Crystal Engineering to Avoid Pairing Dipolar Moments: The Case of 5-Nitrouracil, a Highly Polarizable Molecule

Abstract

5-nitrouracil is a polarizable molecule with a permanent electric dipole moment. Its molecular properties caught the attention of physicists working on nonlinear optics or optoelectronics, but the translation of the molecular assets to the crystalline solid has not been straightforward. This review compares all the known crystal structures incorporating the neutral or ionic 5-nitrouracil, or the two species concomitantly, discussing the effect of the packing in the optimization of the crystalline optical properties. Two new centrosymmetric 5-nitrouracilate salts are also reported for the first time, showing extensive hydrogen bonding between anions and cations. This review also gathers data from nonlinear optical measurements of non-centrosymmetric crystals and thermal stabilities of known polymorphs, showing that a neutral 5-nitrouracil molecule in acentric crystalline environment allows efficient blue-light generation.

1. Introduction

In 1961, P. Franken et al., at the University of Michigan, focused a pulsed ruby laser (λ = 694 nm) into a quartz crystal. Using 3 joules of energy in the red pulse, they generated a few nanojoules of blue light (λ = 347 nm) [1]. This experiment sets the birth of Nonlinear Optics. When Nonlinear Optical (NLO) materials are subjected to intense laser light, dramatic changes may occur in the frequency, phase and polarization of the incoming light.

The nonlinear interaction between the electromagnetic field of the light and of the charge distribution of the crystal originates several phenomena including frequency-mixing processes, such as second-harmonic generation (SHG) (or frequency doubling, generation of light with a doubled frequency—half the wavelength) and third-harmonic generation (THG) (generation of light with a tripled frequency—one-third the wavelength) [2]. It is the second-harmonic generation that allows the expansion of the laser’s spectra up to the ultraviolet, using inorganic crystals such as KTiOPO₄ or LiNbO₃, well-established commercially available materials.

However, non-linearity can also be found in organic compounds such as Rentzepis and Pao, from the Bell laboratories, showed in 1964, by making the first observation of SHG in an organic material, namely in benzapyrene and benzanthracene [3]. Foreseeing applications in optical devices, SHG organic crystals have to provide high SHG efficiency, high transparency, adequate birefringence to allow phase-matching and high damage threshold. The materials should also be easy to grow into large single crystals and be chemical and physical stable [4].

An approach that has been proven successful to obtain high NLO responses is the use of molecules with high dipolar moments [5,6], namely, push–pull organic chromophores, molecules consisting of an electron donor (D) group and an electron-withdrawing (A) group connected via a π-conjugated organic backbone. Para-nitroaniline is the archetypal model of a D-π-A chromophore: NH₂ is the donor group, NO₂ is the acceptor group both substituted across an aromatic benzene ring. It shows an exceptionally strong charge-transfer character associated with a large polarizability and hyperpolarizability [7,8,9]. However, exceptional molecular properties do not often translate into the crystalline form; the polar nature of the push-pull chromophores leads to a tendency to self-assemble in centrosymmetric structures driven by dipole-dipole interactions, hindering their applicability [10].

How can we circumvent such tendency?

One way is to incorporate dipolar chromophores into a polymer host [11] and apply a strong electric field while heating and cooling (electric field poling). The NLO chromophores show a preferential orientation along the field direction [12] Another approach is a controlled crystallization, using counter-ions or co-formers that induce an acentric assembling. Single crystals provide a high degree of ordering as well as a large concentration of chromophores per unit volume and, by using birefringence, phase matching can be achieved [13].

The relation between the macroscopic and the molecular optical response is not straightforward because of interactions between neighboring molecules. However, in a first approximation, the bulk response can be explained by the so called oriented-gas model: molecules are considered to be frozen and non-interacting and an additivity approach is used to account for the crystal nonlinearities [14]. Zyss and Oudar, in 1982 [15], perfected the model by considering the mutual polarization effects of neighboring molecules as local-field corrections. For compounds in which molecules/ions interactions are too strong to be considered a correction, a supermolecule approach can be used. In this approach a cluster containing the main intermolecular interactions takes the role of a single molecule in the oriented gas model [16]. When calculating the macroscopic susceptibility from the molecular/supermolecular hyperpolarizability tensor, one often has also to consider the transformation of molecular reference frame to the crystal reference frame, to consider the symmetry of the molecular assembling and even further simplifying symmetry conditions (like the Kleinman symmetry—all three indices in the hyperpolarizability tensor are universally interchangeable [17]).

Jerphagnon, in 1971, was the first to note that a crystalline form of 5-nitrouracil showed a NLO response comparable to that of the inorganic barium-sodium niobate [18].

5-nitrouracil (5NU) can be considered a cyclic urea derivative, with a strong electron-accepting group (the nitro group), see Figure 1. Further optical studies were presented in conferences in the eighties, but it was Zyss and co-workers that performed a thorough study of the acentric form of 5NU, reporting in 1993 [19] the efficient non-linear response of 5NU; it permits efficient blue-light generation from a pulsed, 1.34-mm Nd³⁺:YAG laser.

Zyss and co-workers reported that 5NU exhibits a transparency interval of circa 1000 nm, a nonlinear optical coefficient of 8.7 pm/V, a laser damage threshold (limit at which a material will be damaged by a laser given the power per area) of 3 GW/cm² (at 1.06 μm wavelength, pulse duration −10 ns). Phase matching is also observed with narrow angular acceptance. Furthermore, 5-Nitrouracil crystals show excellent optical quality and can be grown by a thermal-gradient transport method based on natural convection. The crystals exhibit excellent air conservation.

Table 1. Comparison of 5NU with some well-known mineral and organic crystals; adapted with permission from Ref. [19], 1993, Optica Publishing Group.

Compound	LiNbO3 [20,21]	KTiOPO4 [22,23]	Urea [24,25]	POM [26] 3-Methyl-4-nitropyridine-1-oxide	5NU [19]
Transparency range (nm)	330–6000	350–4500	230–1440	450–1550	410–1550
Symmetry	Trigonal	Orthorhombic	Tetragonal	Orthorhombic	Orthorhombic
Class	3m	mm2	42m	222	222
Nonlinear-optical coefficients (at 1.06 mm)	d15= 4.4 pm/V d22 = 3.6 pm/V d33 = −47 pm/V	d31= 6.5 pm/V d32 = 5.0 pm/V d33 = 13.7 pm/V d15 = 6.5 pm/V d33 = 7.6 pm/V	d14 = 1.4 pm/V	d14 = 10 pm/V	d14 = 8.7 pm/V
Damage threshold	(40 ns) 0.69, >1 GW/cm2	(l ns) 1.06, 15 GW/cm2	(10 ns) 1.06, 0.355, 30 MW/cm2	(10 ns) 1.06, 200 MW/cm2 0.532, 20 MW/cm2	(10 ns) 1.06, 3 GW/cm2 0.532, 1 GW/cm2
Growth Technique	Czochralski method Tm = 1260 °C	Temperature gradient transport	Temperature variation Tm = 135 °C	Temperature variation Tm = 136 °C	Temperature gradient transport
Some remarkable properties	Good air conservation	Excellent air conservation	Hygroscopic	Closed cell with index liquid	Excellent air conservation

shows a comparison of 5NU with some well-known mineral and organic crystals [19] sanctioning 5NU as one of the best nonlinear organic crystals.

Besides the NLO physics community, 5NU also has relevance to the biological and pharmaceutical sciences [27,28,29], reported for example as an active chemotherapeutic and mutagenic agent [30,31]. Its derivatives have shown antibacterial activity, antitumor activity on leukemia cells and inhibitory effects on macrophage [32].

At present, three crystalline forms of 5NU are known, two centric and one acentric. Several other co-crystals, salts and solvates have also been studied. This review is organized as follows: a brief section with the essential theoretical background; a succinct section for methods used in structure determination and ab-initio calculations; a description and comparison of structural feature of 5NU polymorphs with an emphasis on the acentric, second-harmonic generator; a description of co-crystals and solvates containing the 5NU neutral form; a discussion of L-histidinium 5-nitrouracilate, a charge transfer transparent compound; a description of guanidine derivatives 5NU, including two new structures; and a description of other 5NU salts. In the conclusion section, we explore the lessons learned by the collection of 5NU compounds, that have been reported in the literature and reviewed in this paper.

2. Theoretical Background

There are excellent textbooks on nonlinear optics to which the reader is referred if he/she wants to dive deeper into the field [2,33]. We will briefly outline some concepts for the reader to follow.

In the case of conventional (i.e., linear) optics, the induced polarization, $\mathit{P}\left(t\right)$ (electric dipole moment per unit volume), depends linearly on the electric field strength $\mathit{E}\left(t\right)$ in a manner that can often be described by the relationship:

$$\mathit{P}\left(t\right)={\epsilon }_0{\chi }^{\left(1\right)}\mathit{E}\left(t\right)$$

(1)

where the constant of proportionality χ⁽¹⁾ is known as the linear susceptibility and e₀ is the permittivity of free space. For nonlinear optical phenomena, polarization is conveniently expressed as a sum of a linear term and nonlinear terms (Taylor series expansion of the dielectric polarization density P(t) at time t in terms of an electric field E(t) varying in time and space):

$$P\left(t\right)=P_l\left(t\right)+P_{nl}\left(t\right)={\mathsf{\epsilon }}_0\left({\mathsf{\chi }}^{\left(1\right)}E\left(t\right)+{\mathsf{\chi }}^{\left(2\right)}{E}^2\left(t\right)+{\mathsf{\chi }}^{\left(3\right)}{E}^3\left(t\right)+\dots \right)$$

(2)

The quantities χ⁽²⁾ and χ⁽³⁾ are known as the second- and third-order nonlinear optical susceptibilities, respectively. In general, χ⁽ⁿ⁾ is an (n + 1)-th-rank tensor representing both the polarization-dependent nature of the interaction and the symmetries of the nonlinear solid.

Using Maxwell’s equations and linear refractive index n²(ω) =1+ χ⁽¹⁾, one can write:

$$-{\nabla }^{2}E\left(r, t\right)+\frac{n{\left(\omega \right)}^2}{c^2}\frac{{\partial }^{2}E\left(r, t\right)}{{\partial }^{2}t}=-{\mathsf{\mu }}_0\frac{{\partial }^2{P}_{nl}\left(r, t\right)}{{\partial }^{2}t}$$

(3)

Some (anisotropic) materials have a refractive index that depends on the polarization and propagation direction of the light. These are called birefringent.

The microscopic polarization corresponds to the induced dipole moment which can be expanded as function of applied electric field:

$$\mathsf{\mu }={\mathsf{\mu }}_0+\alpha \mathit{E}+\frac{1}{2!}\beta {\mathit{E}}^2+\frac{1}{3!}\gamma {\mathit{E}}^3$$

(4)

where μ₀ is the permanent dipole moment of the molecule. The coefficients α, β and γ are the linear polarizability, second-order nonlinear polarizability (or first hyperpolarizability) and third-order nonlinear polarizability (or second hyperpolarizability), respectively.

The first hyperpolarizability, β, is proportional to the difference between the ground and excited state dipole moments. Going from the molecular properties to the solid response, one has to consider the symmetry of the environment where the molecules/ions are placed and the effect of the environment on the molecular charge distribution. The mathematical relationship is:

$$d_{IJK}=\frac{1}{2}{\chi }_{IJK}^{\left(2\right)}=\frac{N}{V}{f}_I{f}_J{f}_K\frac{1}{N_g}{\displaystyle \sum }_s{\displaystyle \sum }_{ijk}cos{\theta }_{Ii}^{\left(s\right)}cos{\theta }_{Jj}^{\left(s\right)}cos{\theta }_{Kk}^{\left(s\right)}\times {\beta }_{ijk}^{\left(s\right)}$$

(5)

where I, J, K are the crystal axes, N_g is the number of equivalent positions in the unit cell of volume V that has N molecules (or supermolecules), f_I (ω) are local field factors for each crystal axis I, and the cosine product terms represent the transformation from the molecular reference frame to the crystal frame. The equivalent positions are labeled by the index s. The local field factors are essentially a correction for the difference between an applied field that would be felt by the molecule (or supermolecule) in vacuum and the local field within the solid.

The symmetry of the crystal reduces substantially the non-zero elements of the $d_{IJK}$ array. For instance, for the 222 symmetry the array of nonlinear coefficients is reduced to:

$$\left(\begin{array}{ccc}0& 0& 0\\ 0& 0& 0\\ 0& 0& 0\end{array} \begin{array}{ccc}{d}_{14}& 0& 0\\ 0& d_{25}& 0\\ 0& 0& d_{36}\end{array}\right)$$

(6)

The components of the polarization vector are easily related to the electric field components:

$$\left\{\begin{array}{c}{P}_x=2d_{14}{E}_y{E}_z\\ P_y=2d_{25}{E}_x{E}_z\\ P_z=2d_{36}{E}_x{E}_y\end{array}\right.$$

(7)

Further symmetry conditions, such as the Kleinman symmetry [17] conditions (valid when the applied frequencies are much smaller than any resonant frequencies and that assures interchangeability of all n indices in the rank n tensor describing the macroscopic nonlinear polarizability of a system) impose that d₁₄ = d₂₅ = d₃₆.

3. Materials and Methods

3.1. Synthesis

Guanidinium 5-nitrouracilate monohydrate: Guanidine carbonate (Aldrich 99%, 0.5 mmol) and 5-nitrouracil (Aldrich, 98%, 1 mmol) were dissolved in 100 mL of boiling water. The solution was left to evaporate under ambient temperature and pressure. Colorless prismatic single crystals grew from the solution by slow evaporation over a period of a few weeks.

Phenylguanidinium 5-nitrouracilate monohydrate: Phenylguanidine carbonate (Aldrich 99%, 0.5 mmol) and 5-nitrouracil (Aldrich, 98%, 1 mmol) were dissolved in 80 mL of boiling water. Small transparent and yellow crystals were deposited after a few weeks.

3.2. Structure Determination

For the determination of crystal structure by X-ray diffraction, small single crystals were glued to a glass fiber and mounted on a Bruker APEX II diffractometer. Diffraction data was collected at room temperature 293(2) K using monochromated MoKα (λ = 0.71073 Å). Absorption corrections were made using SADABS [34]. The structure was solved by direct methods using SHELXS-97 [35] and refined anisotropically (non-H atoms) by full-matrix least-squares on F² using the SHELXL-97 program [35]. The H positions of the NH2 groups of the guanidinium ion were refined using the shelxl instruction HFIX 93. PLATON [36] and Mercury [37] were used for visualization and analysis of the structure. Atomic coordinates, thermal parameters and bond lengths and angles have been deposited at the Cambridge Crystallographic Data Centre (CCDC). Any request to the CCDC for this material should quote the full literature citation and the reference number CCDC 2222685–2222686.

3.3. Theoretical Methods

The calculation of the permanent dipole moment of the 5NU-5NU⁻ pair was performed with the GAMESS US package [38] within Density Functional Theory (DFT) using the Range-separated functional CAM-B3LYP [39] (Coulomb attenuated B3LYP with 19% HF plus 81% B88 exchange interaction at short-range, and 65% HF plus 35% B88 at long-range, with the intermediate region smoothly described through the standard error function with parameter 0.33) and the 6-311++G(d,p) basis set.

4. Results and Discussion

In this section, we review the structures containing the molecule of 5-nitrouracil or of its mononegative ion, along with the observed optical properties. We also present two new salts of 5NU. The following figures, Figure 2 and Figure 3, portray the most common H-bonded clusters between neutral 5-nitrouracil and negative 5-nitrouracil molecules. The approximate direction of the molecular dipolar moment is shown as a green arrow.

4.1. Neutral 5NU

4.1.1. Polymorphs of 5NU

There are three known polymorphs of 5-nitrouracil: two centric and one acentric. Table 1 contains the main crystallographic information about the three crystal forms. In the two centric forms (P2₁/n and Pbca), the molecules aggregate via H-bonds in chains. Within the chains we can see the M2 and M3 motif, with the dipolar moments anti aligning within the chain (Figure 4). Using Margaret Etter’s [40,41,42] set of rules to describe hydrogen bonds, a first level graph sets rings with graph set symbol R²₂(8) for both M2 and M3 motif (in Etter’s methodology the repeating hydrogen-bonding motifs are designated by descriptors with the general symbolization $G_d^a\left(n\right)$ where G indicates the motif, such as rings (R), chains (C), intramolecular (S) and discrete (D); a and d represent the number of acceptors and donors and (n) the number of atoms contained within the motif).

The crystal structures of (I) and (II) differ only slightly in the crystal packing of the chains.

Compound (III) is the acentric form of 5-nitrouracil. Molecules assemble in layers with an extensive H-bond network, parallel to the bc plane, in which each molecule bonds to four other molecules (Figure 5), and the first-level graph set symbol is C(4).

In the three polymorphs, the asymmetric unit comprises a whole molecule: the intramolecular geometry is essentially the same in the crystal structures and the molecule is nearly planar with the angle between the nitro group plane and the ring plane reaching 7° in compound I (

Table 2. Crystallographic data of 5NU polymorphs.

Compound/ CCDC Code	Unit Cell (Å, Å3)	Space Group	Dihedral Angle between NO2 and Ring (°)	H-Bond Motif	Reference
5-nitrouracil (I) NIMFOE	a = 5.873(1) b = 9.693(1) c = 10.4561(9) β = 104.07(1) V = 577.4(1)	P21/n	6.95(16)	Chains with alternating M2, M3 motifs	[43]
5-nitrouracil (II) NIMFOE01	a = 8.308(3) b = 10.426(3) c = 13.363(4) V = 1157.5(6)	Pbca	1.71(12)	Chains with alternating M2, M3 motifs	[44]
5-nitrouracil (III) NIMFOE02	a = 5.43420(10) b = 9.84060(10) c = 10.36590(10) V = 554.325(13)	P212121	2.01(14)	Layers with M8 motif	[44]

).

Rao and co-workers [44] report in 2000 a charge density study of polymorphic forms II and III. They have calculated dipole moment vectors from the charge density distribution, obtained from X-ray diffraction data measured at low temperatures and processed with XD (a program that employs the multipolar atom model for determination, representation, and the property analysis of electron densities in crystal structures [45]). The approximated direction of such moments is shown in Figure 2, as green arrows, for the reader to quickly grasp the extinction or strengthening of the overall moment in the molecular clusters. Rao and co-workers have also calculated the molecular dipoles using a semi-empirical method for the quantum calculation of molecular electronic structures, Austin Model 1, or AM1 implemented in MOPAC [46]. They have used atomic coordinates directly taken from the experimental X-ray results and obtained similar magnitudes and directions for the dipole moments (circa 6 Debye, see Figure 2) of molecules in the centric (II) and acentric (III) form. Experimental values for the two forms, however, differ significantly. Experimental dipole values for the centric form coincide with the calculated ones, indicating that the effect of the environment is small in the molecular dipole moment. It is the assembling of the moments in a centric form that will reduce the moment of a unit cell to zero. Experimental dipole values for the acentric form differ from the calculated ones, indicating that the effect of an asymmetric crystal field in a noncentric structure can significantly enhance the dipole moment of each molecule. Furthermore, the vectorial summation of the moments will yield a large unit cell moment.

5-nitrouracil single crystals in form (III) can be easily grown [19,47] from acetonitrile and show remarkable NLO properties that can compare to the inorganic counterparts (see Table 1). When form (III) is added to a saturated aqueous solution it dissolves. Moreover, following the thermal behavior of (III) one finds that it transforms into (I) at 252 °C [47].

4.1.2. 5NU Hydrates

There are two known water solvates of 5-nitrouracil. One form was first reported by Craven in 1967 (compound IVa [48]) and more recently re-determined at 120 K by Okoth et al. (IVb [47]); the second form was reported by us in 2008 (compound V [49]), see

Table 3. Crystallographic data of 5NU monohydrates.

Compound/ CCDC Code	Unit Cell (Å, °, Å3)	Space Group	Dihedral Angle between NO2 and Ring (°)	H-Bond Motif	Reference
5-nitrouracil monohydrate (IVa) NURAMH	Reported:	P21/c	4.96 1	Layers with M2 motif	[48]
	a = 5.137(5) b = 21.956(6) c = 9.587(7) β = 143.50(8) V = 642
	Conventional:
	a = 5.137 b = 21.956 c = 6.254 β = 114.24 V = 643
5-nitrouracil monohydrate (IVb) NURAMH02 120 K	a = 5.06420(10) b = 21.9255(5) c = 6.11760(10) β = 113.1080(10) V = 624.77(2)	P21/c	4.65(16)	Layers with M2 motif	[47]
5-nitrouracil monohydrate (V) NURAMH01	a = 6.27990(10) b = 7.8481(2) c = 13.8068(3) β = 93.8420(10) V = 678.94(3)	P21/c	12.51(14)	3D network with M1 motif	[49]

¹ Deposited coordinates do not contain uncertainty information.

.

In (IV), molecules of 5-nitrouracil are hydrogen bonded (N-H…O) in pairs across crystallographic centers of symmetry with the M2 motif (see Figure 2 and Figure 6a). The resulting dimers are further hydrogen bonded through water molecules in layers parallel to the (102̅) plane (conventional unit cell), at an interplanar separation of 2.979 Å [47] In (V) the formation of pairs across crystallographic centers of symmetry is also seen, this time displaying the M1 motif (R²₂(8)). The dimers are interconnected through H-bonds involving the water molecules, forming a three-dimensional network (Figure 6b, [49]). In this form, the nitro group is rotated by 12.4(1)° out of the uracil plane, while in (IV) this rotation is less than 5°.

Okoth et al. [47,50] have reported the dehydration mechanism and the relative thermal stabilities of the hydrated/anhydro forms of 5NU. They have found that (IV) dehydrates to form (II), which then undergoes a phase transformation into (I) at ~270 °C, prior to decomposition.

4.1.3. 5NU Solvates

This section describes the crystal structure of 5NU solvates (pure hydrates are described in the previous section). All solvent molecules (except dioxane) H-bond to 5NU molecules creating diverse forms of molecular arrangements. Table 3 summarizes the main crystallographic features.

The crystallization of 5NU in aqueous ethanol resulted in a centrosymmetric crystal structure that incorporates both water and ethanol solvate molecules. The crystal structure display two types of molecular assembling via H-bons: a cluster (0D) containing a dimer of 5NU two water molecules and two ethanol molecules, with a M2 motif (R²₂(8) in graph set analysis), an element that is also seen in compound (IV) and 5NU/ethanol chains (1D) in which the nitrouracil molecules are not related by an inversion center (Figure 7a,b). The inversion center relates to two distinct chains, therefore annihilating the large dipole that each chain contains.

In the dimethylsulfoxide solvate (VII) of 5NU [43,51], the chromophore molecules are assembled in chains via H-bonds in which the oxygen atom of the solvent moiety acts as a bifurcated acceptor (Figure 8). Within the chains the dipole moment does not cancel but it cancels out in the unit cell (and overall crystal) by the presence of a center of inversion.

In the formamide solvate (VIII) of 5NU, there are six independent molecules (two nitrouracil and four formamide molecules) that interconnect via H-bonds into layers. Figure 9 shows one of such layers with a different color for each symmetry independent residue. As one can see, 5NU molecules do not bond directly; it is the great ability of formamide (with both donors and acceptors) that interconnect all molecules in layers, forming ring patterns. Within the layer, the molecular dipoles cancel out.

In the pyrimidine solvate (IX) of 5NU (Figure 10), the chromophores assemble in chains forming the M7 motif. In this arrangement, the molecular dipoles do not cancel within the chain but wipe out in the unit cell due to a center of symmetry that relates similar chains. The quantitative descriptors for the patterns containing only one type of hydrogen bond (first or primary level hydrogen-bonding) are C(6), C(6) and D(2).

In the hemikis(dioxane) solvate (X) of 5NU (Figure 11), the nitrouracil molecules are joined in centrosymmetric dimers with the M3 motif. The dimers are further interconnected in non-planar layers through N-H…O intermolecular bonds. The quantitative descriptors for the first level hydrogen-bonding are R²₂(8) and C(4). The dioxane solvent molecules are not strongly bonded occupying the center and corners of the unit cell (colored in dark blue in Figure 11a).

4.1.4. 5NU Co-Crystals

We are differentiating cocrystals and solvates based on their physical state of the components. In this section, at least two components are solid at room temperature and a solvent (like water, methanol) has to be added to provide a crystallization medium.

Table 4. Crystallographic data of 5NU solvates.

Compound/ CCDC Code	Unit Cell (Å, °, Å3)	Space Group	Dihedral Angle between NO2 and Ring (°)	H-Bond Motif	Reference
5-Nitrouracil ethanol hemihydrate (VI) JESNAX	a = 11.8264(8) b = 11.8738(8) c = 12.6511(8) β = 98.6960(10) V = 1756.1(2)	P21/c	4.6(5) 12.3(6)	Clusters with M2 motif Chains	[51]
5-Nitrouracil dimethyl sulfoxide solvate (VIIa) NIMGAR	a = 8.858(1) b = 6.9619(6) c = 15.822(1) β = 95.823(8) V = 970.7(1)	P21/n	15.80(16)	Chains	[43]
5-Nitrouracil dimethyl sulfoxide solvate (VIIb) NIMGAR01	a = 8.8723(6) b = 6.9700(5) c = 15.8489(11) β = 95.8760(10) V = 974.95(12)	P21/n	15.7(2)	Chains	[51]
5-Nitrouracil bis(formamide) (VIII) JESMUQ	a = 14.1865(8) b = 11.5840(7) c = 12.7907(7) β = 94.7750(10) V = 2094.7(2)	P21/c	9.0(2) 1.6(2)	Layers	[51]
5-Nitrouracil pyridine (IX) JESMOK	a = 7.5173(4) b = 12.7817(8) c = 10.8938(7) β = 97.78 V = 1037.08(11)	P21/c	5.5(3)	Chains with M7 motif	[51]
5-Nitrouracil hemikis (dioxane) (X) JESMAW	a = 8.3535(12) b = 6.4277(10) c = 15.703(2) β = 101.810(3) V = 825.3(2)	P21/n	2.7(6)	Layers with M3 motif	[51]

summarizes the main crystallographic features.

In compound (XI), 5-nitrouracil and 5-fluorocytosine molecules are hydrogen bonded in zig-zag chains that run approximately parallel to the ab plane,

Table 5. Crystallographic data of 5NU co-crystals.

Compound/ CCDC Code	Unit Cell (Å, °, Å3)	Space Group	Dihedral Angle between NO2 and Ring (°)	H-Bond Motif	Reference
5-Nitrouracil 5-Fluorocytosine dihydrate (XI) GATMUL	a = 10.2066(6) b = 28.2758(11) c = 4.7187(3) β = 111.293(6) V = 1268.85(12)	Cc	3.8(9)	Chains	[52]
5-Nitrouracil piperazine (XII) JESMEA	a = 4.3579(5) b = 9.8014(12) c = 12.731(2) α = 94.712(2) β = 99.452(2) γ = 97.603(2) V = 528.68(11)	P-1	6.4(4)	Chains with M2 motif	[51]
5-Nitrouracil dimethylpiperazine (XIII) JESMIE	a = 7.1052(14) b = 7.601(2) c = 10.150(2) α = 93.023(3) β = 99.452(2) γ = 117.689(2) V = 453.8(2)	P-1	18.7(13)	Chains with M1 motif	[51]
5-Nitrouracil diaza [2.2.2]bicyclooctane (XIV) JESNIF	a = 9.23230(10) b = 9.65980(10) c = 32.2899(6) β = 90.8010(10) V = 2879.40(7)	P21/c	3.0(4) 3.0(4)	3D network with M2 motif	[51]
Aminopyridine 5-Nitrouracil (XV) JESNEB 1	a = 9.7466(2) b = 32.0076(6) c = 10.5372(2) β = 122.2060(10) V = 2781.46(10)	P21/c	2.0(7)	Ribbons with M22− motif	[51]

¹ The deposited crystallographic data contain one extra hydrogen atom.

. These chains are interconnected via O—H···O interactions to water molecules. The two independent water molecules assemble in a such a way that they form ladders along the c axis (see Figure 12, first level graph descriptors C(2)).

In compound (XII), two independent half-piperazine moieties co-exist in the crystal structure. The piperazine molecules that occupy the unit cell corners (see Figure 13) are connected to 5-nitrouracil via a N-H…N bonds joining 5-nitrouracil dimers (M2 motif, R²₂(8)) in chains. The second piperazine molecule occupy the cell edges without significant interactions.

In the co-crystal of 5-nitrouracil and dimethylpiperazine, the dipole moments of 5NU are again antiparallel aligned in dimers with the M1 motif (R²₂(8)). The dimers are further joined in chains, via H-bonds with the co-former (Figure 14). In 5NU the nitro group is able to rotate around the C—N bond. In this crystal structure, such angle rises up to 18.7(13).

In the co-crystal of 5-nitrouracil and diazabicyclo [2.2.2]octane (DIABCO), there are two symmetry independent 5NU, two symmetry independent DIABCO and four symmetry independent water molecules, all strongly linked via H-bonds. The two independent 5NU are joined in dimers with an almost centrosymmetric M2 motif. The water molecules exhibit an extended network that link all the molecules together. A detail of the H-bond network can be seen in Figure 15b, where only water molecules are visible showing the square grid that they shape.

In the co-crystal of 5-nitrouracil and 3-aminopyridine, the coformers are joined in clusters of four neutral molecules that include a dimer of 5-nitrouracil with the M2 motif (R²₂(8)). The cluster are H-bonded to equivalent clusters in a nearly perpendicular orientation forming ribbons (Figure 16).

4.2. 5NU Salts

In this section, we will review the crystal structure and optical properties of 5NU salts, that is, the multicomponent crystals that include at least one ion of 5NU,

Table 6. Crystallographic data of L-Histidinium 5-Nitrouracilate salts.

Compound/ CCDC Code	Unit Cell (Å, °, Å3)	Space Group	Dihedral Angle between NO2 and Ring (°)	H-Bond Motif	Reference
L-Histidinium 5-Nitrouracilate (XVIa) BAQQIW	a = 6.1911(16) b = 7.332(2) c = 13.729(4) β = 99.990(13) V = 613.8(3)	P21	3.33(17)	3D network	[54]
L-Histidinium 5-Nitrouracilate (XVIb) JIMJOH	At 200K: a = 6.1965(2) b = 7.2965(3) c = 13.7236(5) β = 99.919(2) V = 611.21(4)	P21	3.38(11)	3D network	[55]
L-Histidinium 5-Nitrouracilate (XVII) BAQQIW01	a = 5.1555(9) b = 8.3627(15) c = 14.323(3) α = 83.206(5) β = 89.993(5) γ = 88.549(5) V = 612.99(19)	P1	2.02(2) 3.9(2)	3D network with M1 motif	[55]

. Of the two sites available for ionization in the heterocyclic ring of the 5-nitrouracil molecule (N1 and N3, check Figure 1), deprotonation occurs at the more acidic N1 [53]. Although attempts have been made to doubly deprotonate 5-nitrouracil, that form has not yet be observed in the solid state. The deprotonation of 5NU has a dramatic effect on the ground state dipolar moment; its magnitude decreases abruptly to less than 0.1 D [54].

4.2.1. L-Histidinium 5-Nitrouracilate

In 2011, we have deliberately tried a co-crystallization of 5NU with L-histidine (a chiral aminoacid) to force the crystal packing in a non-centrosymmetric environment [54]. Adding both reagents in a 1:1 proportion in an aqueous solution yielded pink crystals. The crystal structure determination revealed that L-histidine acquires a positive charge by the transfer of one hydrogen atom from the 5NU moiety that turns negative. L-histidine, in the zwitterionic form of L-histidinium cation assembles along the 2₁ axis via H-bonds between the amino group and the carboxylate group of neighboring cations. The anions are encapsulated within the cationic layers hampering direct interaction between the charged 5NU (Figure 17). Nonetheless, the almost co-planarity of imidazolium and the pyrimidine rings (at a close distance of 3.5 Å) will have a significant effect on the charge distribution of the ionic pair in an excited state. Thus, the NLO enhanced properties of the crystal are interpreted (as well as a large vibrational circular dichroism response) as a play of two energetic levels, the ground state and a low-lying first excited state where charge migrates from one ring to the adjacent one (Figure 18).

The crystal structure of (XVII) contains two independent formula units [55]. The two symmetry independent 5-nitrouracil anions form pseudo-symmetric dimers linked with double N—H···O type hydrogen bonds, with a M1²⁻ motif (Figure 19). At the primary level, graph patterns corresponded to chains described with C(5) and C(7).

4.2.2. 5NU Salts of Guanidine Derivatives

Guanidinium 5-Nitrouracilate Monohydrate

The crystal structure of the compound guanidinium 5-nitrouracilate monohydrate (XVIII), (

Table 7. Crystal data and structure refinement parameters for (XVIII) and (XIV).

Compound	Guanidinium 5-Nitrouracilate Monohydrate (XVIII)	Phenylguanidinium 5-Nitrouracilate Monohydrate (XIX)
Temperature/K	293	293
Empirical formula	C5H10N6O5	C11H14N6O5
Formula weight	234.19	310.28
Wavelength/Å	0.71073	0.71073
Crystal system	Triclinic	Monoclinic
Space group	P-1	P21/c
a/Å	3.65270(10)	9.7466(2)
b/Å	11.1035(3)	32.0076(6)
c/Å	11.8152(3)	10.5372(2)
a/°	82.383(2)	90
b/°	86.406(2)	122.2060(10)
c/°	89.405(2)	90
Volume/Å3	474.03(2)	2781.46(10)
Z	2	8
Calculated density/(g/cm3)	1.641	1.404
Absorption coefficient/mm−1	0.145	0.105
F(000)	244	1374
θ range for data collection/deg.	1.74–27.46	2.37–28.74
Index ranges	–4 < h < 4,–14 < k < 14, –15 < l < 15	–12 < h < 13,–43 < k < 43, –15 < l < 15
Reflections collected/unique	9678/1545	89166/4531
Completeness to θmax	100%	99.5%
Data/restraints/parameters	1545/0/173[R(int) = 0.0357	4531/0/454 [R(int) = 0.0311
Goodness–of–fit on F2	1.050	1.0026
Final R index [I > 2σ(I)]	R1 = 0.0363 wR2 = 0.0890	R1 = 0.0441 wR2 = 0.1172
R index (all data)	R1 = 0.0591 wR2 = 0.1003	R1 = 0.0786 wR2 = 0.1378
Largest diff. peak and hole (e Å −)3)	–0.162 and 0.256	–0.198 and 0.215

, Figure 20), belongs to the triclinic system with the centrosymmetric space group P-1. The asymmetric unit consists of one guanidinium cation with a 5-nitrouracilate counter-ion and a water molecule.

There are two sites available for deprotonation in the heterocyclic ring of the 5-nitrouracil molecule (N1 and N3) and it occurs at the more acidic N1. In the anion the pyrimidine ring is almost planar and the nitro group is rotated 2.8(2)◦ out of the plane of the uracil fragment. The ions and the water molecules are linked by N—H···O and N—H···N hydrogen bonds forming layers approximately parallel to the plane (112), see Figure 21a,b,

Table 8. Hydrogen bond geometry of guanidinium 5-nitrouracilate monohydrate (Å,°).

D−H···A	D−H	H···A	D···A	D−H···A
N3—H3···O1 i	0.857(17)	1.984(18)	2.8387(15)	174.4(15)
N4—H4B···O1W ii	0.89(2)	2.01(2)	2.884(2)	167.3(18)
N4—H4A···O2 iii	0.87(2)	2.26(2)	3.004(2)	143.9(17)
N5—H5A···N1 ii	0.86(2)	2.35(2)	3.0626(18)	140.4(17)
N5—H5B···O4 iv	0.89(2)	2.07(2)	2.9590(19)	175.0(18)
N6—H6A···O2 iii	0.924(19)	2.132(19)	2.9773(18)	151.5(16)
N6—H6A···O3 iii	0.924(19)	2.274(18)	2.9655(17)	131.2(15)
N6—H6B···O3 iv	0.86(2)	2.30(2)	3.1445(18)	171.6(17)
O1W—H1W···O1	0.86(3)	1.90(3)	2.7522(17)	171(2)
O1W—H2W···O2 v	0.82(2)	2.44(3)	3.2104(18)	157(2)

Symmetry codes i: 2 − x, 1 − y, −z; ii: 1 − x, 1 − y, 1 − z; iii: 2 − x, −y, 1 − z; iv: 1 + x, y, z; v: 1 − x, 1 − y, −z.

. These layers are linked via the water molecules. All six potential donor sites of the guanidinium cation participate in hydrogen bonds. In this structure, the full hydrogen bonding capability of the 5-nitrouracilate anion is also used. Each cation is hydrogen-bonded to three anions and one water molecule. The anions are linked in pairs across an inversion center forming rings of descriptor R²₂(8), and also to three cations and two water molecules.

Phenylguanidinium 5-Nitrouracilate Monohydrate

The crystals of phenylguanidinium 5-nitrouracilate monohydrate (XIX) are monoclinic with the space group P2₁/c. The asymmetric unit cell has two phenylguanidinium cations, two 5-nitrouracilate anions and two water molecules (Table 7, Figure 22). The two symmetry-independent phenylguanidinium cations have very different conformations as evidenced by the values of the torsion angle C7−N8−C8−C13: 61.4(2)◦ for cation C and −51.0(2)◦ for D.

In both symmetry-independent anions, the pyrimidine ring is almost planar and the nitro group is rotated out of the plane of the uracil fragment 1.3(1)◦ and 6.7(1)◦ for anions A and B, respectively. There is an extensive network of N−H· · · O and N−H· · · N hydrogen bonds linking the ions and the water molecules into ribbons (Figure 23,

Table 9. Hydrogen bond geometry of phenylguanidinium 5-nitrouracilate monohydrate (Å,°).

D—H···A	D—H	H···A	D···A	D—H···A
O1W—H1···O4A	0.82(4)	1.99(4)	2.7274(17)	150(3)
O1W—H1A···O7A	0.82(4)	2.42(3)	3.0398(19)	133(3)
O1W—H1B···O2B i	0.75(3)	2.10(3)	2.8450(19)	170(4)
O2—H2A···O4B	0.87(3)	2.03(3)	2.7876(17)	146(3)
O2W—H2A···O7B	0.87(3)	2.29(3)	2.9731(18)	136(3)
O2W—H2B···O2A i	0.74(3)	2.15(3)	2.8746(18)	167(3)
N3—H3···O4B i	0.893(17)	1.961(18)	2.8508(15)	174.0(15)
N3B—H3B···O4A i	0.870(17)	1.993(17)	2.8606(15)	174.1(15)
N6C—H6C1···O2W ii	0.88(2)	2.09(2)	2.930(2)	159.1(18)
N6C—H6C2···O2A	0.93(2)	1.91(2)	2.8354(19)	176.8(18)
N7C—H7C···O7B ii	0.85(2)	2.39(2)	3.0006(18)	129.4(18)
N7C—H7C1···O2W ii	0.85(2)	2.34(2)	3.118(3)	153(2)
N8—H8C···N1A	0.905(19)	2.015(19)	2.9138(17)	172.0(16)
N6D—H6D1···O1W iii	0.86(2)	2.27(2)	3.020(2)	145.9(17)
N6D—H6D2···O2B iv	0.89(2)	1.92(2)	2.8082(18)	177.0(19)
N7D—H7D1···O1W iii	0.86(2)	2.04(2)	2.871(2)	162(2)
N7D—H7D1···O7A iii	0.86(2)	2.55(2)	3.0295(17)	116.4(16)
N8D—H8D···N1B iv	0.873(19)	2.080(19)	2.9495(17)	173.9(17)

Symmetry codes i: −x + 1, −y, −z + 1; ii: x − 1, y, z; iii: x − 1, y, z − 1; iv: x + 1, y, z + 1.

). The anions are linked in pairs forming rings of descriptor R²₂(8), with the M2²⁻ motif.

Diphenylguanidinium 5-Nitrouracilate Dihydrate

The crystals of diphenylguanidinium 5-nitrouracilate [56] incorporate two water molecules per asymmetric unit cell, aggregating anions and cations into H-bonded slabs that stack along the c axis (

Table 10. Crystallographic data of 5NU salts of guanidine derivatives.

Compound/ CCDC Code	Unit Cell (Å, °, Å3)	Space Group	Dihedral Angle between NO2 and Ring (°)	H-Bond Motif	Reference
Guanidinium 5-Nitrouracilate monohydrate (XVIII) CCDC 2222685	a = 3.65270(10) b = 11.1035(3) c = 11.8152(3) α = 82.383(2) β = 86.406(2) γ = 89.405(2) V = 474.03(2)	P-1	2.8(2)	3D network with M12− motif	This work
Phneylguanidinium 5-Nitrouracilate monohydrate (XIX) CCDC 2222686	a = 9.7466(2) b = 32.0076(6) c = 10.5372(2) β = 122.2060(10) V = 2781.46(10)	P21/c	1.3(1) 6.7(1)	Ribbons with M22− motif	This work
Diphenylguanidinium 5-Nitrouracilate dihydrate (XX) BAQPAN	a = 6.6889(2) b = 11.5839(3) c = 13.7723(3) α = 112.910(2) β = 91.715(2) γ = 104.582(2) V = 941.44(4)	P-1	6.04(19)	Slabs with M12− motif.	[56]
Triphenylguanidinium 5-Nitrouracilate (XXI) WIZXAF	a = 10.7495(4) b = 15.6892(7) c = 15.5624(7) β = 123.456(3) V = 2189.74(18)	P21/c	11.4(2)	Columns	[57]

, Figure 24). 5NU ions are strongly H-bonded into dimers, showing the M1²⁻ (R²₂(8)) motif.

Triphenylguanidinium 5-Nitrouracilate

The anions and cations are linked into columns running parallel to the b axis, via hydrogen bonds involving all the NH groups of the guanidinium fragment, the carbonyl O atoms and the deprotonated N atom of the anion [57]. The 5NU ions are lined up within each column without direct interionic interactions (Figure 25). A center of symmetry relates the columns in the crystal, obliterating the overall dipole moment.

4.2.3. Other 5NU Salts

Cytosinium 5-Nitrouracilate

The crystals that grow from a 1:1 aqueous solution of cytosine and 5-nitrouracil [52] after heating, stirring and refluxing, belong to a subclass that intersects the family of cocrystals, salts and solvates [58]. The asymmetric unit of (XXII) contains one neutral molecule of cytosine, one charged ion of cytosine, one neutral molecule of 5-nitrouracil, one charged ion of 5-nitrouracil and two water molecules, see

Table 11. Crystallographic data of more 5NU salts.

Compound/ CCDC Code	Unit Cell (Å, °, Å3)	Space Group	Dihedral Angle between NO2 and Ring (°)	H-Bond Motif	Reference
Cytosinium 5-Nitrouracilate Cytosine 5-Nitrouracil dihydrate (XXII) GATMOF	a = 3.65270(10) b = 11.1035(3) c = 11.8152(3) α = 82.383(2) β = 86.406(2) γ = 89.405(2) V = 474.03(2)	P-1	1.2(5) 1.8(5)	Layers (with neutral/charged pairs)	[52]
Benzamidinium 5-Nitrouracilate dihydrate (XXIII) TUWDEV	a = 4.3625(4) b = 10.4461(11) c = 13.8556(12) α = 78.551(7) β = 86.841(8) γ = 84.051(7) V = 615.13(10)	P-1	1.6(3)	Ribbons with M22− motif.	[59]

for more parameters. In Figure 26, one can see how these molecules/assemble in the solid: they are all hydrogen bonded in layers parallel to the bc plane. The neutral/charged ion of the same species are strongly bonded together by sharing a hydrogen atom between the protonated/deprotonated sites (yellow/red for cytosine and blue/green for nitrouracil for protonated/deprotonated forms in Figure 26).

In order to probe if a charge distribution occur in the neutral/charged pair, we have performed ab-initio calculations using as input the atomic coordinates retrieved from X-ray determination (see Section 3.3 for technical details). The results show a moment of circa 5 D very similar to the neutral molecule alone.

Benzamidinium 5-Nitrouracilate

The benzamidinium and 5-nitrouracilate ions aggregate in ribbons profusely H-bonded (Figure 27). One can spot the dimer formation with the M2²⁻ motif (R²₂(8)) [59]. Ions within the dimers are related by an inversion center.

5. Conclusions

5-nitrouracil is an achiral molecule with large optical response and its properties could be translated to a solid, ensuring that it remains neutral in a chiral environment. Such an environment not only enhances the ground dipolar moment but also assures that a nonzero second-harmonic generation can be obtained. From an overview of all reported structures so far, one can conclude that changing the crystallization solvent has a dramatic influence on the molecular packing, either by promoting an achiral assembling (acetonitrile), or by avoiding the pairing of dipolar moments (sulfoxide, formamide). For 5-nitrouracil, exploring polymorphism (a pervasive phenomenon) looks like the promising route to discover molecular environments that boost second-order nonlinear optical susceptibilities. Co-crystallization with a neutral molecule has not (yet) shown the ability to induce a chiral environment. Regrettably, upon losing one H+ and gaining an overall negative charge, the dipole moment of 5-nitrouracil drops substantially. However, the electron cloud of 5NU- can still be quite affected by an electric field. Salt formation with a chiral zwitterion has shown the phenomenon of through space charge transfer, with the charge moving from one ion to the other in piles of stacked rings with strong p-p interactions. This ionic assembling has shown that both linear and nonlinear optical responses are greatly enhanced.