π*) electronic state of acrolein: determination of structural parameters by cavity ringdown spectroscopy and quantum-chemical methods.

The cavity ringdown absorption spectrum of acrolein (propenal, CH(2)=CH-CH=O) was recorded near 412 nm, under bulk-gas conditions at room temperature and in a free-jet expansion. The measured spectral region includes the 0(0)(0) band of the T(1)(n, π*) ← S(0) system. We analyzed the 0(0)(0) rotational contour by using the STROTA computer program [R. H. Judge et al., J. Chem. Phys. 103, 5343 (1995)], which incorporates an asymmetric rotor Hamiltonian for simulating and fitting singlet-triplet spectra. We used the program to fit T(1)(n, π*) inertial constants to the room-temperature contour. The determined values (cm(-1)), with 2σ confidence intervals, are A = 1.662 ± 0.003, B = 0.1485 ± 0.0006, C = 0.1363 ± 0.0004. Linewidth analysis of the jet-cooled spectrum yielded a value of 14 ± 2 ps for the lifetime of isolated acrolein molecules in the T(1)(n, π*), v = 0 state. We discuss the observed lifetime in the context of previous computational work on acrolein photochemistry. The spectroscopically derived inertial constants for the T(1)(n, π*) state were used to benchmark a variety of computational methods. One focus was on complete active space methods, such as complete active space self-consistent field (CASSCF) and second-order perturbation theory with a CASSCF reference function (CASPT2), which are applicable to excited states. We also examined the equation-of-motion coupled-cluster and time-dependent density function theory excited-state methods, and finally unrestricted ground-state techniques, including unrestricted density functional theory and unrestricted coupled-cluster theory with single and double and perturbative triple excitations. For each of the above methods, we or others [O. S. Bokareva et al., Int. J. Quantum Chem. 108, 2719 (2008)] used a triple zeta-quality basis set to optimize the T(1)(n, π*) geometry of acrolein. We find that the multiconfigurational methods provide the best agreement with fitted inertial constants, while the economical unrestricted Perdew-Burke-Ernzerhof exchange-correlation hybrid functional (UPBE0) technique performs nearly as well.

Lowest triplet (n,π*) state of 2-cyclohexen-1-one: characterization by cavity ringdown spectroscopy and quantum-chemical calculations.

The cavity ringdown (CRD) absorption spectrum of 2-cyclohexen-1-one (2CHO) was recorded over the range 401.5-410.5 nm in a room-temperature gas cell. The very weak band system (ε ≤ 0.1 M(-1) cm(-1)) in this spectral region is due to the T1(n, π*) ← S0 electronic transition. The 0(0)(0) origin band was assigned to the feature observed at 24,558.8 ± 0.3 cm(-1). We have assigned 46 vibronic transitions in a region extending from -200 to +350 cm(-1) relative to the origin band. For the majority of these transitions, we have made corresponding assignments in the spectrum of the deuterated derivative 2CHO-2,6,6-d3. From the assignments, we determined fundamental frequencies for several vibrational modes in the T1(n, π*) excited state of 2CHO, including the lowest ring-twisting (99.6 cm(-1)) and ring-bending (262.2 cm(-1)) modes. These values compare to fundamentals of 122.2 cm(-1) and 251.9 cm(-1), respectively, determined previously for the isoconfigurational S1(n, π*) excited state of 2CHO and 99 cm(-1) and 248 cm(-1), respectively, for the S0 ground state. With the aid of quantum-mechanical calculations, we have also ascertained descriptions for these two modes, thereby resolving ambiguities appearing in the previous literature. The ring-twisting mode (ν39) contains a significant contribution from O=C-C=C torsion, whereas the ring-bending mode (ν38 in the ground state) involves mainly the motion of C-5 with respect to the plane containing the other heavy atoms. The CRD spectroscopic data for the T1(n, π*) state have allowed us to benchmark several computational methods for treating excited states, including time-dependent density functional theory and an equation-of-motion coupled cluster method. In turn, the computational results provide an explanation for observed differences in the T1(n, π*) vs. S1(n, π*) ring frequencies.

A systems-based method to repurpose marketed therapeutics for antiviral use: a SARS-CoV-2 case study.

This study describes two complementary methods that use network-based and sequence similarity tools to identify drug repurposing opportunities predicted to modulate viral proteins. This approach could be rapidly adapted to new and emerging viruses. The first method built and studied a virus-host-physical interaction network; a three-layer multimodal network of drug target proteins, human protein-protein interactions, and viral-host protein-protein interactions. The second method evaluated sequence similarity between viral proteins and other proteins, visualized by constructing a virus-host-similarity interaction network. Methods were validated on the human immunodeficiency virus, hepatitis B, hepatitis C, and human papillomavirus, then deployed on SARS-CoV-2. Comparison of virus-host-physical interaction predictions to known antiviral drugs had AUCs of 0.69, 0.59, 0.78, and 0.67, respectively, reflecting that the scores are predictive of effective drugs. For SARS-CoV-2, 569 candidate drugs were predicted, of which 37 had been included in clinical trials for SARS-CoV-2 (AUC = 0.75, P-value 3.21 × 10-3). As further validation, top-ranked candidate antiviral drugs were analyzed for binding to protein targets in silico; binding scores generated by BindScope indicated a 70% success rate.

Studying Stimulated Raman Activity in Surface-Enhanced Femtosecond Stimulated Raman Spectroscopy by Varying the Excitation Wavelength.

We present the first multiwavelength surface-enhanced femtosecond stimulated Raman spectroscopy (SE-FSRS) study, as well as the first observation of anti-Stokes vibrational features in SE-FSRS spectra. We compare stimulated Raman loss (SRL) and stimulated Raman gain (SRG) signals at three pump wavelengths chosen to sample different portions of nanoparticle aggregate localized surface plasmon resonances. The SE-FSRS signals exhibit similar signal magnitudes in the SRL or SRG regions of the spectra regardless of Raman pump or probe wavelength. The spectral lineshapes, however, differ dramatically with excitation wavelengths. The observed trends in spectral line shape show a strong dependence on the relative position of the excitation fields with respect to the plasmon resonance but do not match predictions from any existing SE-FSRS theory. These results suggest the need for further theoretical efforts with complementary experimental studies of individual aggregates to remove the effects of inherent ensemble averaging.

Surface-Enhanced Femtosecond Stimulated Raman Spectroscopy at 1 MHz Repetition Rates.

Surface-enhanced femtosecond stimulated Raman spectroscopy (SE-FSRS) is an ultrafast Raman technique that combines the sensitivity of surface-enhanced Raman scattering with the temporal resolution of femtosecond stimulated Raman spectroscopy (FSRS). Here, we present the first successful implementation of SE-FSRS using a 1 MHz amplified femtosecond laser system. We compare SE-FSRS and FSRS spectra measured at 1 MHz and 100 kHz using both equal pump average powers and equal pump energies to demonstrate that higher repetition rates allow spectra with higher signal-to-noise ratios to be obtained at lower pulse energies, a significant advance in the implementation of SE-FSRS. The ability to use lower pulse energies significantly mitigates sample damage that results from plasmonic enhancement of high-energy ultrafast pulses. As a result of the improvements to SE-FSRS developed in this Letter, we believe that SE-FSRS is now poised to become a powerful tool for studying the dynamics of plasmonic materials and adsorbates thereon.