KR20110069836A - Methods for preparing nanocrystals using electron transfer agents - Google Patents

Abstract

Core nanocrystals compositions and methods are provided using mismatched precursors and two or more electron transfer agents to independently control granulation nucleation and growth steps.

Description

METHODS FOR PREPARING NANOCRYSTALS USING ELECTRON TRANSFER AGENTS

Cross Reference to Related Application

This application claims the benefit of US Provisional Application No. 61 / 102,589, filed October 3, 2008.

Statement of Rights to Invention Made with Federal Research Assistance

Some of the examples disclosed herein were made with government support in accordance with the National Consortium of Technology and US Department of Commerce, co-operation agreement 70NANB4H3053. The government reserves certain rights in the technology disclosed.

Technical field

The present invention provides a method for synthesizing nanoparticles using two kinds of electron transfer agents. More specifically, the present invention provides methods for preparing nanoparticles useful in a variety of fields including biology, analytical and combinatorial chemistry, medical diagnostics, genetic analysis, solar energy conversion and display.

Semiconductor nanocrystals have unique optical properties between single molecules and bulk materials, and are increasingly important for the detection, tracking and observation of biological and biochemical structures by single molecule and microscope in various experimental protocols of biology, chemistry, pharmacy and genetics. . Nanocrystals are easily observed and output a fluorescent signal that is bright enough to be practically observed with single nanocrystals.

Many methods for forming core nanocrystals from metal-anionic bicomponent salts are known in the art. These methods can be classified according to the estimation mechanism based on the type of reactants commonly used and the oxidation state comparison method of the reactants.

In the first method, both the reacting metal and nonmetallic components are provided in the form of such neutral atoms. For example, Murray, et al., J. Am. Chem. Soc, 1993, 115: 8706 releases neutral cadmium (Cd ⁰ ) and selenium (Se ⁰ ) atoms in solution, respectively, resulting in dimethyl cadmium (Me 2 Cd) and no electron transfer required for oxidation state matching; Trioctylphosphine selenide (TOPSe) reaction is described. Since the reactants are in the proper form to react with each other, this situation is regarded as a 'match' of the oxidation state, and nothing needs to be oxidized or reduced for the reaction to proceed, resulting in no net electron imbalance. Since cadmium and selenium atoms form cadmium selenide (CdSe) as soon as they collide, this type of reaction generally proceeds very quickly.

In the second category, both metal and nonmetallic components are provided in ionic form. For example, Peng, et al., J Am. Chem. Soc, 2001, 123: 183, silver cadmium oxide (CdO) as a source of cadmium ions, in the presence of TOPO and phosphonic acid ligands such as hexylphosphonic acid (HPA) tetradecylphosphonic acid (TDPA) or octylphosphonic acid (OPA) Use to describe CdSe and cadmium telluride (CdTe). Bis (trimethylsilyl) sulfide (TOPSe) Se ² in a solution of ^cadmium salt and at the same time releasing emits Cd ^{2 +} ions in the solution. Cadmium and sulfur ions also react instantaneously to form cadmium sulfide (CdSe), so this reaction proceeds very quickly. This type of reaction is also regarded as 'match' because no species oxidation and reduction is required and a suitable stoichiometric reaction yields a neutral product.

In each of these categories, the extreme reactivity of the intermediates with each other makes it difficult to control particle size, particle yield and particle size dispersion. Once released from solution, the reactive species react at or near this rate of diffusion-domination. In some examples, ligands or solvents may be used to slow the reaction slightly, but these methods do not provide a general method for controlling particle formation.

In particular, for example, it is sometimes impossible to prevent the formation of new nanocrystals, referred to as nucleation, with this kind of reaction, and it can be difficult to control the reaction aimed at adding a shell to existing nanocrystals. Shells enhance the chemistry and photo-stability of nanocrystalline cores, so it is typically necessary to form shells on nanocrystals for use in certain applications. The shell is usually made of a complementary semiconductor material different from the bottom core nanocrystals; Thus, when the shell-forming reaction reaches nucleation, it forms new nanocrystals of different composition than desired and mixes with the desired one, and when formed into a mixture, it is extremely difficult to separate the nanocrystals.

In a third method, one precursor provides neutral atoms in the reaction solution and the other precursors are selected to provide ions. For example, may be used as precursors mismatch, Cd ^{2 +} ion source with a mixture of cadmium alkylphosphonate and trioctyl phosphine selenide as Se ⁰ source. These precursors cannot react to form neutral species unless there is an electron transfer agent that regulates the oxidation state of one of the reactive species to provide a 'matched' species that can proceed. For example, to deliver electrons to the Cd ^{2 +} 2 of non-ionic species (i.e., Cd ⁰ and Se ^0), or by transfer of electrons to the Se ⁰ 2 of ion species (i.e., Cd ^{2 +} and Se ^{2 -)} a Reducing agents can be used to provide. In either method, once the atomic species are 'matched', these reactions can proceed, but without these electron transfer agents the reactions cannot proceed. Alternatively, two ionic species having the same charge (ie two cations or two anions) are also 'mismatched'. For example, mismatched precursors can be used that provide two cationic species, where one species can be provided which can be reduced to undergo a 'match' reaction. For example, ² Se or Se ^{+ 4 + 2} Se is selenium anions ^- and can be reduced in order to provide, it may proceed with the metal cation species, for example, Cd ^{2 +} and reaction. In other embodiments, two cationic species can be reduced to both neutral species. 1 depicts nucleation and growth steps to illustrate how a reducing agent is involved.

In another embodiment, an oxidant may be used as the electron transfer agent in the reaction between neutral and anionic species. For example, Cd ⁰ as a precursor And Se ^{-2 can} be used, wherein an oxidant is applied to oxidize Se ^-2 to Se ⁰ to provide two neutral species that can undergo a 'match' reaction. The need for this electron transfer process and formulation has been largely overlooked: due to the small scale and complexity of the reactions involved, the role of the electron transfer agent is often performed by impurities present in the starting material or coincidentally formed at the same time.

Some reactions with the addition of an electron transfer agent have been reported: For example, Zehnder and Treadway, US Pat. No. 7,147,712, describe the use of promoters that are oxygen or reducing agents to promote and control nucleation and accelerate crystal growth. A single reducing agent is added to initiate nucleation or nanocrystals formation, which promotes nanocrystals growth once nucleation occurs. This method controls particle yield and final particle size. However, since the same reducing agent is used in both nucleation and growth phases, separation of the two phases can only be achieved by indirect means.

There is a need for a method for producing nanocrystals by controlling high yield and high levels of particle size and particle dispersion, and there is a need to separately control the nucleation and growth stages of nanocrystals.

Provided herein are methods of controlling and promoting growth that is nanocrystals under conditions that avoid or minimize nucleation using two kinds of electron transfer agents to temporarily separate nucleation and growth steps. These methods provide methods for preparing nanocrystals with new composition and nanocrystals that exhibit production reproducibility and control properties. The methods described herein can provide independent control of nanocrystal nucleation and growth steps in nanocrystal preparation.

The examples provided herein preferably provide nanocrystals with reproducible product characteristics by the use of electron transfer agents that independently control nanocrystal formation and growth. The methods are reliable because they can reproduce and provide nanocrystals even when there is a slight variation in the reagent addition rate in the nanocrystal production reaction. In some embodiments, two kinds of reducing agents are used to control the nanocrystal forming process.

In one aspect, a first precursor; Second precursor; Strong electron transfer agent; And providing a mixture consisting of the weak electron transfer agent; And heating the mixture to a constant temperature for a time sufficient to induce the formation of nanocrystal populations, wherein the first and second precursors have mismatched oxidation states, and have strong electron transfer. The agent is in a sufficient amount to produce the desired degree of nucleation, and weak electron transfer agents differ from strong electron transfer agents.

In another aspect, providing a mixture of a first precursor and a second precursor, wherein the first precursor and the second precursor have mismatched oxidation states; Adding a substoichiometric content of a strong electron transfer agent to the mixture in an amount sufficient to produce a desired degree of nucleation; Optionally heating the mixture to produce a desired degree of nucleation; Adding a weak electron transfer agent to the mixture in an amount sufficient to grow a desired degree of nanocrystals; And optionally heating the mixture for a time sufficient to grow the desired degree of nanocrystals.

In another embodiment, a first precursor; Second precursor; And providing a mixture consisting of a third precursor; And optionally heating the mixture to a constant temperature for a time sufficient to induce the formation of nanocrystals, wherein the first precursor and the second precursor have mismatched oxidation states, and the third precursor Has a coincidence oxidation state with either the first precursor or the second precursor.

Other aspects and advantages of the present methods and compositions will become apparent from the following detailed description, in light of other embodiments of the embodiments contained herein with reference to certain embodiments. It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

Figure 1 illustrates that two separate reducing agents can be used to promote nucleation and subsequent growth in the formation of ZnTe, which is a nanocrystal.
2 illustrates the use of a weak reducing agent produced in the precursor compound itself in the growth phase of the nanocrystals. Zinc undecylenate is an example of a precursor compound that also provides a weak reducing group as an unsaturated carboxyl group. As can be seen from the higher right absorbance level in FIG. 2, the particle yield was higher in the zinc undecylenate case than in the zinc stearate case. Zinc undecylenate provides a weak reducing group to promote crystal growth.

The embodiments described herein may be more readily understood by reference to the following detailed description and the embodiments included therein. It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art belonging to the embodiments disclosed herein.

As used herein, 'a' or 'an' means 'at least one' or 'one or more'.

As used herein, 'about' means that the numerical values are approximate and that small deviations do not significantly affect the implementation of the disclosed embodiments. If there is a numerical limitation, unless otherwise indicated in the context, 'about' means that the numerical value can vary by ± 10% and is within the scope of the disclosed embodiments.

As used herein, 'nanoparticle' refers to any particle having at least one major dimension in the nanosize range. Nanoparticles generally have at least one major dimension in the range of about 1 to 1000 nm.

Examples of nanoparticles include nanocrystals, such as core / shell nanocrystals and nanocrystals, including any tightly-bonded organic coatings or other materials on the surface of nanocrystals. Nanoparticles also include core nanoshells or core / shell nanocrystals with core / shell nanocrystals themselves, TDPA, OPA, TOP, TOPO, or other material layers that are not removed from the surface by conventional solvation. Nanoparticles can have a ligand layer on the surface that is cross-linked; And nanoparticles can have other or additional surface coatings that can alter particle properties such as, for example, increased or decreased solubility in water or other solvents. This kind of layer on the surface is included in the term 'nanoparticle'.

As used herein, 'nanocrystal' refers to nanoparticles typically made from inorganic materials having an ordered crystal structure. It refers to nanocrystals with crystalline cores (core nanocrystals) or nucleus / shell nanocrystals. Generally, nanocrystals have core diameters in the largest dimension in the range of 1-100 nm, preferably in the range of about 1-50 nm.

Core nanocrystals are nanocrystals with no shell applied; Generally it is a semiconductor nanocrystal and is generally made of a single semiconductor material. It may have a uniform composition, or the composition may vary depending on the nanocrystal internal depth. Many types of nanocrystals are known, and nanocrystal core fabrication and shell application methods are well known in the art. The nanocrystals disclosed herein are frequently bright fluorescent nanocrystals and nanoparticles made therefrom are also generally bright, for example at least about 10%, sometimes at least about 20%, sometimes at least about 30%, sometimes at least about 40% And sometimes at least about 50% or more of quantum yield. It is advantageous for the nanocrystals to have a ligand surface layer to protect the nanocrystals from degradation during use or storage.

As used herein, 'quantum dot' refers to nanocrystalline particles made of a material that is semiconductor or insulator in volumetric material and has variable photo-physical properties in the near-ultraviolet (UV) to far-infrared (IR) range.

As used herein, 'water soluble' means dissolved or suspended in an aqueous solution, such as water, aqueous or buffered solutions, including those used in biological or molecular detection systems, as known to those skilled in the art. Water-soluble nanoparticles are not truly 'dissolved' in the sense that the term is intended to describe individually solvated small molecules, and since they are solvated and suspended in solvents that are compatible with the outer surface layer, Nanoparticles that are readily dispersed in water are considered water-soluble or water-dispersible. Water soluble nanoparticles are also considered hydrophilic because the surface layer is compatible with water and water soluble.

As used herein, 'hydrophobic nanoparticles' means nanoparticles that are readily dispersed or soluble in water-insoluble solvents such as hexane, toluene and the like. Nanoparticles of this kind generally do not readily disperse in water.

As used herein, 'hydrophilic' means solid surface properties or liquid volumetric properties, where solids or liquids show greater miscibility and solubility in higher dielectric media than in lower dielectric media. For example, materials that are more soluble in methanol than in hydrocarbon solvents such as decane are considered hydrophilic.

Nanoparticles can be synthesized in other complex shapes such as spheres, rods, discs, triangles, nanorings, nanoshells, tetrapods, nanowires, and the like. Each of these geometries has distinctive characteristics: surface charge space distribution, polarization orientation dependence of incident light, and electric field space distribution. In some embodiments the nanocrystals herein are approximately spherical.

In some embodiments the nanoparticles provided herein are core / shell nanocrystals having nanocrystalline cores covered by a semiconductor shell. The thickness of the shell may be suitable to provide the desired particle characteristics. The thickness of the shell can affect fluorescence wavelength, quantum yield, fluorescence stability and other light stability characteristics.

Nanocrystalline cores and shells can be prepared from any suitable metal and nonmetallic atoms known to form semiconductor nanocrystals. Suitable semiconductor materials for the core and / or shell include, but are not limited to, 2-16, 12-16, 13-15, and Group 14 element-based semiconductors such as ZnS, ZnSe, ZnTe, CdS, CdSe, CdTe, HgS, HgSe, HgTe, MgS, MgSe, MgTe, CaS, CaSe, CaTe, SrS, SrSe, SrTe, BaS, BaSe, BaTe, GaN, GaP, GaAs, GaSb, InP, InAs, InSb, AlS, AlP, AlSb, PbS, PbSe, Ge, and Si and mixtures of three and four components thereof. In general, the core and shell of the core / shell nanocrystals are made of different semiconductor materials, and at least one atomic type of the two-component semiconductor material of the core / shell core is different from the shell atom type of the nucleus / shell nanocrystals. it means. The nanocrystalline core and shell are made of any suitable metal and nonmetallic atoms known to form semiconductor nanocrystals. Semiconductor nanocrystals can be prepared by applying known techniques. See, eg, US Pat. Nos. 6,048,616, 5,990,479, 5,690,807, 5,505,928 and 5,262,357, International Publication No. WO99 / 26299, published May 27, 1999. These methods generally produce nanocrystals with a coating of hydrophobic ligand on the surface to protect from rapid degradation.

Nanocrystals can be characterized by percentage of emitted light quantum yield. For example, the nanocrystals disclosed herein have a quantum yield of at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at about 80 At least%, at least about 90%, and between these two values. The quantum yield may generally be at least about 30%, and preferably at least 50%, at least 70% and sometimes at least 80%.

In some embodiments the shell layer metal atoms on the nanocrystalline core are selected from Cd, Hg, Zn, Be, Al, Ga, Mn, Cu and Mg. The second element in this semiconductor shell layer may be selected from S, Se, Te, O, P, As, N and Sb.

Nanoparticles can be any suitable size; It is generally sized to output fluorescence in the UV-visible portion of the electromagnetic spectrum, since this range is convenient for use in sensing biological and biochemical phenomena in the media involved. The relationship between size and fluorescence wavelength is well known, and therefore, smaller nanocrystals need to select InP as the core in certain materials, such as core / shell nanocrystals that are specifically designed to give a suitable wavelength at small sizes.

In many embodiments, the nanocrystals described herein may be about 1 nm to about 100 nm in diameter, sometimes about 1 to about 50 nm in diameter, and sometimes about 1 to about 25 nm in diameter. The nanocrystals specific size range is not limited: about 0.5 nm to about 5 nm, about 1 nm to about 50 nm, about 2 nm to about 50 nm, about 2 nm to about 50 nm, about 1 nm to about 20 nm, about 2 nm to about 20 nm, or about 2 nm to about 10 nm. More specific size examples of nanocrystals include, but are not limited to: about 0.1 nm, about 0.5 nm, about 1 nm, about 2 nm, about 3 nm, about 4 nm, about 5 nm, about 6 nm, about 7 nm, about 8 nm, about 9 nm, about 10 nm, about 11 nm, about 12 nm, about 13 nm, about 14 nm, about 15 nm, about 16 nm, about 17 nm, about 18 nm, about 19 nm, about 20 nm , About 25 nm, about 30 nm, about 35 nm, about 40 nm, about 45 nm, about 50 nm, and any range between these two values. For substantially non-spheres, for example rod-shaped nanocrystals, the smallest diameter is about 1 nm to 100 nm, or about 1 nm to about 50 nm, about 1 nm to about 25 nm, about 1 nm to about 10 nm, or sometimes about 1 nm. To about 5 nm.

In some embodiments the nanocrystalline cores provided herein can be less than about 10 nm in diameter or less than about 7 nm in diameter, or less than about 5 nm in diameter. Because the nanocrystals disclosed herein are unexpectedly bright at this size, the small size of these nanocrystals is beneficial for many applications.

Typical monochromatic nanoparticles preparations preferably have crystals of substantially the same size and shape. Nanocrystals generally appear in spherical or nearly spherical shape, but may actually be in any shape. Alternatively the nanocrystals may be non-spherical in shape. For example, the nanocrystal shape can be changed to a spheroidal spheroid for more red color. At least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95% and, ideally, about 100% of the particles are preferably the same size. The size deviation is measured as the mean square root ('rms') and has an rms of less than about 30%, preferably less than about 20%, more preferably less than about 10%. The size deviation is about 10% rms, less than about 9% rms, less than about 8% rms, less than about 7% rms, less than about 6% rms, less than about 5% rms or any of these two figures. It can be a range between. This group of particles is sometimes referred to as 'monodispersity'. Those skilled in the art will understand that nanocrystals sizes, such as semiconductor nanocrystals, are generally obtained with a particle size distribution.

It is known that the color of semiconductor nanocrystals can be 'varied' by changing the nanocrystal size and composition. Nanocrystals can absorb a broad wavelength spectrum and emit a narrow range of light wavelengths. The excitation and emission wavelengths are generally different and do not overlap. Monodispersed populations of nanoparticles can be characterized by fluorescence emission with a relatively narrow wavelength band. Examples of emission widths (FWHM) include less than about 200 nm, less than about 175 nm, less than about 150 nm, less than about 125 nm, less than about 100 nm, less than about 75 nm, less than about 60 nm, less than about 50 nm, less than about 40 nm, less than about 30 nm, about 20 nm. Less than about 10 nm. The emission width may preferably be less than about 50 nm, more preferably less than about 35 nm in the full width at half maximum (FWHM). The emitted light preferably has symmetrical emission wavelengths. The maximum emission can generally be any wavelength from about 200 nm to about 2,000 nm. Examples of maximum emission are not limited: about 200 nm, about 400 nm, about 600 nm, about 800 nm, about 1,000 nm, about 1,200 nm, about 1,400 nm, about 1,600 nm, about 1,800 nm, about 2,000 nm , And any range between these two values. In certain embodiments, the wavelength of the green region is selected because green is preferred.

Nanoparticles can have surface coatings that add various functionality. For example, nanocrystals can be lipids, phospholipids, fatty acids, polynucleic acids, polyethylene glycols, primary antibodies, secondary antibodies, antibody fragments, protein or nucleic acid based aptamers, biotin, streptavidin, proteins, peptides, small organic molecules. , Organic or inorganic dyes, precious metal clusters.

The spectral properties of the nanoparticles can generally be inspected using any suitable photo-measurement or photo-accumulation instrument. Examples of such devices are CCD (charge coupled device) cameras, video devices, CIT imaging mounted on fluorescence microscopes, digital cameras, photomultipliers, fluorometers and illuminometers, microscopes of various configurations and even the human eye. Release can be checked continuously or at one or more discrete time points. The light stability and sensitivity of the nanoparticles enables the recording of potential changes over an extended period of time.

In some embodiments, nanoparticles provided herein can be part of a monodisperse population of nanoparticles of the same composition. In some embodiments the monodisperse particle population exhibits a variation of less than about 30% rms, preferably less than about 20% rms, more preferably less than about 10%, at the diameter or lowest dimension of the core. It is done. In some embodiments the monodisperse particle population exhibits an rms of less than about 50%, or less than about 3%, at the diameter or lowest dimension of the core. Those skilled in the art will understand that nanocrystals sizes, such as semiconductor nanocrystals, are actually obtained with a particle size distribution.

Monodispersed populations of nanoparticles are characterized by fluorescence emission with relatively narrow wavelength bands. In some embodiments, when the monodisperse particle population is irradiated, the population emits light having a half width (FWHM) of less than about 60 nm, or an FWHM of less than about 50 nm and sometimes less than about 40 nm.

In some embodiments the core semiconductor nanocrystals can be modified to enhance the efficiency and stability of fluorescence emission by adding an overcoating layer or shell to the semiconductor nanocrystal cores prior to ligand modifications described herein. Surface defects in semiconductor nanocrystal cores dissipate electron or hole traps or absorbed photon energy that degrade the semiconductor nanocrystal core electrical and optical properties, or at least slightly affect the fluorescence emission wavelength to expand the emission band. It is desirable to have a shell, as this may lead to a mechanism of radiation energy loss. The insulating layer at the core surface, which is a semiconductor nanocrystal, can provide an atomic rapid rise in chemical potential at the interface that eliminates energy states that can function as electron and hole traps. This increases the efficiency in the light emission process.

Suitable materials for the shell include semiconductor materials having a higher band gap energy than semiconductor nanocrystalline cores. In addition to having greater band gap energy than semiconductor nanocrystal cores, suitable materials for the shell must have good conductivity and valence band offsets for the core semiconductor nanocrystals. Thus, the conduction band is preferably higher and the valence band may preferably be lower than those of the core semiconductor nanocrystals. Semiconductor nanowires that emit energy in visible light (e.g., CdS, CdSe, CdTe, ZnS, ZnSe, ZnTe, GaP, GaAs, GaN) or near IR (e.g., InP, InAs, InSb, PbS, PbSe) For the crystalline core, a shell material having a bandgap energy in the ultraviolet region can be used. Exemplary shell materials include, but are not limited to: CdS, CdSe, InP, InAs, ZnS, ZnSe, ZnTe, GaP, GaN and magnesium chalcogen compounds such as, for example, MgS, MgSe and MgTe. For semiconductor nanocrystal cores emitting at near IR, a shell material such as CdS or CdSe having a bandgap energy in visible light may be used. Coated semiconductor nanocrystal preparation is described, for example, in Dabbousi et al. (1997) / J. Phys. Chem. B 101: 9463, Hines et al. (1996) / J. Phys. Chem. 100: 468-471, Peng et al. (1997) / J. Am. Chem. Soc. 119: 7019-7029, and Kuno et al. (1997) / J. Phys. Chem. Found at 106: 9869. Also, since the actual fluorescence wavelength for a particular nanocrystalline core depends not only on the composition but also on the core size, the classification is approximate and the nanocrystalline cores described for emission in visible or near IR are actually more dependent on the core size. It should be understood that it can emit long or shorter wavelengths.

When core / shell fluorescent semiconductor nanocrystals are used, it is advantageous to make the nanoparticles as small as possible; Thus in some embodiments the nanocrystals are less than about 20 nm in diameter, and sometimes less than about 8 nm, and sometimes less than about 6 nm in diameter, and, in some embodiments, the nanocrystals are less than about 5 nm in diameter or size, or in diameter or The size may be less than 4 nm.

Nanocrystalline precursors may sometimes be referred to as first precursors and second precursors. The first precursor may be a metal-containing salt such as a halide, carboxylate, phosphonate, carbonate, hydroxide, or diketone compound of a metal, or a mixed salt thereof (eg halogen carboxylate, such as Cd (Halo) (oleate)), wherein the metal may be, for example, Cd, Zn, Mg, Be, Mn, Cu, Co, Pb Hg, Al, Ga, In, or Tl. The second precursor may be, for example, O, S, Se, Te, N, P, As, or Sb. The second precursor mixture may be an amine such as a primary amine (eg C ₈ -C ₂₀ alkylamine). The second precursor may include, for example, a phosphine chalcogenide, bis (silyl) chalcogenide, dioxygen species, ammonium salt, tris (silyl) phosphine, or the like.

In one embodiment, the first precursor and the second precursor may be combined to contact a metal or metal-containing salt, and a reducing agent to form a metal-containing precursor. The reducing agent may include alkyl phosphines, 1,2-diol or aldehydes such as C ₆ -C ₂₀ alkyl diols or C ₆ -C ₂₀ aldehydes.

Suitable metal-containing salts include but are not limited to cadmium acetylacetonate, cadmium iodide, cadmium bromide, cadmium chloride, cadmium hydroxide, cadmium carbonate, cadmium acetate, cadmium oxide, zinc acetylacetonate, zinc iodide, zinc bromide Zinc Chloride, Zinc Hydroxide, Zinc Carbonate, Zinc Acetate, Zinc Oxide, Magnesium acetylacetonate, Magnesium Iodide, Magnesium Bromide, Magnesium Chloride, Magnesium Hydroxide, Magnesium Carbonate, Magnesium Acetate, Magnesium Oxide, Mercury Acetyl Acetonate Mercury iodide, mercury bromide, mercury chloride, mercury hydroxide, mercury carbonate, mercury acetate, aluminum acetylacetonate, aluminum iodide, aluminum bromide, aluminum chloride, aluminum hydroxide, Aluminum carbonate, aluminum acetate, gallium acetylacetonate, gallium iodide, gallium bromide, gallium chloride, gallium hydroxide, gallium carbonate, gallium acetate, indium acetylacetonate, indium iodide, indium bromide, indium chloride, indium Hydroxides, indium carbonate, indium acetate, thallium acetylacetonate, thallium iodide, thallium bromide, thallium chloride, thallium hydroxide, thallium carbonate, or thallium acetate. Also for example, suitable metal-containing salts include phosphates as well as carboxylates such as oleate, stearate, myristate, and palmitate, halogen carboxylate mixtures such as M (halo) (oleate) It includes.

Alkyl may be a branched or unbranched saturated hydrocarbon group of 1-100, preferably 1-30 carbon atoms, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, octyl, decyl, tetradecyl, hexadecyl, eicosyl, tetracosyl and the like, and cycloalkyl groups such as cyclopentyl, cyclohexyl and the like. Optionally, the alkyl may have 1-6 linkages selected from the group consisting of O—, —S—, —M— and —NR—, where -R is hydrogen, or C ₁ -C ₈ alkyl or lower Alkenyl.

Prior to combining the metal-containing salt with the second precursor, the metal-containing salt may be contacted with a coordinating solvent to form the metal-containing precursor. Typical coordinating solvents include alkyl phosphines, alkyl phosphine oxides, alkyl phosphonic acids, alkyl phosphinic acids or carboxylic acid containing solvents; However, other coordinating solvents such as pyridine, furan and amines are also suitable solvents for the preparation of nanocrystals. Suitable coordinating solvent examples include pyridine, tri-n-octylphosphine (TOP) and tri-n-octylphosphine oxide (TOPO). Also included are acid-containing solvents such as oleic acid, stearic acid, myristic acid, palmitic acid, TDPA, OPA and the like. Coordinating solvents may include 1,2-diol or aldehydes. 1,2-diol or aldehyde can promote the reaction between the metal-containing salt and the second precursor, thereby improving the growth process and improving the quality of nanocrystals obtained in the process.

The second precursor is generally a chalcogenide donor or group V element, such as a phosphine chalcogenide, bis (silyl) chalcogenide, dioxygen, ammonium salt or tris (silyl) phosphine. Suitable second precursors are dioxygen, elemental sulfur, bis (trimethylsilyl) selenide ((TMS) ₂ Se), trialkyl phosphines such as (tri-n-oxylphosphine) selenide (TOPSe) or (tri -n-butylphosphine) selenide (TBPSe), trialkyl phosphine telluride e.g. (tri-n-oxylphosphine) telluride (TOPTe) or hexapropylinamide telluride (HPPTTe), bis (trimethyl Silyl) telluride ((TMS) ₂ Te), sulfur, bis (trimethylsilyl) sulfide ((TMS) ₂ S), trialkyl phosphine sulfides such as (tri-3-oxylphosphine) sulfide (TOPS), Tris (dimethylamino) arsine, ammonium salt, for example ammonium halide (e.g. NH ₄ Cl), tris (trimethylsilyl) phosphide ((TMS) ₃ P), tris (trimethylsilyl) arsenide ((TMS ) ₃ As), or tris (trimethylsilyl) antimonide ((TMS) ₃ Sb). In certain embodiments, the first precursor and the second precursor can be part within the same molecule.

As used herein, 'coordinating solvent' refers to solvents that effectively coordinate to the nanocrystalline surface, such as TOP, TOPO, TDPA, OPA, carboxylic acid and amine. Coordination solvents also include phosphines, phosphine oxides, phosphonic acids, phosphines, amines and carboxylic acids that are often used in nanocrystals growth mediators and form coatings or layers on nanocrystal surfaces. Hydrocarbon solvents that do not have heteroatoms that provide bonding electron pairs to coordinate with the nanocrystalline surface, such as hexane, toluene, hexadecane, octadecene, are excluded. Hydrocarbon solvents that do not contain heteroatoms that coordinate to the nanocrystalline surface, such as O, S, N or P, are referred to herein as non-coordinating solvents. The term 'solvent' is used in the conventional sense: to refer to a medium that maintains, dissolves, or disperses the substances and the reaction therebetween but does not participate in or be altered by the reactant reaction.

Precursor

The formation of nanoparticles generally consists of two other steps: a first step in which a significant number of precursors are incorporated, a nucleation, and a second step in which precursors are added to an existing nucleus, growth. If the precursor atoms are of the same type (ie both non-ionic material (neutral) or one is a cation and the other an anion), they react very quickly. This type of rapid reaction produces extensive nucleation even when nucleation is undesirable, and growth and nucleation occur simultaneously, resulting in a population of particles lacking a uniform particle size.

Since the nucleation step determines the nanoparticle yield and the growth step determines the final nanoparticle size, independent control of these two formation steps is valuable.

Separation of the nucleation step in the growth phase of nanocrystal formation to provide a uniform nanoparticle size distribution, monodisperse population of nanocrystals so that all nanocrystals form at about the same time and then all grow at about the same time It is important. It is difficult to achieve a uniform size if new small nuclei are formed after other particles have been formed and grown for a period of time.

Provided herein are methods for separating nucleation and growth steps while improving control for each step.

The two steps control method of particle formation is achieved using 'mismatched' precursors. 'Mismatched' precursors cannot proceed without receiving or losing electrons such that both precursors are in a complementary ionic or neutral state in solution; Otherwise they cannot be combined to form a neutral product. In the absence of an electron transfer agent, for example a reducing agent or an oxidant, the lack of reactivity of 'mismatched' precursors allows the temporary transfer of particle formation by controlling the content and nature of the electron transfer agent present in the reaction mixture with the mismatched precursors. Nucleation and growth steps can be controlled.

If one precursor provides neutral species for nanocrystal formation in solution and the other precursor provides ionic species in solution at the reaction conditions in use, or each of the precursors is of the same charge ion species (ie two kinds of cations or two kinds of Anion), the precursors provided herein are considered 'mismatched'. Examples of mismatched precursors include cationic species providing precursors paired with non-ionic (ie neutral) species or precursors providing other cations, or precursors providing non-ionic (ie neutral) species or other anionic species. Paired anion species providing precursors. Related species are reaction species that exist under shell-forming reaction conditions.

In some embodiments, a dual oxidant system can be used. In other embodiments, dual reducing agent systems may be used. In another embodiment, a mixed electron transfer system (ie, one oxidant and one reducing agent) can be used. In some such embodiments, a set of precursors may be used in which one provides a neutral species and the other provides a cation. In such a system, a reducing agent may be added to reduce the neutral species to anions or to reduce the cationic species to neutral oxidation.

In some embodiments, the first precursor consists of metal atom M and the second precursor consists of nonmetallic atom X, wherein the precursors are selected such that the oxidation states are inconsistent.

The nanocrystalline core and shell can be made of any suitable metal and nonmetal atoms known to form semiconductor nanocrystals. Suitable semiconductor materials for the core and / or shell are, but are not limited to, 2-16, 12-16, 13-15, and Group 14 element-based semiconductors such as ZnS, ZnSe, ZnTe, CdS, CdSe, CdTe , HgS, HgSe, HgTe, MgS, MgSe, MgTe, CaS, CaSe, CaTe, SrS, SrSe, SrTe, BaS, BaSe, BaTe, GaN, GaP, GaAs, GaSb, InP, InAs, InSb, AlS, AlP, AlSb , PbS, PbSe, Ge and Si and their two, three and four component mixtures.

The choice of semiconductor nanoparticle composition affects the particle's characteristic spectroscopic emission wavelength. Thus the specific composition of nanoparticles provided herein can be selected based on the region of the spectrum being inspected. For example, semiconductor nanocrystals that emit energy in the visible range include, but are not limited to, CdS, CdSe, CdTe, ZnSe, ZnTe, GaP, and GaAs. Semiconductor nanocrystals that emit energy in the near IR range include, but are not limited to, InP, InAs, InSb, PbS and PbSe. Finally, examples of semiconductor nanocrystals emitting energy in blue to near ultraviolet light include, but are not limited to, ZnS and GaN. In each case, some additional fluorescence wavelength tuning can be achieved by the shell added to the nanocrystalline core.

Precursors useful as the 'first' precursors in the methods disclosed herein include compounds containing elements of the Periodic Tables 2 and 12 (eg, Zn, Cd, Hg, Mg, Ca, Sr, Ba, etc.), Group 13 Elements of the Periodic Table of the Elements ( Al, Ga, In, etc.) containing compound, and the compound containing element 14 (Si, Ge, Pb, etc.) of an periodic table of elements. Many forms of precursors are disclosed herein and may be used in the method.

Examples of compounds useful as the first precursor may be organometallic compounds such as alkyl metal species or salts such as metal halides, metal carboxylates, metal phosphonates, metal phosphinates, metal oxides or other salts. In some embodiments the first precursor provides a neutral species in solution. For example, alkyl metal species such as diethylzinc (Et ₂ Zn) or dimethyl cadmium are generally considered to be a source of neutral zinc atoms (Zn ⁰ ) in solution. In another embodiment, the first precursor provides ionic species (ie, metal cations) in solution. For example, zinc chloride (ZnCl ₂₎ and other zinc halides, zinc acetate (Zn (OAc) ₂₎ and zinc carboxylic acid salts are generally considered in a source of Zn ^{2 +} cation solution.

In an embodiment, suitable first precursors that provide neutral metal species include dialkyl metal sources, such as dimethyl cadmium (Me ₂ Cd), diethyl zinc (Et ₂ Zn), and the like. Suitable first precursors for providing metal cations in solution include, for example, cadmium acetate (Cd (OAc) ₂ ), cadmium nitrate (Cd (NO ₃ ) ₂ ), cadmium oxide (CdO) and other cadmium salts; And zinc salts such as zinc chloride (ZnCl ₂ ), zinc acetate (Zn (OAc) ₂ ), zinc oleate (Zn (oleate) ₂ ), zinc chloro (oleate), zinc undecylenate, zinc salicylate Silates, and other zinc salts. In some embodiments the first precursor is a Cd or Zn salt. In some embodiments, the first precursor is a halide, acetate, carboxylate or oxide salt of Cd or Zn. In another embodiment, the first precursor is a salt of the form M (O ₂ CR) X, wherein M is Cd or Zn, X is a halide or O ₂ CR; And R is a C ₄ -C ₂₄ alkyl group which is optionally unsaturated. Other suitable forms of Group 2, 12, 13 and 14 elements useful as first precursors are well known in the art.

Precursors useful as 'second' precursors in the methods disclosed herein include compounds containing an element of the Periodic Table of the Group 16 (eg, S, Se, Te, etc.), Group 15 Elements of the Periodic Table of the Elements (N, P, As, Sb, etc.) A compound containing, an element containing element 14 (Ge, Si, etc.) of the periodic table of elements, and a compound containing element 17 (halogen) of the periodic table of elements. Many forms of precursors can be used in the methods disclosed herein. It can be appreciated that in some embodiments, the second precursor provides neutral species in solution and in other examples the second precursor provides ionic species in solution.

In certain embodiments, it should be understood that the nanoparticle core and / or shell may be composed of two or more precursors. For example, the same method described herein can be applied to form three component nanoparticles using three kinds of precursors, four component nanoparticles using four kinds of precursors, and the like.

If the first precursor consists of a metal cation, the second precursor preferably provides a chargeless (ie neutral) nonmetallic atom in solution. In many embodiments, when the first precursor is a metal cation, the second precursor provides a neutral chalcogen atom, most commonly S ⁰ , Se ⁰ or Te ⁰ .

For example, suitable second precursors that provide neutral chalcogen atoms include elemental sulfur (sometimes as an amine solution such as decylamine, oleylamine or dioctylamine, or as an alkene solution such as octadecene), and Tri-alkylphosphine adducts of S, Se and Te. Such trialkylphosphine adducts are sometimes described herein as R ₃ P═X, wherein X is S, Se, or Te, and each R is independently H or straight, branched, cyclic, or combinations thereof Is a C ₁ -C ₂₄ hydrocarbon group, which may be unsaturated. Typical second precursors of this type are tri-n- (butylphosphine) selenide (TBP = Se), tri-n- (oxylphosphine) selenide (TOP = Se), and corresponding sulfur and tellurium reagents. , TBP = S, TOP = S, TBP = Te, and TOP = Te. These reagents are formed by combining a desired element such as Se, S or Te with a suitable coordinating solvent such as TOP or TBP. Precursors that provide anionic species at reaction conditions are typically used as first precursors that provide neutral metal atoms, such as alkylmetal compounds and others known above or in the art.

In some embodiments the second precursor provides a negatively charged nonmetal ion in solution (eg, S- ² , Se- ² or Te- ² ). Suitable second precursor examples for providing ionic species include silyl compounds such as bis (trimethylsilyl) selenide ((TMS) ₂ Se) bis (trimethylsilyl) sulfide ((TMS) ₂ S), and bis (trimethylsilyl ) Telluride ((TMS) ₂ Te). In addition, hydrogenated compounds such as H ₂ Se, H ₂ S, H ₂ Te; And metal salts such as NaHSe, NaSH or NaHTe. In this situation, the oxidant oxidizes the neutral metal species to a cationic species that can react with the anion precursor in a 'mismatched' reaction, or the oxidant provides an anion to provide a neutral species capable of 'matching' the neutral metal species. Increases precursor oxidation.

Other typical organic precursors are described in US Pat. Nos. 6,207,299 and 6,322,901 to Bawendi et al., And synthetic methods using weak acids as precursor materials are described in this Qu et al., (2001) Nano Lett., L (6): 333-337. , Each of which is incorporated herein by reference in its entirety.

Both the first and second precursors can be combined with a suitable solvent for solution formation for use in the methods disclosed herein. The solvent or solvent mixture used to form the first precursor solution may be the same or different from that used to form the second precursor solution. The precursors may be dissolved separately or combined together in a single solution.

Mixture heating may be performed before or after precursor mixing and before or after combining the solvent and / or precursors with a reducing agent. In some embodiments the first precursor, the second precursor and the weak reducing agent are all optionally combined in an appropriate solvent or solvent mixture to form a reaction mixture, and the reaction mixture is heated to an appropriate temperature prior to the addition of the strong reducing agent.

The order and rate of precursor additions are generally not critical to the method disclosed herein.

In some embodiments precursors are added at a rate limited only by the actual factors associated with maintaining the desired reaction temperature, and precursor addition can be made as quickly as temperature control is allowed. Similarly, the precursors may all be present in the reaction mixture when heated to the desired reaction temperature, and after reaching the operating temperature, one or a positive electron transfer agent may be added. In some embodiments, at least the strong electron transfer agent is not added to the reaction mixture until the reaction mixture reaches the desired reaction temperature.

Coordination Solvent

Suitable co-solvents, although not limited to exemplary purposes, include hydrocarbons, amines, alkyl phosphines, alkyl phosphine oxides, carboxylic acids, ethers, furans, phosphonic acids, pyridine and mixtures thereof. The solvent actually consists of a solvent mixture and is referred to herein as a 'solvent system'. In a preferred embodiment the solvent consists of at least one coordinating solvent. In some embodiments the solvent system is a second amine and trialkyl phosphine (eg TBP or TOP), phosphonic acid (eg TDPA OPA) or trialkylphosphine oxide (eg TOPO) It is composed.

The coordinating solvent may be essentially a mixture of non-coordinating solvents such as alkanes and ligands as defined below.

Suitable hydrocarbons include alkanes, alkenes and aromatic hydrocarbons of 10 to about 30 carbon atoms, examples include octadecene and squalene. Hydrocarbons may consist of alkanes, alkenes and aromatic moieties such as alkylbenzene (eg mesitylene) mixtures.

Suitable amines include, but are not limited to, monoalkylamines, dialkylamines, and trialkylamines such as trioctylamine, dioctylamine, octylamine, oleylamine, decylamine, dodecylamine, hexyldecylamine, and the like. Include. Alkyl groups for such amines generally have about 6-24 carbon atoms per alkyl, include unsaturated carbon-carbon bonds, and each amine has about 10-30 carbon atoms in all of the alkyl groups.

Exemplary alkyl phosphines include but are not limited to trialkyl phosphines, tri-n-butylphosphine (TBP), tri-n-octylphosphine (TOP), and the like. Alkyl groups for such phosphines have about 6-24 carbon atoms per alkyl, include unsaturated carbon-carbon bonds, and each phosphine has about 10-30 carbon atoms in all of the alkyl groups.

Suitable alkyl phosphine oxides include, but are not limited to, trialkylphosphine oxides, tri-n-octylphosphine oxides (TOPO), and the like. Alkyl groups for such phosphine oxides have about 6-24 carbon atoms per alkyl, include unsaturated carbon-carbon bonds, and each phosphine oxide has about 10-30 carbon atoms in all of the alkyl groups.

Exemplary fatty acids include, but are not limited to, stearic acid, oleic acid, palmitic acid, myristic acid lauric acid, and other carboxylic acids having the formula R-COOH, wherein R is a C6-C24 hydrocarbon group, Can be included

Exemplary ethers and furans include, but are not limited to, tetrahydrofuran and methylated forms, glymes, and the like.

Suitable phosphonic acids and phosphinic acids include, but are not limited to, hexylphosphonic acid (HPA), tetradecylphosphonic acid (TDPA) and octylphosphonic acid (OPA), in combination with alkyl phosphine oxides such as TOPO. do. Suitable phosphonic acids and phosphinic acids are of the formula RPO ₃ H ₂ or R ₂ PO ₂ H, wherein each R is independently a C 6 -C ₂₄ hydrocarbon group and may comprise unsaturated carbon-carbon bonds.

Exemplary pyridines include, but are not limited to, pyridine, alkylated pyridine, nicotinic acid, and the like.

Suitable alkenes include, for example, octadecene, squalene and other unsaturated C4-C30 hydrocarbons.

The solvents may be used alone or in combination. TOP-TOPO solvent systems are commonly used in the art as other related (eg butyl) systems. For example, TOP alone can be used to form a selenium solution and at the same time TOP and TOPO can be used in combination to form a cadmium solution (eg TOP + cadmium acetate or TOP + cadmium nitrate).

Industrial solvents may be used and benefit from the presence of beneficial impurities in this kind of solvent such as TOP, TOPO or both. In certain embodiments, the solvent consists of at least one coordinating solvent. In one preferred embodiment the solvent is pure. In general, this means that the solvent comprises less than 10 vol% and more preferably less than 5 vol% of impurities which can function as electron transfer agents. Thus solvents such as TOPO of 90% or 97% purity and TOP of 90% purity are particularly suitable for use in the methods disclosed herein, solvents of 99% purity or higher being preferred.

The presence of a slight amount of impurities can provide an unexpected source of electron transfer agents, and if they promote nucleation of the inconsistent shell precursor, may defeat the purpose of the embodiments disclosed herein. In addition, certain reagents may be weak reducing agents / oxidants in one system and strong reducing agents / oxidants or ineffective reducing agents / oxidants in other systems: weak and strong must be the specific shell precursor used in the nanocrystalline core-forming reaction. And solvent used and temperature.

For example, in some systems, the unsaturated bond provided in one of the solvents or precursors may be a weak reducing agent / oxidant as discussed; In other systems, such as in metal salts containing unsaturated groups such as oleate, the unsaturated bonds may be ineffective as weak reducing agents / oxidants, and weak reducing agents / oxidants may be added to promote nanocrystal growth. .

In order to precisely control the two steps of nanocrystal formation, it is sometimes desirable to identify and understand the presence of any strong or weak reducing agent / oxidant in the solvents and reagents used for these methods. Thus, in some embodiments, the reagents used in the methods described herein require an effect assessment for certain systems. Suitability of reagents, solvents, reducing agents or precursors for the present method can be determined by testing whether these materials serve as strong reducing agents / oxidants in the system of interest or contain impurities that serve them. If the reagents function as or function as strong reducing agents / oxidants, the reactants must be removed, replaced or further purified for the methods disclosed herein.

Ligand

In one preferred embodiment a ligand is included in the reaction. Ligands are compounds that complex with precursors and / or nanoparticles. Suitable ligands include, but are not limited to, phosphonic acids such as hexylphosphonic acid and tetradecylphosphonic acid (TDPA), octylphosphonic acid (OPA), carboxylic acids such as octadecanoic acid isomers, amines, amides, alcohols, and Ethers. In some cases, the ligand and the solvent may be identical.

Electron transfer agent :reducing agent

In the embodiments disclosed herein control of the granulation nucleation and growth steps can be achieved by application of a mismatched precursor that cannot react without receiving and losing electrons by the electron transfer agent. The use of two separate electron transfer agents, in particular one or more reducing agents, can independently promote nucleation or growth to the desired extent and improve the temporary separation of these two formation steps. This method allows independent control of particle yield and particle size, and can also produce particles with a narrower size distribution.

As used herein, 'strong' or 'stronger' reducing agent (reducing agent) means a reducing agent that can promote the onset of nucleation or particle formation under the specific conditions of the reaction in which it is used. 'Weak' or 'weaker' reducing agent means a reducing agent that can promote the onset of significant nucleation or particle formation under the specific conditions used, but can promote particle growth under such conditions.

It will be appreciated by those skilled in the art that whether a particular reducing agent is a weak reducing agent or a strong reducing agent depends on the case and depends on the specific reaction conditions in which they are used. Electron transfer can proceed more readily on the surface of the growth particles than on free ions in the solution needed for nucleation (ie growth stage process). By determining whether the test reducing agent behaves as a strong or weak reducing agent under these conditions, the test reducing agent can be divided into strong or weak for a given system (nanocrystal-forming reaction). To determine if a particular test reducing agent is a strong reducing agent, the test reducing agent and the precursor of interest are contacted under suitable reaction conditions without primary nanocrystals (additional nanocrystals in the initial reaction mixture) to confirm that nucleation is observed; In general, if nucleation proceeds at a significant rate, for example at a rate of at least about 50% higher than in the absence of a test reducing agent, the test reducing agent promotes nucleation and is considered a strong reducing agent in such systems. If the rate of nucleation does not increase significantly in the presence of a test reducing agent, the test reducing agent in this system is not a strong reducing agent.

To determine if a particular test reducing agent is a weak reducing agent, contacting the test reducing agent with the particular precursor of interest under shell-forming reaction conditions in the presence of the same type of primary (additional) nanocrystals formed by that precursor; In general, if nanocrystal growth proceeds at an increasing rate, for example, at least twice the rate of growth than without a test reducing agent, the test reducing agent is considered to be a suitable reducing agent for promoting nanocrystal growth. It may therefore be a suitable weak reducing agent if it does not function as a strong reducing agent in the system of interest.

The test reducing agent can be considered as a weak reducing agent if the test promotes nanocrystal growth and is not a strong reducing agent in the particular system of interest. Since the relative strength of the reducing agent depends on these factors, this functional reducing agent classification is applied to any particular test reducing agent by routine tests and is a useful method for classifying weak or strong reducing agents.

Because electron transfer can proceed more easily on the surface of the growth particles than on free ions in the solution needed for nucleation (ie, during the growth stage), stronger reducing agents may be needed in nucleation than growth. This difference in reactivity allows the two steps to be separated by providing large quantities of strong electron transfer agents that are easily consumed in the nucleation process and weaker electron transfer agents that allow for continuous growth. Core nanocrystal size can be determined immediately during the growth phase by examining the fluorescence wavelength.

In the examples provided herein, the degree of nucleation can be controlled by controlling the content of the strong reducing agent used in the reaction. In some embodiments, the strong reducing agent may be added in an amount sufficient to proceed the desired degree of nucleation. In other embodiments, the strong reducing agent may be added in sub-stoichiometric amounts relative to the precursor (s) being reduced. In some such examples the additive strong reducing agent content may be less than about 1/10, about 1/10, less than about 2/10, less than about 3/10, or less than about 4/10 required for the stoichiometric reaction of the nanocrystalline precursor. have. In certain embodiments the strong reducing agent content added may be about 1/10 required for the stoichiometric reaction.

After the consumption of the strong reducing agent, which can proceed quickly at a suitable reaction temperature, further formation of small nuclei is substantially terminated. Therefore, it is possible to isolate the nucleation step in the growth stage by limiting the content of the strong reducing agent. This method allows independent control of particle yield and particle size, and can also produce particles with a narrower size distribution. Since the precursors are inconsistent, continued growth of the nanocrystal nuclei requires the addition of a second electron transfer agent. The addition of a weak reducing agent enables particle growth but does not promote another nucleation, thus providing particles of uniform size.

Since reaction control is achieved by electron transfer agent application, careful control over the rate of precursor addition is not critical as in some nanocrystal manufacturing methods. Nanocrystalline precursors can be added in one portion as quickly as possible without causing significant cooling of the reaction mixture; Slow addition of the precursor to prevent the formation of undesirable new nuclei is not necessary in many embodiments of the present methods. Indeed, the precursor and optionally the weak reducing agent are included in a suitable solvent and can be heated to the desired reaction conditions without causing nanocrystal formation and can be initiated by addition of a strong reducing agent.

In a preferred embodiment the strong reducing agent may be added at an operating temperature sufficient to generate nucleation. At these temperatures, it appears to lead to rapid nucleation by the addition of strong reducing agents, thereby rapid consumption of the reducing agent. Under these conditions, all core nanocrystals form at about the same time and all grow for the same time, resulting in a uniform particle size distribution and providing a monodisperse particle population.

Those skilled in the art will understand that whether a particular reducing agent is a strong or weak reducing agent depends on the specific reaction conditions in which the reducing agent is used.

Exemplary and non-limiting suitable reducing agents include compounds such as tertiary phosphine, secondary phosphine, primary phosphine (eg, diphenylphosphine, dicyclohexylphosphine, and dioctylphosphine); Amines (eg, decyl- and hexadecylamine); Hydrazine; Hydroxyphenyl compounds (eg hydroquinone and phenol); Hydrogen; Hydrides (eg, sodium borohydride, lithium triethyl borohydride, sodium hydride and lithium aluminum hydride, etc.); Metals (eg mercury and potassium); Boranes (eg, THF: BH ₃ and B ₂ H ₆ ); Aldehydes (eg, benzaldehyde and butylaldehyde); Alcohols and thiols (eg, ethanol and thioethanol); Reducing halides (eg, I ⁻ and I ₃ ⁻ ); Alkenes (eg, oleic acid); Alkyne, and a multifunctional reducing agent, such as a single species having one or more reducing moieties, wherein each reducing moiety has the same or different reducing powers, for example tris- (hydroxypropyl) phosphine and ethanolamine); And the like.

Typically hydrides (metal hydrides such as aluminum hydrides or metal borides) and boranes function as strong reducing agents. Depending on the specific reaction conditions, other reducing agents may function as strong reducing agents or weak reducing agents. For example, alkylphosphines may function as strong reducing agents in CdSe synthesis, but are weak reducing agents in ZnTe synthesis. Other reducing agents, such as alkenes, alkynes, amines, etc., are generally weak reducing agents.

In some embodiments the weak reducing agent may be provided as one component of the precursor. For example, unsaturated carboxyl groups such as oleate may function as weak reducing agents in the embodiments disclosed herein. Figure 2 is a Zn ^{+ 2} indicates a paper mismatch tellurium precursor (TOPTe) as reaction to reaction. The left, the first graph, Zn ^{+ 2} salt is the reducing agent was not present because it is about saturated salt. In the second graph to the right, the salt comprises an unsaturated carboxylic acid group, which provides a reducing agent. Both show low particle yields in the reactions and require a strong reducing agent to promote efficient nucleation; However, reactions involving unsaturated carboxylates, which apparently act as weak reducing agents, provide faster nanocrystal formation.

In certain embodiments, to provide a weak reducing agent to promote nanocrystal growth, sometimes the metal-containing precursor may be provided as a metal carboxylate of formula M (O ₂ C—R ′) n, where M is a metal N is an integer of 1-3 determined by the metal atom oxidation state, and R 'is a C ₄ -C ₁₀₀ unsaturated hydrocarbon group. In other embodiments, the salt may consist of such unsaturated carboxylate counterions and one or more other counterions, such as halogen ions. They provide a convenient way of providing a weak reducing agent without the need to add additional materials to the reaction mixture and ensure that at least one weak reducing agent per precursor atom is provided by reaction stoichiometry. However, in some systems it is necessary to confirm that they act as weak reducing agents and not as strong reducing agents.

In other embodiments, solvents such as alkenes, alkynes or amine solvents may function as weak reducing agents. This method is particularly useful in reactions in which an overdose of drug reducing agents is desired. However, in some systems it is necessary to confirm that the solvent acts as a weak reducing agent and not as a strong reducing agent.

Since the cathode serves as the electron source, it can be expected that there are certain advantages with respect to the application of the electrochemical system (cathode-anode system) as reducing agent. By using the electrode as a reducing equivalent source, the coulombic equivalent can be immediately counted and the delivery rate can be directly controlled. The use of electrodes also allows control of the physical localization of the reduction phenomenon and the potential for direct formation of particle arrays at the electrode surface. Since the negative electrode is disposed inside the reaction chamber, it is preferable that the selection material does not react with the precursor, the ligand or the coordinating solvent. Since the anode is disposed outside the reaction vessel, the material selection is not limited, and any known anode material can be used. Typical anode materials include platinum, silver or carbon. Exemplary methods of delivering reduced equivalents to the cathode include the use of constant current or potentiostatics in a two-electrode (operating and auxiliary) or three-electrode (operating, auxiliary and reference) configuration.

Appropriate reducing agent selection for precursor specific compositions is within the skill level.

Electron transfer agent ： Oxidizer

In the embodiments disclosed herein control of the granulation nucleation and growth steps can be achieved by using a mismatched precursor that cannot react without electron accepting and loss by the electron transfer agent. The use of two separate electron transfer agents, in particular one or more oxidants, can independently promote nucleation or growth to the desired extent and improve the temporary separation of these two formation steps. This method allows independent control of particle yield and particle size, and can also produce particles with a narrower size distribution.

As used herein, 'strong' or 'stronger' oxidant (oxidizing agent) means an oxidant that can promote nucleation or initiation of granulation at the specific conditions of the reaction in which it is used. 'Weak' or 'weaker' oxidant means an oxidant that can promote nucleation or initiation of granulation under the specific conditions used, but can promote particle growth under such conditions.

It will be appreciated by those skilled in the art that whether a particular oxidant is a weak or strong oxidant is dependent on the case and depends on the specific reaction conditions in which they are used. Electron transfer can proceed more readily on the surface of the growth particles than on free ions in the solution needed for nucleation (ie growth stage process). By determining whether the test oxidant behaves as a strong or weak oxidant under these conditions, the test oxidant can be classified as strong or weak for a given system (nanocrystal-forming reaction). To determine if a particular test oxidant is a strong oxidant, contact the test oxidant with the particular precursor of interest under suitable reaction conditions without primary nanocrystals (additional nanocrystals in the initial reaction mixture) to confirm that nucleation is observed; In general, if nucleation proceeds at a significant rate, for example at a rate of at least about 50% higher than in the absence of test oxidants, the test oxidant promotes nucleation and is considered a strong oxidant in such systems. If the rate of nucleation does not increase significantly in the presence of the test oxidant, then the test oxidant is not a strong oxidant.

To determine if a particular test oxidant is a weak oxidant, contacting the test oxidant with the particular precursor of interest under shell-forming reaction conditions in the presence of the same type of primary (additional) nanocrystals formed by that precursor; In general, if nanocrystal growth proceeds at an increasing rate, for example at a rate of at least twice the rate of growth without the test oxidant, the test oxidant is considered an oxidant suitable for promoting nanocrystal growth. Thus, it may be a suitable weak oxidant if it does not act as a strong oxidant in the system of interest.

The test oxidant may be considered a weak oxidant if it promotes nanocrystal growth by the test and is not a strong oxidant in the particular system of interest. Since the relative strength of the oxidant depends on these factors, this functional oxidant classification is applied to any particular test oxidant by routine tests and is a useful method for classifying weak or strong oxidants.

Because electron transfer can proceed more easily on the surface of the growth particles than on free ions in the solution needed for nucleation (ie, during the growth stage), stronger oxidants may be needed in nucleation than growth. This difference in reactivity allows the two steps to be separated by providing large quantities of strong electron transfer agents that are easily consumed in the nucleation process and weaker electron transfer agents that allow for continuous growth. Core nanocrystal size can be determined immediately during the growth phase by examining the fluorescence wavelength.

In the methods provided herein the degree of nucleation can be controlled by controlling the strong oxidant content used in the reaction. In some embodiments a strong oxidant may be added in an amount sufficient to proceed the desired degree of nucleation. In a preferred embodiment the strong oxidant may be added in a sub-stoichiometric content relative to the precursor (s) to be reduced. In some such examples the added strong oxidant content may be less than about 1/10, about 1/10, less than about 2/10, less than about 3/10, or less than about 4/10 required for the stoichiometric reaction of the nanocrystalline precursor. have. In certain embodiments the strong oxidant content added may be about 1/10 required for the stoichiometric reaction.

After the consumption of strong oxidants, which can proceed quickly at a suitable reaction temperature, further formation of small nuclei is substantially terminated. Therefore, it is possible to isolate the nucleation stage in the growth stage by limiting the content of the strong oxidant. This method allows independent control of particle yield and particle size, and can also produce particles with a narrower size distribution. Since the precursors remain inconsistent, continued growth of the nanocrystal nuclei requires the addition of a second electron transfer agent. The addition of a weak oxidant allows particle growth but does not promote another nucleation, thus providing particles of uniform size.

Since reaction control is achieved by electron transfer agent application, careful control over the rate of precursor addition is not critical as in some nanocrystal manufacturing methods. Nanocrystalline precursors can be added in one portion as quickly as possible without causing significant cooling of the reaction mixture; Slow addition of the precursor to prevent the formation of undesirable new nuclei is not necessary in many embodiments of the present methods. Indeed, the precursor and optionally the weak oxidant are included in a suitable solvent and can be heated to the desired reaction conditions without causing nanocrystal formation and can be initiated by the addition of strong oxidants.

In a preferred embodiment the strong oxidant may be added at an operating temperature sufficient to generate nucleation. At this temperature, it appears to lead to rapid nucleation by the addition of strong oxidizers, thereby rapid oxidant consumption. Under these conditions, all core nanocrystals form at about the same time and all grow for the same time, resulting in a uniform particle size distribution and providing a monodisperse particle population.

Those skilled in the art will understand that whether a particular oxidant is a strong or weak oxidant depends on the specific reaction conditions in which the oxidant is used. Exemplary and non-limiting suitable oxidants include compounds such as potassium nitrate; Hypochlorite, chlorite, chlorate, perchlorate and other similar halogen compounds; t-butyl hypochlorite; Halogen such as fluorine, chlorine, bromine and iodine; Permanganate and compounds; Cerium ammonium nitrate; Hexavalent chromium compounds such as chromic acid and dichromic acid and chromium trioxide, pyridinium chlorochromate (PCC), and chromate / dichromate compounds; Peroxide compounds; Tolene reagent; Sulfur oxides; Peroxysulfuric acid; Oxygen; ozone; Osmium tetraoxide; nitric acid; Nitrous oxide; Silver (I) compounds; Copper (II) compounds; Molybdenum (IV) compounds; Iron (III) compounds; Manganese (IV) compounds; N-methylmorpholine-N-oxides and other N-oxides; Trimethylamine N-oxide; 3-chloroperoxide benzoic acid, and other peroxide acids; Or peracetic acid.

In some embodiments the weak oxidant may be provided as one component of the precursor.

Since the cathode serves as the electron source, it can be expected that there are certain advantages with respect to the application of the electrochemical system (cathode-anode system) as oxidant. By using the electrode as the source of oxidation equivalent, the coulombic equivalent can be immediately counted and the delivery rate can be directly controlled. The use of electrodes also allows control of the physical localization of oxidation phenomena and the potential for direct formation of particle arrays at the electrode surface. Since the negative electrode is disposed inside the reaction chamber, it is preferable that the selection material does not react with the precursor, the ligand or the coordinating solvent. Since the anode is disposed outside the reaction vessel, the material selection is not limited, and any known anode material can be used. Typical anode materials include platinum, silver or carbon. Exemplary methods of oxidative equivalent transfer to the cathode include the use of constant current or potentiostatics in a two-electrode (operating and auxiliary) or three-electrode (operating, auxiliary and reference) configuration.

Strong and / or weak Electron transfer agent  Method of generating nanocrystals using

Provided herein are methods for producing nanocrystals using mismatched precursors in the state of addition of an electron transfer agent. In some embodiments two different electron transfer agents may be used to separately control the nucleation and growth stages of particle formation.

In one aspect, (a) a first precursor, a second precursor, a first (ie, strong) electron transfer agent (eg, an amount sufficient to produce a desired level of nucleation), and a second (ie, about ) Providing a mixture consisting of an electron transfer agent (eg, sufficient to form a desired level of nanocrystal growth), and optionally a solvent (eg, a coordinating solvent); And (b) heating the mixture to a constant temperature for a time sufficient to induce formation of a population of nanocrystals.

In some embodiments the nanocrystal formation reaction proceeds in a continuous flow reactor system. In other embodiments the nanocrystal formation reaction occurs in a batch reactor system.

In certain embodiments, the first and second electron transfer agents are oxidants. In another embodiment, the first and second electron transfer agents are reducing agents. In some embodiments the first electron transfer agent is an oxidant and the second electron transfer agent is a reducing agent or vice versa.

In some embodiments the oxidation state of the first precursor or the second precursor is changed to a neutral state by the strong and weak electron transfer agent. In another embodiment, the oxidation states of the first and second precursors are matched by the strong and weak electron transfer agents.

In certain embodiments the method further comprises step (c), which is the step of cooling the mixture to stop further growth of the nanocrystals or diluting the mixture to stop further growth of the nanocrystals. In some embodiments the method further comprises isolating the nanocrystals produced by the method. In another embodiment, the method further includes adding a shell to the isolated or unisolated nanocrystals.

The reaction mixture components (ie, the first precursor, the second precursor, the first reducing agent, and the second reducing agent) are optionally added in any order, optionally in a solvent or solvent or solvent mixture, and the reactants are added before the addition of one or more mixture components and / or Or during. Precursors can often be combined with a suitable solvent or solvent mixture to form a solution for use in the methods disclosed herein. The first precursor and the second precursor solvent can be the same or different.

In some embodiments a mixture consisting of a first precursor, a second precursor, a first electron transfer agent, a second electron transfer agent, and optionally a solvent is formed, after which the mixture has a constant temperature for a time sufficient to cause the formation of nanocrystals. Heated to

In many embodiments, as described herein, in the reaction conditions of use, the first electron transfer agent is a strong electron transfer agent, and the second electron transfer agent is a weak electron transfer agent.

In another embodiment, a mixture consisting of a first precursor, a second precursor, a weak electron transfer agent, and optionally a solvent, is heated; The strong electron transfer agent is added to an amount sufficient to promote nucleation to a desired degree, and the reaction mixture is heated to a constant temperature for a time sufficient to induce the formation of nanocrystals.

In another embodiment, a mixture consisting of a first precursor, a weak electron transfer agent and optionally a first solvent is heated; Optionally in the second solvent (same or different than the first solvent) a second precursor is added to the heated mixture; The strong electron transfer agent is then added in an amount sufficient to promote nucleation and continues to be heated at a constant temperature for a time sufficient to cause nanocrystals to form.

In another embodiment, the mixture consisting of the first precursor, the second precursor, the strong electron transfer agent and optionally a solvent is heated to a temperature sufficient to promote nucleation crystal formation; The weak electron transfer agent is then added to the mixture to promote particle growth, and the reaction mixture is further heated to a constant temperature for a time sufficient to induce the formation of nanocrystals.

In another embodiment, the mixture consisting of the first precursor, the second precursor, and optionally the solvent is heated to a temperature sufficient for nucleation that may occur in the presence of a strong electron transfer agent, followed by a strong electron transfer agent and a weak electron transfer agent. The agent is added to the heated mixture at the same time and then heated to a constant temperature for a time sufficient to induce the formation of nanocrystals.

In a preferred embodiment the first electron transfer agent and the second electron transfer agent are different. In a particularly preferred embodiment the first electron transfer agent is a strong oxidant / reducing agent and the second electron transfer agent is a weak oxidant / reducing agent, as described herein. The first electron transfer agent and the second electron transfer agent may be independently a chemical oxidant / reducing agent or a negative electrode.

In another aspect, providing a mixture of a first precursor and a second precursor, wherein the first precursor and the second precursor have mismatched oxidation states; Adding a substoichiometric content of a strong electron transfer agent to the mixture in an amount sufficient to produce a desired degree of nucleation; Optionally heating the mixture to produce a desired degree of nucleation; Adding a weak electron transfer agent to the mixture in an amount sufficient to grow a desired degree of nanocrystals; And optionally heating the mixture for a time sufficient to grow the desired degree of nanocrystals.

In certain embodiments the strong and weak electron transfer agent is an oxidizing agent. In another embodiment, the strong and weak electron transfer agents are reducing agents. In some embodiments the strong electron transfer agent is an oxidant and the strong electron transfer agent is a reducing agent or vice versa.

In certain embodiments the strong electron transfer agent is provided in an amount sufficient to achieve the desired level of nucleation. In certain embodiments the weak electron transfer agent is provided in an amount sufficient to achieve the desired level of nanocrystal growth.

In some embodiments the first precursor or second precursor oxidation state can be changed to neutral by strong and weak electron transfer agents. In another embodiment, the first precursor and second precursor oxidation states are matched by the strong and weak electron transfer agent.

In another aspect, (a) providing a first mixture consisting of a first precursor, a second precursor, and optionally a solvent; (b) heating the first mixture at a sufficiently high temperature to promote nucleation in the presence of a strong electron transfer agent; (c) adding a strong electron transfer agent in an amount sufficient to promote nucleation to provide a second mixture; And (d) heating the second mixture at a constant temperature for a time sufficient to induce the formation of nanocrystals.

In some embodiments the method further comprises step (e) being a step of cooling the second mixture to stop further growth of the nanocrystals or diluting the reaction mixture to stop further growth. Optionally the method further comprises isolating the nanocrystals from the reaction mixture. The method may also further comprise the step of optionally adding a shell to the core nanocrystals or the isolated core nanocrystals of the reaction mixture.

In a preferred embodiment, the first mixture is maintained at a temperature high enough to promote nucleation during the addition of the strong electron transfer agent.

In a preferred embodiment the method further comprises the step of adding the weak electron transfer agent before, simultaneously and after addition of the strong electron transfer agent.

In some embodiments the first mixture consists of a weak electron transfer agent. In some such embodiments the weak electron transfer agent is provided by a solvent or by an unsaturated group present in one of the precursors.

In another embodiment step (c) further comprises the step of adding the weak electron transfer agent before, at the same time and after the addition of the strong electron transfer agent. In some such embodiments the weak electron transfer agent is added separately at the same time as the strong electron transfer agent.

In another embodiment step (c) further comprises adding the weak electron transfer agent after addition of the strong electron transfer agent. In some such embodiments the weak electron transfer agent is added after a sufficient time to allow nucleation crystal formation. In another embodiment the weak electron transfer agent is added after addition of the strong electron transfer agent but before completion of the nucleation step.

In certain embodiments the strong and weak electron transfer agent is an oxidizing agent. In another embodiment, the strong and weak electron transfer agents are reducing agents. In some embodiments the strong electron transfer agent is an oxidant and the strong electron transfer agent is a reducing agent or vice versa.

In some embodiments, the first precursor or the second precursor may change its oxidation state to neutral by strong and weak electron transfer agents. In other embodiments, the first precursor and second precursor oxidation states are matched by the strong and weak electron transfer agent.

In one aspect, the composition comprises (a) (i) a first precursor, (ii) a second precursor, (iii) a strong electron transfer agent, (iv) a weak electron transfer agent, and (v) optionally one or more solvents. Providing a mixture; And (b) heating the mixture to a constant temperature for a time sufficient to induce the formation of nanocrystals, wherein the first precursor and the second precursor have inconsistent oxidation states, and the weak electron carrier is coupled with a strong electron transfer agent. Is provided another, nanocrystal or population thereof.

In another embodiment, small amounts of 'matched' precursors can be used with large numbers of mismatched pairs suitable to maintain growth after nucleation. 'Matched' precursors can react immediately, leading to nucleation even without strong electron transfer agents. Once the 'matched' precursor is consumed, the weak electron transfer agent in the reaction mixture can be used to maintain growth without further nucleation. For example, such more reactive precursors of zinc, such as a small amount of diethyl ahyeonwa can be used with R ₃ P = Se, it may be combined with a large amount of Zn ^{2 +} precursor. For example, Zn ⁰ precursors such as diethylzinc can be used in sufficient amounts to induce a desired degree of nucleation. Then it proceeds quickly in a suitable reaction temperature of the one-consuming, and Zn ^{2 +} precursor is present in an amount sufficient for the growth of the desired degree, it is possible to generate the nanocrystals size desired in the presence of about an electron transfer. Nanocrystal size can be determined immediately during the growth phase by examining the fluorescence wavelength.

In one aspect, providing a mixture of a first precursor, a second precursor, a third precursor, and optionally a solvent; And heating the mixture to a constant temperature for a time sufficient to induce the formation of nanocrystals, the method of producing nanocrystals or populations thereof, wherein the first precursor and the second precursor have mismatched oxidation states, and The precursor has a coincidence oxidation state with the first precursor or the second precursor.

In some embodiments the mixture further comprises a weak electron transfer agent. In some such embodiments, the weak reducing agent may be added before, simultaneously, or after the second precursor addition.

In certain embodiments the weak electron transfer agent is an oxidizing agent. In another embodiment, the weak electron transfer agent is a reducing agent.

In some embodiments the nanocrystal formation reaction proceeds in a continuous flow reactor system. In another embodiment, the nanocrystal formation reaction proceeds in a batch reactor system.

In another aspect, (a) providing a first mixture consisting of a first precursor, a second precursor, and optionally a solvent; (b) heating the first mixture at a sufficiently high temperature to promote nucleation in the presence of a third precursor; (c) adding a third precursor in an amount sufficient to promote nucleation; And (d) heating the second mixture at a constant temperature for a time sufficient to induce the formation of nanocrystals, wherein the first precursor and the second precursor have mismatched oxidation states and the third precursor is the first precursor. Or a method of producing a core nanocrystal or a population thereof having a coincidence oxidation state with a second precursor.

In some embodiments of the methods described herein, the strong electron transfer agent may comprise tertiary phosphine, secondary phosphine, primary phosphine; Amines; Hydrazine; Hydroxyphenyl compound; Hydrogen; Hydrides; metal; Borane; Aldehydes; Alcohol; Thiols; It is a chemical reducing agent selected from the group consisting of reducing halides and polyfunctional reducing agents.

In some embodiments of the methods described herein the strong electron transfer agent is a chemical oxidant, for example: potassium nitrate; Hypochlorite, chlorite, chlorate, perchlorate and other similar halogen compounds; t-butyl hypochlorite; Halogen such as fluorine, chlorine, bromine and iodine; Permanganate and compounds; Cerium ammonium nitrate; Hexavalent chromium compounds such as chromic acid and dichromic acid and chromium trioxide, pyridinium chlorochromate (PCC), and chromate / dichromate compounds; Peroxide compounds; Tolene reagent; Sulfur oxides; Peroxysulfuric acid; Oxygen; ozone; Osmium tetraoxide; nitric acid; Nitrous oxide; Silver (I) compounds; Copper (II) compounds; Molybdenum (IV) compounds; Iron (III) compounds; Manganese (IV) compounds; N-methylmorpholine-N-oxides and other N-oxides; Trimethylamine N-oxide; 3-chloroperoxide benzoic acid, and other peroxide acids; Or peracetic acid.

In another embodiment of the methods described herein, the strong oxidant / reducing agent is the negative electrode. In some such embodiments the cathode is made of a material selected from the group consisting of platinum, silver and carbon.

In many embodiments of the process strong oxidants / reducing agents are added in sub-stoichiometric amounts. In some such embodiments, the additive strong reducing agent content may be less than about 1/10, about 1/10, less than about 2/10, less than about 3/10, or less than about 4/10 required for the stoichiometric reaction. The strong reducing agent content added in preferred embodiments may be about 1/10 required for stoichiometric reactions. In a preferred embodiment the strong oxidizer / reducing agent is added at a sufficient operating temperature at which the nuclear planet can proceed.

In certain embodiments of the process, while the strong oxidizer / reducing agent is added, the reaction mixture is heated to a temperature sufficient to promote nucleation and maintained at a constant temperature.

In some embodiments of the methods described herein the drug electron transfer agent may comprise tertiary phosphine, secondary phosphine, primary phosphine; Amines; Hydrazine; Hydroxyphenyl compound; Hydrogen; Hydrides; metal; Borane; Aldehydes; Alcohol; Thiols; It is a chemical reducing agent selected from the group consisting of reducing halides and polyfunctional reducing agents.

In some embodiments of the methods described herein the weak electron transfer agent is a chemical oxidant, for example: potassium nitrate; Hypochlorite, chlorite, chlorate, perchlorate and other similar halogen compounds; t-butyl hypochlorite; Halogen such as fluorine, chlorine, bromine and iodine; Permanganate and compounds; Cerium ammonium nitrate; Hexavalent chromium compounds such as chromic acid and dichromic acid and chromium trioxide, pyridinium chlorochromate (PCC), and chromate / dichromate compounds; Peroxide compounds; Tolene reagent; Sulfur oxides; Peroxysulfuric acid; Oxygen; ozone; Osmium tetraoxide; nitric acid; Nitrous oxide; Silver (I) compounds; Copper (II) compounds; Molybdenum (IV) compounds; Iron (III) compounds; Manganese (IV) compounds; N-methylmorpholine-N-oxides and other N-oxides; Trimethylamine N-oxide; 3-chloroperoxide benzoic acid, and other peroxide acids; Or peracetic acid.

In another embodiment of the methods described herein, the weak oxidant / reducing agent is a negative electrode. In some such embodiments the cathode is made of a material selected from the group consisting of platinum, silver and carbon.

In some embodiments of the methods described herein, the solvent is selected from the group consisting of hydrocarbons, amines, alkyl phosphines, alkyl phosphine oxides, carboxylic acids, ethers, furans, phosphonic acids, pyridine and mixtures thereof. In some such embodiments the solvent consists of a solvent mixture. In many embodiments the reaction mixture consists of at least one solvent, preferably at least one cosolvent.

In certain embodiments, solvent mixtures consisting of alkyl phosphine and alkyl phosphine oxides, for example TOP / TOPO, are used. In other embodiments, solvent mixtures consisting of amines, in particular secondary amines and alkyl phosphine or alkyl phosphine oxides, are used. For example, dioctylamine can be used in combination with TBP, TOP or TOPO. For example, examples of specific solvents include TOPO, TOP, tributylphosphine, decylamine, dioctylamine, oleylamine, octadecane, stulane, oleic acid, stearic acid, tetradecylphosphonic acid and mixtures thereof. Include.

In some embodiments the first precursor consists of metal atoms and the second precursor does not comprise metal atoms. In certain embodiments the first precursor in the heated reaction mixture contributes metal cations in core formation. In some such embodiments the first precursor may be a salt of Cd or Zn. In certain embodiments, the first precursor may be a halide, acetate, carboxylate, phosphonate, or oxide of Cd, Zn, In or Ga.

In some embodiments the second precursor in the heated reaction mixture contributes a chargeless non-metallic atom to the core formation. In certain embodiments, the second precursor may be a group of Formula R 3 P═X, wherein X is S, Se or Te, and each R is independently H or a C 1 -C 100 hydrocarbon group. In certain embodiments, the second precursor is tri-n- (butylphosphine) selenide (TBP = Se), (tri-n- (octylphosphine) selenide (TOP = Se), (butylphosphine) sulfide (TBP = S), tri-n- (octylphosphine) sulfide (TOP = S), (butylphosphine) telluride (TBP = Te) or tri-n- (octylphosphine) telluride (TOP = Te )to be.

In many embodiments no precursor is present other than the first and second precursors.

In certain embodiments, a third precursor is present in addition to the first precursor and the second precursor. In some such embodiments the third precursor provides a reactive species having a coincidence oxidation state with the first precursor or the second precursor. In some such embodiments the third precursor provides neutral metal species. For example, the third precursor may be a dialkylmetal precursor (eg, Et ₂ Zn or Me ₂ Cd) that provides a neutral metal species, such as Zn0 or Cd0. In another embodiment, the third precursor contributes a charged non-metal atom to the core formation. For example, a third precursor S ^{2 -} it is possible to provide ^a-Se or ^2.

Nanocrystalline cores can be made of any suitable metal and nonmetallic atoms known to form semiconductor nanocrystals, as described herein. In certain embodiments the core may consist of CdSe, CdS, CdTe, InP, InAs, ZnS, ZnSe, ZnTe, GaP or mixtures thereof.

In another aspect, provided herein is a nanocrystalline core produced by one of the methods described herein.

In the methods described herein, the heating step (s) is performed at a temperature sufficient to induce discrete homogeneous nucleation temporarily to form a monodisperse population of individual nanocrystals. Typically the heating step is carried out in the range of about 150-350 ° C., more preferably at about 220-350 ° C. In addition, mixing and heating steps can be performed in a vessel discharged and filled and / or washed with an inert gas such as nitrogen. The filling can be periodic and can also be made after continuous washing for a set period of time. In some embodiments, for example, the mixing step can include cooling to, for example, a temperature range of about 50-150 ° C. prior to exposure to the first or second reducing agent.

It will be understood that the above ranges are exemplary only and are not intended to be limiting in any way as the actual temperature will vary depending on the relative stability of the reducing agent, precursor, ligand and solvent. Somewhat higher or lower temperatures may be suitable for certain reactions. Determination of appropriate time and temperature conditions for providing nanoparticles is within the skill level of the art.

The nanocrystal forming reaction described herein is advantageously carried out with the exclusion of oxygen and moisture. In some embodiments the reaction is carried out in an inert atmosphere, for example in a dry box. Solvents and reagents are also typically refined to remove moisture and oxygen and other impurities, and are handled and transported using methods and apparatus designed to minimize moisture and / or oxygen exposure. In addition, mixing and heating steps may be performed in a vessel vented and filled and / or washed with an inert gas such as nitrogen. The filling can be periodic and can also be made after continuous washing for a set period of time. Sufficient solvent and reagent purity is required to achieve the desired shell forming reaction and not to introduce strong reducing agents into the reactants.

The solvent in these reactions sometimes consists of amines and includes hexadecylamine as a typical example, and dioctylamine as another suitable example. Amine solvents are difficult to purify sufficiently for use in such particularly sensitive systems because of the high sensitivity to moisture and air that the reaction components and products exhibit in ZnTe nanocrystal core reactions. Nanocrystal preparation is typically carried out in an inert atmosphere with purification solvents and reagents, but special surroundings and steps are required for amine solvent purification used to prepare ZnTe nanocrystals. The amine used as solvent for this reaction is placed in a flask that is repeatedly washed and filled with anhydrous inert atmosphere. Anhydrous NaOH or KOH, vacuum dried above 100 ° C., is added to the amine solvent and the suspension is stirred for at least 8 hours. In an inert atmosphere, the amine is filtered to remove solids, after which the amine is distilled in an inert atmosphere and stored in an inert atmosphere.

Zn ^{+ 2,} and Te is ^0, because it is difficult to freely reduced in the solution to the steel without a reducing agent added to ZnTe nucleation difficult synthesis can Yale particularly good embodiment for implementing the method disclosed herein. In the absence of a strong electron transfer agent in the ZnCl ₂ and Bu ₃ P = Te mixture, no nucleation is observed (ie no particles are formed). This is due to a mismatch between the oxidation states of the tellurium and zinc precursors used: Zinc chloride is a +2 oxidation state under the reaction conditions, but the tellurium precursor Bu ₃ P = Te gives Te ⁰ under the reaction conditions. The uncharged delurium species cannot be easily reacted with Zn ^+2, and it seems that a reduction of Te ⁰ to Te ^{2 −} or a reduction of Zn ⁺² to Zn ⁰ is necessary for the reaction to occur. With the addition of a strong electron transfer agent (ie a reducing agent) the reaction may possibly occur by reduction of Te ⁰ to Te ^{2 −} . In the practice provided in Example 1, lithium triethylboron hydride (LiEt ₃ BH) is used as the strong nucleation-promoting reducing agent. In this process, the oleic acid acts as a reducing agent about, even when added LiEt ₃ BH considerably less than stoichiometric levels should continue to maintain growth after the LiEt ₃ BH consumption.

In addition to improved control over particle size and yield, another advantage of the method lies in the scale and manufacturing capacity improvements inherent in the examples disclosed herein. Most current methods for the synthesis of zinc chalcogenide particles are Zn ^0, which generates a significant amount of gas. The use of diethylzinc as the source adds variability and limits manufacturing capacity. Due to their resistance to reduction when zinc salts are used, it is generally necessary to use strong reducing agents accompanied by gas-emission. The method allows sub-stoichiometric use of such reducing agents. In the examples below, the content of the additive strong reducing agent is one tenth of what is required for the stoichiometric reaction. In addition, as described above, the present method relies less on things such as the rate of addition of the nanocrystal precursors and thus increases the nanocrystal synthesis reliability since the reducing agent provides the rate reaction rate.

Methods of Using Nanocrystals Provided herein

Core nanocrystals prepared according to the methods provided herein can be used to form core / shell nanocrystals by applying conditions known to those skilled in the art.

In addition, nanocrystals prepared according to this method can be further modified by altering the ligands present on the surface of the nanocrystals, as known in the art. For example, ligands on the surface of nanocrystals can be exchanged with other ligands to introduce new properties such as water solubility of the nanocrystals. Methods of making nanocrystals with water soluble ligands are well known in the art. For example, Adams, et al. Provide a process for preparing water soluble nanocrystals by coating an amphoteric polymeric material on a hydrophobic nanocrystal surface. US Patent No. 6,649,138. The process starts with hydrophobic nanocrystals, for example nanocrystals with hydrophobic ligands such as trialkylphosphine oxides, alkylamines, or alkylphosphonic acids as described herein. An outer layer consisting of multiple amphoteric dispersion molecules consisting of at least two hydrophobic regions and at least two hydrophilic regions is added thereto. In some embodiments the amphoteric polymer consists of an acrylic or methacrylic acid polymer, which converts the acrylic acid group to an amide with a hydrophobic amine group such as a monoalkylamine or a dialkylamine having at least 4-12 carbons per alkyl group; And free carboxylic acid groups for promoting water solubility. Such and other suitable amphoteric dispersants suitable for this use are described in Adams column 14-18, which is incorporated herein by reference.

Thus, in one aspect, the disclosed examples provide nanocrystals described herein having an amphoteric dispersant coating described in Adams et al. Thus, the nanocrystals become water soluble, and they are suitable for use in a number of methods known to be used, such as quantum dots. Soluble nanocrystals and methods for their preparation are disclosed herein.

Several methods of modifying nanocrystals are described in Naasani, et al., US Pat. No. 6,955,855 and US Pat. No. 7,198,847. These methods include coating nanocrystals with small amounts of water soluble ligands, for example imidazole-containing compounds such as dipeptides. Suitable 'imidazole-containing compounds are described in column 7 of the Naasani patent of' 855.

As used herein and in the claims, an 'imidazole-containing compound' means at least one imidazole that can be used to bind a metal, such as zinc or other metal cation, or a substrate containing a cation of this kind. A molecule having a group (eg imidazole ring) is meant. In part terms, preferably at least one imidazole moiety is at a terminal position in terms of the structural aspect of the molecule. In general, imidazole ring nitrogens often function as coordinating ligands for operatively binding metal ions such as zinc or cadmium. In one embodiment, the imidazole-containing compound consists of one amino acid or two or more amino acids bound together (eg, known in the art as 'peptidyl' or 'oligopeptide'), but they are not limited Cytidine, carnosine, anserine, valene, homocarnosine, 1-methylhistidine, 3-methylhistidine, imidazolysin, imidazole-containing ornithine (e.g., (beta)-( 2-imidazolyl) -L (alpha) alanine), carcinin, histamine and the like. Imidazole-containing amino acids can be synthesized by methods known in the art (see, eg, Stankova et al., 1999, J. Peptide Sci. 5: 392-398, which is incorporated herein by reference).

As used herein, the term "amino acid" means a compound containing at least one amine group and at least one carboxyl group. As is known in the art, amine groups may be present at adjacent positions of the carboxyl groups or at any position along the amino acid molecule. In addition to at least one imidazole moiety, the amino acid may comprise one or more additional reactive functional groups (eg, amino, thiol, carboxyl, carboxamide, etc.). The amino acid may be a natural amino acid, a synthetic amino acid, a modified amino acid, an amino acid derivative, an amino acid precursor, in D (right turn) form, or L (left turn) form. Exemplary derivatives include, but are not limited to, functions as coatings that maintain amino acid function with the coatings described herein (eg, impart water solubility, sufficient buffering, fluorescence intensity in the pH range between about 6 to about 10). And N-methylated derivatives, amides or esters, as known in the art, having one or more reactive functional groups used to operatively associate with molecular probes. Amino acids of the above-described amino acids can be used in the preferred embodiments, and preferred amino acids can be used separately in the compositions of the disclosed embodiments, excluding amino acids other than the preferred amino acids. Histidine is a particularly suitable imidazole-containing compound for coating functionalized, fluorescent nanocrystals.

Ligands on the nanocrystals disclosed herein can be crosslinked for improved stability and improved properties of the composition being nanocrystals. The surface coating of the ligands on the nanocrystals disclosed herein can be crosslinked by applying the method described by Naasani using various crosslinkers. Preferred crosslinkers that may be used in the disclosed examples include those described by Naasani et al., Including tris (hydroxymethyl) phosphine (THP) and tris (hydroxymethyl) phosphinic acid-propionate (THPP). . Nanocrystals with crosslinked water soluble ligand coatings are another example disclosed herein.

Nanocrystals prepared according to this method can be used in molecular tracking methods known in the art. For example, they can be linked to various target molecules according to known methods. Usually they are linked to affinity molecules or used for further transformation. This additional transformation introduces a selective target (or cargo) molecule of interest, such as an antibody or other specific affinity molecule, to the nanocrystal surface. Methods of attaching such affinity molecules to fluorescent carriers are known in the art and can be readily applied in the present invention. For example, US Pat. No. 6,423,551 describes bi-functional agents, which can be used to link nanocrystalline surfaces to target molecules and to nanocrystalline surfaces. This method is also used to introduce multiple functional molecules or layers to the nanocrystalline surface, where the functional molecules provide new surface properties to the nanoparticles, such as water-dispersibility. In some embodiments modified nanocrystals are provided for affinity molecule attachment to detect a desired target compound, cell or cell organelle.

Modified nanocrystals can be linked to an affinity molecule and used in methods of tracking, identifying or localizing a molecule of interest to which an affinity molecule can be bound, to show the presence of a molecule of interest and the point of distribution or localization. Nanocrystals can also be used in binding experiments to visualize the molecular distribution recognized by affinity molecules. If the target compound is identified, the selection of appropriate affinity molecules is within the ordinary level in the art; For example, conventional methods can be applied and used to generate or identify antibodies suitable for specifically binding to a target molecule of interest. Thus, an antibody can be linked to the nanocrystals disclosed herein, and thus can be used to identify the presence, position or movement of a target compound as a fluorescent label using the nanocrystal. In some embodiments, a method of identifying or tracking a target molecule is provided, which optionally allows linking a suitable affinity molecule that binds the target molecule to the nanocrystal and allowing the affinity linked nanocrystal to contact the target molecule. It consists of steps. Tracking or detection can be accomplished using conventional methods of tracking fluorescent label residues using a fluorescent image processing system, microscope or camera.

In some embodiments, functional nanocrystals are provided as described herein. Nanocrystals can be linked with affinity molecules selected to specifically bind to the target of interest. Nanocrystals, optionally linked to affinity molecules, can be combined with target molecules of interest to form fluorescent label complexes. Target molecules of interest include proteins, enzymes, receptors, nucleic acids, hormones and cell surface antigens specific for certain types of cells.

Many of the techniques described or referenced herein can be understood and applied according to conventional methodology by those skilled in the art. Procedures involving the use of commercially available kits and reagents are generally carried out in accordance with manufacturer-supplied protocols and / or parameters unless specifically noted.

The discussion of the generic methods given herein is for illustrative purposes only. Other alternative ways and embodiments will be apparent to those skilled in the art upon reviewing this disclosure.

The group of items connected by the conjunction 'or' should not be interpreted mutually exclusive of the group, but rather should be understood as 'and / or' unless otherwise indicated. Although the items, elements, or components disclosed herein are described and claimed in the singular, the plural forms also fall within the scope unless explicitly limited to the singular.

All patents, patent applications, patent publications, articles and other references mentioned herein are incorporated herein by reference in their entirety.

As used in the claims and specification, the words 'comprises' (and any constructive form such as 'constitutes' and 'consists' and 'consists of'), 'having' (and 'having' and 'having') Such as having any), 'comprising' (and any including form, such as 'comprising' and 'comprising'), or 'containing' (and any containing form such as 'including' and 'containing') Are included or open and do not exclude additional, non-listed elements and method steps.

The following examples are provided as further guidance on the use and use of the methods disclosed herein and should not be construed as limiting the various embodiments of these methods.

Example  One

ZnTe  Core Nanocrystals Formation

All reagents used are anhydrous and all operations are performed in an inert atmosphere except as noted. Zinc chloride (685 mg, 5 mmol) was weighed in a 250 mL round bottom flask with two 14/20 joints and a round glass stopcock. Dioctylamine (35 mL) and oleic acid (1.6 mL, 5 mmol) were added and the flask was equipped with a magnetic stir bar. The glass stopcock was lubricated and closed, one glass joint was closed with a rubber septum, and one joint was equipped with a stainless steel thermocouple connected to a temperature controller to adjust the adapter and a 180 W heating mantle. The flask was placed in a heating mantle and the stopcock was connected to the flowing nitrogen source and opened. The temperature controller was set to heat the flask to 115 ° C. and maintained at that temperature with gentle stirring until the zinc salt dissolved. The flask was then discharged and refilled with nitrogen three times.

The temperature was then raised to 230 ° C., at which time 15 mL of 1 M tellurium solution in tributylphosphine was added via syringe through the septum and the flask contents cooled slightly. When the temperature returned to 220 ° C., 1 mL of 1M triethylboride hydride solution in tetrahydrofuran was added quickly through the syringe. The temperature was raised to 240 ° C. and maintained for 15 seconds to 30 minutes until the desired particle size was reached, followed by rapid cooling.

Claims (39)

In the method of generating a population of nanocrystals,
A first precursor; A second precursor having a mismatched oxidation state with the first precursor; A strong electron transfer agent in an amount sufficient to produce a desired level of nucleation; And a weak electron transfer agent different from the strong electron transfer agent; And heating the mixture to a constant temperature for a time sufficient to induce formation of the population of nanocrystals. The method of claim 1, wherein the nanocrystal formation reaction occurs in a batch reactor system. The method of claim 1, wherein the nanocrystal formation reaction proceeds in a continuous flow reactor system. The method of claim 1, wherein the first precursor or second precursor oxidation state is changed to a neutral state by the strong and weak electron transfer agent. The method of claim 1, wherein the oxidation states of the first precursor and the second precursor are matched by a strong and weak electron transfer agent. The method of claim 1, wherein the strong and weak electron transfer agent is an oxidant. The method of claim 1, wherein the strong and weak electron transfer agent is a reducing agent. The method of claim 1, wherein the one or more precursors and the electron transfer agents are heated prior to mixing. The method of claim 6, wherein the strong and weak reducing agent is a tertiary phosphine, secondary phosphine, primary phosphine, amine, hydrazine, hydroxyphenyl compound, hydrogen, hydride, metal, borane, aldehyde, alcohol, thiol , Reductive halide, polyfunctional reducing agent, and mixtures thereof. 8. The method of claim 7, wherein the strong and weak oxidizing agent comprises: potassium nitrate; Hypochlorite, chlorite, chlorate, perchlorate and other similar halogen compounds; t-butyl hypochlorite; Halogen such as fluorine, chlorine, bromine and iodine; Permanganate and compounds; Cerium ammonium nitrate; Hexavalent chromium compounds such as chromic acid and dichromic acid and chromium trioxide, pyridinium chlorochromate (PCC), and chromate / dichromate compounds; Peroxide compounds; Tolene reagent; Sulfur oxides; Peroxysulfuric acid; Oxygen; ozone; Osmium tetraoxide; nitric acid; Nitrous oxide; Silver (I) compounds; Copper (II) compounds; Molybdenum (IV) compounds; Iron (III) compounds; Manganese (IV) compounds; A method of producing a population of nanocrystals selected from the group consisting of N-methylmorpholine-N-oxide, 3-chloroperoxide benzoic acid, peroxide, peracetic acid, and mixtures thereof. The method of claim 1, wherein the strong reducing agent is the negative electrode. The method of claim 1, wherein the weak reducing agent is a negative electrode. The method of claim 1, further comprising a solvent in the mixture. The method of claim 13, wherein the solvent is selected from the group consisting of hydrocarbons, amines, alkyl phosphines, alkyl phosphine oxides, carboxylic acids, ethers, furans, phosphonic acids, pyridine and mixtures thereof. The method of claim 13, wherein the solvent is a coordinating solvent. The method of claim 1, further comprising the step of cooling the mixture. The method of claim 1, wherein the first precursor is selected from the group consisting of salts of Cd, Zn, Ga, In, Al, Pb, Ge, Si, Hg, Mg, Ca, Sr, Ba, and mixtures thereof. Method of Generating Nanocrystals. The population of nanocrystals according to claim 1, wherein the second precursor is R ₃ P═X, wherein X is S, Se or Te, and each R is independently H or a C ₁ -C ₂₄ hydrocarbon group. Way. The method of claim 1, wherein the second precursor is S, Se, or Te dissolved in alkylphosphine, alkenes or amines. The method of claim 1, wherein the second precursor is dissolved in tributylphosphine or trioctylphosphine. The method of claim 1, further comprising: isolating a population of nanocrystals; And adding a shell to each population of nanocrystals. The method of claim 21, wherein the shell material is ZnS, ZnSe, ZnTe, CdS, CdSe, CdTe, HgS, HgSe, HgTe, MgS, MgSe, MgTe, CaS, CaSe, CaTe, SrS, SrSe, SrTe, BaS, BaSe, BaTe, and mixtures thereof. The nanomaterial of claim 21 wherein the shell material is selected from the group consisting of GaN, GaP, GaAs, GaSb, InP, InAs, InSb, AlS, AlP, AlSb, PbS, PbSe, Ge, Si, and mixtures thereof. How to Create a Decision Group. The method of claim 1, wherein the first or second precursor functions as a weak electron transfer agent. The method of claim 1, wherein the weak electron transfer agent is provided in an amount sufficient for the desired nanocrystal growth. In the method of producing nanocrystals,
Providing a mixture of the first precursor and the second precursor, wherein the first precursor and the second precursor have mismatched oxidation states; Adding a substoichiometric content of a strong electron transfer agent to the mixture in an amount sufficient to produce a desired degree of nucleation; Optionally heating the mixture to produce a desired degree of nucleation; Adding a weak electron transfer agent to the mixture in an amount sufficient to grow a desired degree of nanocrystals; And optionally heating the mixture for a time sufficient to grow the desired degree of nanocrystals. The method of claim 26, wherein the nanocrystal formation reaction occurs in a batch reactor system. The method of claim 26, wherein the nanocrystal formation reaction proceeds in a continuous flow reactor system. 27. The method of claim 26, wherein the first precursor or second precursor oxidation state is changed to a neutral state by the strong and weak electron transfer agent. 27. The method of claim 26, wherein the oxidation states of the first precursor and the second precursor are matched by a strong and weak electron transfer agent. The method of claim 26, wherein the strong and weak electron transfer agent is a reducing agent. The method of claim 26, wherein the strong and weak electron transfer agent is an oxidant. In the method of producing nanocrystals,
Providing a mixture consisting of a first precursor, a second precursor, and a third precursor; And heating the mixture to a constant temperature for a time sufficient to induce the formation of nanocrystals, wherein the first precursor and the second precursor have mismatched oxidation states, and the third precursor is associated with the first precursor or the second precursor. A method of producing nanocrystals having a coincidence oxidation state. The method of claim 33, wherein the mixture further comprises a weak electron transfer agent. The method of claim 34, wherein the weak electron transfer agent is a reducing agent. 35. The method of claim 34, wherein the weak electron transfer agent is an oxidant. The method of claim 33, wherein the third precursor is added in an amount sufficient to promote the desired degree of nucleation. The method of claim 34, wherein the weak electron transfer agent is added in an amount sufficient to promote the desired degree of nanocrystal growth. 34. The method of claim 33, further comprising: forming a pre-mix containing the first precursor and the second precursor before adding the third precursor; And optionally heating the pre-mix before adding the third precursor.

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