Luminescent Photoinduced Electron Transfer (PET) Molecules for

The response in the digital regime leads to Boolean logic gates. ... molecular logic operations have found applications already in object identificati...
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Luminescent Photoinduced Electron Transfer (PET) Molecules for Sensing and Logic Operations A. Prasanna de Silva* School of Chemistry and Chemical Engineering, Queen’s University, Belfast BT9 5AG, Northern Ireland ABSTRACT: Chemical species can serve as inputs to supramolecular devices so that a luminescence output is created in a conditional manner. Conditionality is built into these devices by employing the classical photochemical process of photoinduced electron transfer (PET) to compete with luminescence emission. The response of these devices in the analogue regime leads to sensors that can operate in nanometric, micrometric, and millimetric spaces. Some of these devices serve in membrane science, cell physiology, and medical diagnostics. The response in the digital regime leads to Boolean logic gates. Some of these find application in improving aspects of medical diagnostics and in identifying small objects in large populations.

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eople need to gather information about environments outside and inside of them, especially in health-related contexts. This need can be addressed rather uniquely with luminescent sensing molecules, particularly when the environments concern small submillimetric spaces. Luminescent PET sensors form a powerful class of these molecules.1 A growing need also exists to process information that originates in small spaces.2 This need can be fulfilled by molecular logic-based computation.3 Naturally, many design principles support this field, but the luminescent PET switching approach is the oldest of these4 and remains popular.5

The response of luminescent PET devices in the analogue regime leads to sensors that can operate in nanometric, micrometric, and millimetric spaces. These luminescent PET switching molecules arise from the union of three separate disciplines, molecular photophysics, coordination/supramolecular chemistry, and photochemistry. The first discipline contributes a lumophore with suitable absorption and emission properties, while the second discipline brings in a receptor that selectively binds to a chosen chemical species in an appropriate concentration range. PET is the photochemistry process that involves both the lumophore and the receptor. A spacer is employed to hold the lumophore and the receptor apart at a short distance while allowing for intramolecular PET (Figure 1). PET is usually faster than the luminescence emission process if favorable PET thermodynamics is arranged by careful choice of the lumophore and receptor components. One possible situation is shown in the frontier orbital energy diagram r 2011 American Chemical Society

(Figure 1b) where PET takes place from the receptor to the lumophore. When the receptor is occupied by the input chemical species, the frontier orbital diagram changes to Figure 1c so that luminescence wins due to the retardation of PET. This amounts to quantitatively predictive, chemically commanded “off on” switching of luminescence, whether it be fluorescence, phosphorescence, lanthanide f f emission, or MLCT (metal-toligand charge transfer) luminescence. The generality of luminescent PET switching within “lumophore spacer receptor” systems was first demonstrated in the 1980s,6 though the phenomenon was described without explanation in the 1970s.7,8 Molecular logic-based computation took much longer to arise as an experimental field,4 but this is not surprising as a union of very disparate disciplines (computer science, electronics, and chemistry) was necessary. Another method for molecular computation without Boolean logic arose soon after,9 but this molecular biology approach has lost momentum in recent years10 after the initial optimism. Molecular biology laboratories engaged in molecular computation have also made important advances by resorting to the logic-based approach.11,12 Critical voices, especially those wedded to the classical semiconductor computing paradigm, were raised against molecular logic, but these have gradually subsided as the biological computing paradigm has been increasingly recognized.3 Some of these criticisms targeted the early lack of progress regarding molecular logic integration. However, smallscale integration is routinely accessible now.13 Some types of largerscale integration are also available in oligonucleotide devices.11,12 Furthermore, even simple molecular logic operations have found applications already in object identification14 and intelligent medical diagnostics.15 17 Several recent developments from Belfast and collaborating laboratories in these two fields of sensing and logic are featured in the following sections. These highlight the predictive design, Received: September 27, 2011 Accepted: October 21, 2011 Published: October 21, 2011 2865

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Figure 1. (a) “Lumophore spacer receptor” system and its frontier orbital disposition (b) before and (c) after occupation by a suitable chemical species.

flexibility, and extension capability of luminescent PET molecules in this regard.1 This is in contrast to other available mechanisms for luminescent switches such as those based on internal charge transfer (ICT) excited states, excimers, electronic energy transfer, excited-state proton transfer, and vibrational relaxation.1 Mapping Species Concentration in Nanospaces. The nanometric size of luminescent molecules has allowed the visualization of some intracellular species with micrometric resolution for several decades now.18 Would it be possible to obtain information about species distributions with subnanometric resolution without modern microscopic techniques? While the general answer to this question still appears to be no, a positive outcome is available for certain simple situations.19 For instance, the environment of spherical detergent micelles in water contains a characteristic distribution of ions like H+. Membrane-bounded H+ distributions are important because they form the foundations of bioenergetics. Though a luminescent pH sensor can readily measure the effective H+ density in its immediate vicinity after appropriate calibration,20 the same sensor needs to be equipped with a means of determining its spatial position so that H+ density position data pairs can be built up. A series of such data pairs can be combined to produce the H+ density distribution or the H+ density map. How can such multiplexed sensors be constructed? This question can be answered by considering the following scenario.

Some Boolean logic gates find application in improving aspects of medical diagnostics and in identifying small objects in large populations. As we move along the radial line from the center of a spherical micelle, the local polarity would initially correspond to that of alkanes but would finally reach the value of bulk water. As we pass by the micelle head groups, the bound water molecules would announce themselves by displaying a polarity value that is

significantly reduced as compared to that of bulk water. Thus, the spatial position of a test point can be estimated by measuring the polarity of its immediate neighborhood. There are many molecular spectroscopic probes of polarity, but the most relevant case for our application arises from the emission wavelength shifts of lumophores with ICT excited states.21 In keeping with the luminescent PET sensor design, the format of the multiplexed sensor becomes “gross targeting unit ICT lumophore spacer receptor fine targeting unit” (Figure 2). The terminals are equipped with targeting units so that the sensor molecule can be constrained to the micelle while manoeuvring the receptor and the lumophore to a characteristic location. Two issues limit the spatial resolution of the probe position. First, the exact positions of the lumophore (where the polarity is measured) and of the receptor (where the H+ density is measured) are offset by a few Angstrom units, which is the time-averaged length of the spacer. Second, the hydrophobicity of the receptor (and hence its position along the micellar radial line) changes when it captures a H+. Thus, the net probe position is averaged over protonated and unprotonated situations. Despite these limitations, this method gives valuable insights into membrane-bounded H+ distributions, as shown by Figure 3 for the sensor series 1 in aqueous micelles of the neutral detergent Triton X-100. The abscissa gives the probe position in terms of the neighborhood polarity as measured by the mean dielectric constant. The latter was chosen owing to the wide availability of data useful for the calibration of series 1. The ordinate gives the local H+ density (referred to that in bulk water) as measured by the pKa shift in the micellar medium versus bulk water. It is clear from Figure 3 that the H+ density increases rapidly as the different members of the series 1 are positioned farther and farther away from the micelle center. Also, the H+ density levels off as less hydrophobic members are positioned toward bulk water, farther away from the micelle head groups. Figure 3 offers graphic proof that ions are repelled away from the relatively apolar membrane toward bulk water20 and quantitates the effect as well. Applying Sensing to Blood Diagnostics. An important development in luminescent PET sensor research was to move these sensors from homogeneous solution to solid liquid interfaces.22 While the ability of a sensor molecule to roam free in homogeneous solution leads to fertile applications in intracellular 2866

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Figure 2. (a) “Gross targeting unit ICT lumophore spacer receptor fine targeting unit” system. (b) Schematic illustration of the different positions in a detergent micellar environment that are taken up by two members of series 1, which carry different targeting groups.

Figure 3. Local effective proton density (as measured by the shift of acidity constant relative to bulk water, ΔpKa) as a function of position (as measured by the local dielectric constant, ε).

regimes, for example,23 solid-bound sensors are robust enough to be used outside of research laboratories. The latter means use at the hospital bedside, in the battlefield, or even on the street. For instance, the blood of healthy people contains around 0.1 M Na+. In order to sensitively measure changes of Na+ concentration around this value, the sensor must possess a binding constant (βNa+) of 10 M 1 in water. This is where the predictive power of luminescent PET sensors becomes invaluable. For receptors with multipoint attachment, the species binding constant is preserved upon construction of the solid-linked “lumophore spacer receptor” system. Therefore, we searched for receptors possessing this βNa+ value and found suitable lariat ethers24 with adequate selectivity profiles for our purpose. The lumophore choice was dictated by the following consideration. While a careful filtering of whole blood solves the problem of performing luminescence measurements in a dark red liquid, the serum still cannot transmit light in the ultraviolet region. Excitation with an inexpensive blue-light-emitting diode was crucial for cost and stability reasons. 4-Aminonaphthalimides are cheap commodity-type chemicals that fit the bill. Importantly, known data on the electro- and photochemical properties of this lumophore receptor pair can be used to safely predict that 2

would function as an off on luminescent sensor for Na+.25 The dimethylene spacer permitted reasonably fast PET rates when thermodynamically allowed and guarded against slow hydrolytic separation of the receptor from the lumophore upon long-term storage. Aminocellulose fibers formed the solid part of the interface. A reasonably long linker was used to attach the sensor to the solid so that the perturbation of sensor properties by the solid was minimal. K+ and Ca2+ in whole blood was sensed similarly by altering the receptor unit of 2.25 When mounted together in a cassette (Figure 4), these sensors form the business end of the OPTI and OPTI-LION blood gas and electrolyte analyzers26 working in hospitals, surgeries, and ambulances worldwide. Simplifying Logic with Self-Assembly. In contrast to the conventional computing paradigm, the first demonstration that launched molecular logic as an experimental science used purpose-built molecules for each logic operation.4 More recent advances5 have relied on functional integration methods and logic reconfiguring to produce significant numbers of distinct logic operations per molecule. To encourage this trend and to simplify logic experiments, we have shown how a small set of easily accessible molecular components can be self-assembled in different ways to produce multiple logic operations.27 2867

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Figure 5. Fluorescence emission spectra for Na+,H+,Zn2+-driven AND gate 8 under various ionic conditions. Figure 4. OPTI-LION (top) and OPTI R (bottom) cassettes sold by Optimedical Inc. (www.optimedical.com). Reproduced from de Silva, A. P.; Vance, T. P.; West, M. E. S.; Wright, G. D. Org. Biomol. Chem., 2008, 6, 2468 by permission of The Royal Society of Chemistry.

Boole’s analysis of language led to binary logic that was subsequently exploited for computing via various logic gates. Because a PASS 0 logic behavior produces a “low” output signal under all input conditions, a H+-driven PASS 0 gate with luminescence output simply means a solution with no lumophore. The solution contains detergent micelles to facilitate selfassembly of molecular building blocks via hydrophobic forces to produce other gates. Addition of lumophore 3 produces a strong emission output whatever the pH of the solution so that PASS 1 logic is achieved. Lumophore 3 was particularly chosen because of its rather long excited-state lifetime to facilitate intermolecular PET processes in subsequent experiments. Further addition of receptor 4 gives the desired PET process and quenches the emission of 3. This emission output is switched back on if the H+ input is applied at a “high” level so that the phenolate is neutralized. YES logic performance is the result. If receptor 5 is employed instead of 4, PET occurs only when protonated 5 is arranged by acidification. Therefore, we have NOT logic performance instead. Pallavicini’s prior experiments on PET sensors self-assembled in micelles need to be noted here.28 Two-input logic gates can also be built from these components in combination with others. If lumophore 3 is accosted by receptor 4 and receptor 6 at pH 12, emission recovers only if PET processes arising from 4 and 6 are blocked with high levels of H+ and Ca2+, respectively. Therefore, we have H+,Ca2+-driven AND logic. If receptor 4 is omitted from this system and if the starting pH value is adjusted to 8, H+ Ca2+-driven OR logic can be arranged. This is because receptor 6 binds H+ (log βH+ = 5.8) besides Ca2+ (log βCa2+ = 1.6). Therefore, PET is arrested by the application of high levels of either cation. Because six different logic types can be arranged in this way, the self-assembly approach is clearly a route to minimize synthetic chemistry investment in molecular logic research. Applying Logic to Rapid Diagnosis. In many instances, medical practitioners assist patients in the following way. A sample of blood or other fluid is taken and sent to a clinical chemistry laboratory. A series of measurements are made to determine the levels of various species. These levels are compared to those found in normal members of the population, so that flags

Figure 6. Fluorescence micrographs under acidic and basic conditions for a population of Tentagel beads carrying various MCID tags.

indicating low, normal, or high can be attached to each species level. The medical practitioner uses his/her education and knowledge to interpret this pattern of low and high species levels to assign a particular disease state. Once the disease has been diagnosed, a treatment regime can be put in place. However, there are situations where the expertise of medical professionals is not available to the patient within a reasonable time scale. It would be very useful then if certain disease states can be diagnosed, at least in a preliminary fashion, by molecules on a test strip or in a test tube. This approach can be implemented with molecular logic gates. An AND gate would produce a high signal, for example, a strong luminescence output only when, say, three chosen species levels go high simultaneously. Three electrolyte levels could behave in this way due to a renal dysfunction for instance. Molecular PET system 7 has a “receptor1 spacer1 lumophore spacer2 receptor2 spacer3 receptor3” construction so that an electron can be transferred from any of the three receptors to the excited lumophore. A strong luminescence emission arises only if each of the three receptors is occupied by its corresponding species. Specifically, 7 is a Na+,H+,Zn2+-driven AND gate15,29 that carries benzocrown ether, amine, and N-phenyliminodiacetate receptors to capture the three species of interest. The emission spectra in Figure 5 clearly show that our expectation of a lab-on-amolecule is realized. The high level of each species concentration 2868

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Figure 7. Structures of 1 10.

is taken as being an order of magnitude larger than the reciprocal of the species receptor binding constant, for example, the high level of Zn2+ is 10 3.1 M whereas βZn2+ of the N-phenyliminodiacetate unit of 7 is 104.0 M 1 in neutral water. Useful examples of this overall concept are now known.16,17 Applying Logic to Object Identification. People in a population are most commonly identified by their faces, or by their passports if certified information is sought. Radio frequency ID (RFID) chips provide a semiconductor-based solution to this problem in the case of machine-readable passports, as well as for various goods of commerce. However, these RFID chips lose their convenience and cost-effectiveness when their dimension drops below about 0.1 mm. This leaves many important objects without a suitable means of identification when they exist in large populations. For instance, micrometric polymer gel beads are widely used to carry drug or assay candidates in combinatorial libraries. Even more critically, biological cells from large numbers of patients need to be screened during diagnostic procedures. A molecular computing solution is now available for these situations, demonstrating that molecules can tackle computational issues that semiconductor devices cannot.14 The general matter of object identification can be viewed as a program of asking a series of questions about that object and then comparing the replies with a set of stored answers that characterize the object. When we use luminescent PET molecular logic gates as ID tags, this series of questions and example answers can be specified as follows. (a) What is the characteristic

wavelength of excitation? 370 nm. (b) What is the characteristic output emission wavelength? 420 nm. (c) What is the characteristic input (species or property) that interacts productively with the tag? H+. (d) What is the Boolean logic type of the input output profile? YES. (e) What is the binding strength of the input species as defined by the log β value? 7.0. (f) What is the pairwise combination of logic gates (defined by the above questions) that is applied to the object if it is doubly tagged? PASS 1 + YES. Luminescent PET molecules can be used to implement the questions and answers in the previous paragraph. The answers to questions (a) and (b) are properties of the lumophore component. Indeed, these two questions on their own have been used previously for tagging combinatorial library members.30 The answers to questions (c) and (e) are properties of the receptor component, though the object itself will perturb these values unless long and rigid linkers are used. The answer to question (d) depends on the detailed design of the luminescent PET system, for example, an AND gate will require two selective receptors, whereas a YES gate requires only one. As a demonstrator, Tentagel beads (0.1 mm diameter) tagged with H+-driven YES, PASS 1, and NOT logic gates (8, 9, and 10, respectively) are used. Notably, the PASS 1 logic tag is devoid of a receptor. The H+driven NOT logic tag functions by launching a PET process from the lumophore to the protonated pyridyl receptor so that the emission is quenched in acidic solution. Figure 6 shows micrographs when 8, 9, 10, and other beads are interrogated with acidic 2869

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The Journal of Physical Chemistry Letters and basic solutions (see also Figure 7 for structures). The different logic tags are clearly discernible even in a single emission color. Large numbers of these small objects can be uniquely tagged in this way because several definable answers are possible for each question. Question (f), in particular, multiplies the diversity because a pair of tags is being used rather than a single one. However, it must be noted that such a combination of logic gates produces a summed output emission so that multivalued logic schemes31 can be productively applied. Because we need to make only a few serial measurements of a simple emission intensity (each with experimental errors of ∼1%), the overall error remains below 10%. This allows easy distinction of the output logic levels of 0, 1, 2, 3, and even 4. In our original paper,14 we restricted our experiments to ternary and quaternary logic. In contrast, conventional computing uses many steps in series so that errors accumulate and rapidly pass 50% so that only binary logic remains practicable. Future Directions. It is clear that luminescent PET sensors will play their part in the examination of chemical species levels in various small spaces in the days to come. While simple cationic species are discussed here, a growing variety of compounds can be handled in a similar manner. Cell physiology, medical monitoring, and membrane biophysics are likely to benefit most directly. Luminescent PET molecules can be expected to spearhead the proliferation of molecular logic devices into more complex and/or useful forms.5 Besides combinatorial logic discussed here, further developments in sequential logic31,32 can also be expected. Overall, the availability of a rational light-switching mechanism such as PET will hold the attention of bright molecular designers for the foreseeable future.

The availability of a rational lightswitching mechanism such as PET will hold the attention of bright molecular designers for the foreseeable future. ’ AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected].

’ BIOGRAPHY Sri Lankan-born A. P. de Silva is at the Queen’s University of Belfast, Northern Ireland. He introduced the field of molecular logic and generalized the luminescent PET sensor/switch principle. He contributed to the chemistry module of the OPTI blood gas/electrolyte analyzer (Optimedical Inc.), which has sales of 80 M USD. (See http://www.ch.qub.ac.uk/staff/desilva/index. html.) ’ ACKNOWLEDGMENT I remain grateful to Kaoru Iwai (Nara Women’s University, Japan), Seiichi Uchiyama (University of Tokyo, Japan), Jim Tusa and Huarui He (Optimedical Inc. and Roche Diagnostics,

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Atlanta, U.S.A.), Marc Leiner (Roche Diagnostics, Graz, Austria), Jean-Philippe Soumillion and the late Jean-Louis Habib-Jiwan (Universite Catholique de Louvain, Belgium), and Otto Wolfbeis (University of Regensburg, Germany) for their collaboration and their friendship.

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