Molecular Sciences C-nmr Based Evaluation of the Electronic and Steric Interactions in Aromatic Amines

Chemical shifts of the para carbon atoms, δ(13 C-4), in a series of aromatic amines were used to calculate the σ p , σ R and O R σ substituent constants for different amino groups. 1-Pyrrolidino, N,N-din -butylamino and N,N-diethylamino groups were found to be the most strong electron-donors. ortho-Substitution decreases the donor properties of the amino group. The amino groups in 2,6-di-i-propylaniline and N,N-2,6-tetramethylaniline have very weak electron-donor properties. The nitrogen atom in benzoquinuclidine and N,N-dimethyl-2,6-di-i-propylaniline have an electron-acceptor character. The calculated substituent constants of the amino groups studied are consistent with the spectral and reactivity data available in literature. Values of δ(15 N) cannot be used as a direct measure of electronic effects of the N atom in anilines.


Introduction
The nature of the interactions between different molecular moieties is well known for aniline and its common derivatives [1,2].Little is known, however, about electronic and steric effects of uncommon amino groups.Due to its +R effect the primary amino group is a strong electron-donor ( R σ = -0.76[3][4][5], -0.78 [6]).The inductive effect of NH 2 ( I σ = 0.10 [7], 0.11 [6]) slightly moderates its donating power (σ p = -0.66[8]).Further, amino group is much stronger electron donor ( + σ p = -1.3[9]) when there is another substituent of the -R type at the para position of the benzene ring.Due to the inductive (+I) effect of the N-alkyl groups, alkylamino substituents are even stronger electrondonors [6,8,9].In addition to common amino groups, e.g.NH 2 , NHR, NR 2 (R = alkyl) and cyclic polymethyleneimino derivatives, N(CH 2 ) n , some aromatic amines, e.g.indoline and julolidine, contain alkane bridges between the amino nitrogen and the ring ortho-carbon atom(s).In consequence, their molecules are conformationally rigid and therefore reveal very interesting properties.It is noteworthy, that although some important aspects of the electronic effect of the amino groups were discussed by Chuchani [1] and recently by Shorter [2], some interesting uncommon amino derivatives were, however, not included there.
The energetically optimal conformation of aromatic amines is a compromise between the tendency of the amine nitrogen atom to be pyramidal (sp 3 ) and its tendency to assume the planar sp 2 hybridization in order to maximize the resonance interaction with aromatic part of the molecule.The term "steric inhibition of resonance" refers to a non-planar sterically hindered molecule while the unhindered reference molecule is planar [10].
An extent of the conjugation of aromatic part of the molecule with its amino substituent is an indicator for the ability of the nitrogen atom to possess the sp 2 -hybridization.In the Hückel MO theory this property is expressed by the overlap integral of the lone-pair orbital, n N , and the π-orbital of the benzene ring, π Ar [11].On the other hand, the coulomb integral reflects the electro-negativity of the amino nitrogen atom.It has been found [11] that different N,N-dialkylamino and polymethyleneimino, N(CH 2 ) n , groups reveal similar inductive effects.Thus, the donor strength of the amino group depends mainly on its resonance interactions with aromatic ring, which are related to the C Ar -N bond length, R-N-R bond angle and other geometrical parameters such as torsion angle of the amino group with respect to benzene ring.
Since the chemical shifts of heavy nuclei (other than protons) depend both on the diamagnetic and paramagnetic shielding tensors of the nuclei [12], their δ values are related to the electronic charges at these atoms and interatomic bond orders.Thus, one may expect that there are more or less direct relations between the σ substituent constants and the NMR chemical shifts for substituted aromatic amines.So, the knowledge of the electronic and steric properties of substituents is very important in interrelating the structural and spectral data.Since Exner [13] has stated that "… a single scale of mesomeric constants is an unrealizable objective", we intended to differentiate various amino groups from a point of view of their electronic and steric properties rather than to determine the absolute σ constants.

Results and Discussion
The chemical shifts of nitrogen (N) and para (with respect to the amino group) carbon (C-4) atoms in the NMR spectra of anilines are collected in Table 1.π-Electron density at the para carbon atom in aromatic compounds depends on the twist angle of the substituent [14] and thus, its chemical shift can be used to calculate these angles for the amino groups in anilines. 13C-NMR chemical shifts for unsubstituted aniline were found to be quite sensitive to the orientation of the NH 2 group [15].This relation was also confirmed by both theoretical (GIAO, Gauge-Independent Atomic Orbital) and experimental results [15].The amino group in aniline itself is tilted away from the ring plane by 42° [15].The chemical shift values increase (deshielding effect) as the amino group is moved away from the planar orientation with the largest changes appearing at the ipso, ortho and para positions [15]. 13C-NMR spectra show that N-phenylaziridine is the least conjugated among N-phenyl cyclic polymethyleneimines [16].It has been found that p-substituent in N-phenylaziridines only slightly affects electron distribution in aziridine ring [17].This proves that n N -π Ar conjugation in these compounds is insignificant.The chemical shifts of para carbon atom in the spectra N,N-dimethyl-and N,N-diethylanilines and 1-phenylaziridine, 1-phenylpyrrolidine and 1-phenylpiperidine correlate well with other known measures of benzene ring-nitrogen resonance such as oscillator strength of the UV bands and exaltation of molar refraction [16,18].[19][20][21].σ p values for the NMe 2 and NH 2 [8] as well as these for other non-amine substituents [22] are known [8].Since in chloroform solutions δ( 13 C-4) values are 117.68, 116.38, 120.72, 125.38, 128.36, 126.43, 126.82, 132.84 and 134.72 ppm for aniline, N,N-dimethylaniline, anisole, toluene, benzene, chlorobenzene, bromobenzene, benzonitrile and nitrobenzene [23], respectively, the dependence between the substituent constant and the chemical shift of para carbon atom is σ p = 0.089 δ( 13 C-4) -11.22.This equation can be used to calculate the substituent constants for other groups (Table 1).It is known that different N,N-dialkylamino and polymethyleneimino, N(CH 2 ) n , groups reveal similar inductive effects [11].σ value based on reactivity measurements is -0.52 [28].d -0.66 [8].e In CDCl 3 [29].f Benzoquinuclidine.g In methylene chloride-d 2 [30].h In benzene-d 6 [31].
Available σ I values are equal to 0.14, 0.12, 0.10 and 0.10 for p-NH 2 , p-NHMe, p-NMe 2 and p-NEt 2 , respectively [24].This shows that the resonance effect of the N atom in anilines considerably predominates over its inductive effect.
Analysis of the δ( 13 C-4) values in Table 1 shows that σ p substituent constants for different dialkylamino groups change in the following order: N(n-Bu) 2 ≈ NEt 2 < NMe 2 < N(Me)Et < N(i-Pr) 2 .Thus, in general, those containing longer alkyls are stronger electron-donors.On the other hand, dialkylamino groups including secondary alkyl, e.g.i-propyl, are weaker donors.This may be caused by the strong steric interaction of the N-i-propyl group with ortho-hydrogen atoms.It seems interesting that σ p-N(Me)Et ≈ σ p-NHMe = σ p-NHEt .
Substitution at the ortho carbon in N,N-dimethylaniline causes NMe 2 group to twist out of the ring plane, so the nitrogen valences become more pyramidal [28].Thus, ortho-substitution decreases the donor properties of the amino group.Comparison of δ( 13 C-4) values for different ortho-substituted anilines, o-R-C 6 H 4 -NH 2 (17 and 21-23 in Table 1) with that of the aniline itself ( 16), shows that σ p substituent constants depend on R in the following order: H < Me < Et ≈ t-Bu < i-Pr.On the other hand, substitution in both ortho positions (12, 14 and 15) increases the donor properties of the amino (NH 2 ) group as compared to parent aniline 16. 2,6-Di-i-propyloaniline ( 28) is an exception: the amino group in this compound seems to have very weak electron-donor properties.This may be caused by the strong steric interaction of the ortho-i-propyl and NH 2 groups.When comparing different 2,6-R,R'substituted anilines 12, 14-17, 21-23 and 28 one can see that σ p substituent constant of the amino group change in the following order: R,R' = Me,Me < Et,Et < Me,Et = H,H < H,Me < H,Et = H,t-Bu ≈ H,i-Pr << i-Pr,i-Pr.Due to strong steric interactions, the amino group in 2,N,N-trimethylaniline ( 20) is a weak electron-donor (calculations based on the band intensities show ortho-methyl group in ethyl N,N,3-trimethyl-4-aminobenzoate to produce a 56 % steric inhibition to resonance [32]).These interactions are much stronger in 2,6-dialkyl-N,N-dimethylanilines 29 and 30.It is noteworthy that the twist angles in 2,6-diethyl-and 2,6-di-i-propyl-N,N-dimethylanilines were found to be equal to 77 and 88°, respectively [33].
The nitrogen atom in benzoquinuclidine (31) clearly reveals electron-acceptor properties.Studies of molecular structures of benzoquinuclidine and its 6-cyano derivative in the crystal state confirm that there is no n N -π Ar conjugation in these compounds (the aromatic π and nitrogen electron lone pair orbitals are orthogonal) [31,34].Thus, there is no resonance interaction between the amino nitrogen atom and the benzene ring in benzoquinuclidine [35].
Molecular models show that due to the angle strain in the five-membered ring, the C Ar -C Ar -N valence angle in indoline (19) and its N-methyl derivative 13 is expected to be much smaller than 120°.Bicyclic structures in N-methylindoline (13) and N-methyl-1,2,3,4-tetrahydroquinoline (4) were shown to be planar [36].On the other hand, the seven-membered ring in N-methyl-homotetrahydroquinoline ( 7) is highly puckered [36].The UV spectrum of this compound shows considerable difference from the spectra of two lower homologues, and this difference is certainly due to the conformational freedom of the seven-membered ring [37].
Although large differences in basic properties were found for N,N-diethylaniline and Nphenylpyrrolidine, close similarity of their 13 C-NMR spectra (Table 1) shows that electron distributions in the benzene rings are nearly the same in these two compounds [16].1-Pyrrolidino group (1) was found to be a very powerful electron-donor [38].It is much stronger electron-donor than 1-piperidino group (25).Decreased n N -π Ar interaction in 1-(p-nitrophenyl)piperidine, which reflects the relative rigidity of the chair conformation of the six-membered piperidine ring, is also consistent with the downfield shift for signals of protons 2 and 6 in spectra of 1-(p-nitrophenyl)pyrrolidine, 1-(pnitrophenyl)hexamethyleneamine and N,N-dialkylanilines, where alkyl = Me, Et [39].Low ε max value of the band at 425 nm in the spectrum of N-(p-nitrophenyl)piperidine, as compared to the spectra of N-(p-nitrophenyl)pyrrolidine and N-(p-nitrophenyl)hexamethyleneimine, proves there is a serious steric inhibition to resonance in its molecule.The angle of twist of the CNC plane with respect to that of the benzene ring in N-(p-nitrophenyl)piperidine is equal to 33° [40].Due to interaction between the nitrogen atom and phenyl ring, the resonance energy in N-phenylcyclopolymethyleneimines changes in the following order of the ring size: n = 3 < 6 < 4 < 5 [41].Analysis of the chemical shift values for the ring protons in 1 H-NMR spectra of aniline derivatives shows that donor strength of the amino substituents in the ground state of aromatic amines change in the following order [11]: 1-pyrrolidino > dimethylamino >1-piperidino.
Of course, confusion may result from the above discussion having its source in the dispersion of the substituent constants available for the amino groups [13].One should be aware of differentiation between these parameters depending e.g. on application (or not) of the correction for the tautomeric equilibria possible in solutions of such compounds [13].Thus, the amino substituent in N,N,2,6tetramethylaniline (29) was found to be a very weak electron-donor.However, comparison of the δ( 13 C-4) values for this compound (124.72 ppm) and unsubstituted benzene (128.5 ppm) shows that this cannot be true.We have found that O R σ values for some amino groups known [25][26][27] (Table 1) are linearly related to the obtained NMR chemical shifts of C-4 (Table 1): δ( 13 C-4) = 36.401O R σ + 135.922 (R = 0.9931 for five correlation points).This equation was used by us to calculate the respective substituent constants for other amino substituents (Table 1).It can be seen that all substituents studied are electron-donor by character but, as expected, their releasing properties are very much differentiated.
The obtained substituent constants seem worthy to be compared to the results of earlier studies (only some amino groups were studied by other authors).Substituent O R σ constants for the amino and dimethylamino groups, based on fluorine chemical shift in the NMR spectra of the respective fluoroanilines, are equal to -0.48 and -0.53, respectively [42,43].Due to the steric inhibition to resonance of the ortho-methyl group in N,N,2-trimethyl-4-fluoroaniline the O R σ constant for the twisted p-dimethylamino substituent in this compound is equal to -0.24 [28]. 19F-NMR chemical shifts of 4-amino-3,5-dimethylfluorobenzene and of its N,N-dimethyl derivative were interpreted in terms of a strong steric inhibition to resonance in their molecules but they are insufficient to push these amino groups out of conjugation with the benzene ring [44].
Dipole moment of aniline (1.15 D [48]) was found to be only slightly affected by the orthoand Nmethyl groups: its value is appreciably diminished only in 2,6,N-trimethylaniline and especially in 2,N,N-trimethyl-and 2,6,N,N-tetramethylanilines [46,49].Charge distribution in the molecules of aromatic amines shows the order of electron-donor strength of the amino groups to be (CH 2 ) 4 N > Et 2 N > (CH 2 ) 5 N [50,51] and NEt 2 > N(CH 2 ) 4 > NMe 2 > N(CH 2 ) 5 [50].The calculated and measured dipole moments confirm the considerable twist of NMe 2 group in ortho-methyl substituted N,N-dimethylanilines [52].Thus, there is a strong steric inhibition to resonance in these molecules [53].Comparison of the experimentally observed and theoretically calculated dipole moments of 2,N,N-trimethylaniline shows the hybridization of the nitrogen atom to be close to sp 3 [14].
The sequence of the base strength of anilines of formula C 6 H 5 -NR 1 R 2 in water changes in the following order [54]: R 1 /R 2 = H/H < H/Me < Me/Me < H/Et < H/i-Pr < Et/Et.These results confirm that N-alkyl groups cause an increase in basicity of aniline due to their +I effect.On the other hand, Nalkylation may significantly change effectiveness of solvation of both amine and its conjugate acid.Alkyl groups in the ortho positions in aniline always decrease its pK a [55].On the other hand, substitution of the amino hydrogen atom(s) by alkyl(s) causes an increase of the base strength of aromatic amines.Ortho alkyl groups in N,N-dialkylanilines prevent the dialkylamino group from assuming coplanarity with the ring and hence decrease its resonance effect and increase the basicity of the compound.On the other hand, 2,N-dimethylaniline is weaker and 2,N,N-trimethylaniline is a stronger base than N-methylaniline.Unexpectedly, 2,6,N,N-tetramethylaniline has a lower pK a than 2,N,N-trimethylaniline [55].
Benzoquinuclidine (31, Scheme 1), is a particular aromatic amine.As expected, it is relatively strong base, its pK a value being the greatest one in a series of selected anilines measured in 50 % aqueous ethanol at 25°C [56]: pK a : C 6 H 5 -NH 2 < C 6 H 5 -NMe 2 < o-Me-C 6 H 4 -NMe 2 < C 6 H 5 -NHBu-t << C 6 H 5 -N(Me)Bu-t < benzoquinuclidine.1,2,4,5-Tetrahydropyrrolo[3,2,1-hi]indole (27) was unexpectedly found to be stronger base (pK a = 4.1, in 50 % aqueous ethanol) than julolidine (5) (pK a ∼3.6) [57].Perhaps, in this case the pK a value also reflects both the conformational changes in the molecule and differences in steric hindrance to solvation [58].It has been found that linear correlation between the twist angle of the amino group and pK a values of aniline derivatives is very rough due to peculiar solvation effects [31].Thus, the anomalies in the base strength attributed to the steric hindrance of solvation [58] also enable evaluation of the conformation of aromatic amines [26,59].Acidities of p-aminobenzoic acids, R 2 N-C 6 H 4 -CO 2 H, and the rates of reduction of pnitroanilines, R 2 N-C 6 H 4 -NO 2 , show the following order of the electron donating effect for different amino substituents [60]: N(CH 2 ) 5 < NMe 2 < N(CH 2 ) 4 < NEt 2 < N(i-Pr) 2 .Decreased mesomerism that results from the twisting of the NCC plane out of the benzene ring plane, is illustrated by the pK a value for p-(N-piperidino)benzoic acid, which is lower as compared to other p-aminobenzoic acids, p-R 2 N-C 6 H 4 -CO 2 H [39] (see also ref. [60]) : pK a : Et 2 N > (CH 2 ) 4 N > Me 2 N > (CH 2 ) 5 N.
The σ substituent constants for some amino groups defined on the basis of dissociation constants of p-aminobenzoic acids, p-R 2 N-C 6 H 4 -CO 2 H, are equal to -0.41 for N(CH 2 ) 5 , -0.62 for NH 2 , -0.69 for NMe 2 and N(CH 2 ) 4 , and -0.71 for NEt 2 [61].The pK a values of 4-amino-3,5-dimethylbenzoic acid and its N,N-dimethyl derivative, as well as saponification rates for the respective ethyl esters, have been interpreted in terms of steric inhibition to resonance [62].
Although benzoquinuclidine ( 31) is an aromatic amine, there is no resonance interaction between the amino nitrogen and the benzene ring in its molecule.It has been proven by its unsuccessful diazo coupling with p-nitrobenzenediazonium salts [35].The σ R o for the twisted -N< group in benzoquinuclidine is equal to -0.134 [63] (as compared to -0.53 for NMe 2 group [64]).On the other hand, another hindered amine, i.e. 2,6-di-(t-butyl)aniline, can be readily coupled with arenediazonium salts to give the respective p-aminoazobenzenes [35,59,65].Due to steric inhibition to resonance in Nt-butyl-N-methylaniline, this compound does not react with nitrous acid nor with ethyl nitrite to give the para-nitroso derivative [65].The formation of 4'-nitro-4-(N-t-butyl-N-methylamino)azobenzene from this compound and p-nitrobenzenediazonium chloride proceeds extremely slowly with only 10 % yield [65].None of N,N-dimethylanilines containing 2-t-butyl and 2,6-dimethyl groups can be nitrosated [65].
The nitrogen chemical shifts are influenced by the substituent via polar [66] and steric effects [67] and thus can be useful to estimate the degree of n-π interaction in anilines [68].The effect of Nmethylation on the 15 N-NMR chemical shift of aniline is known for long and consistent with the present data (8, 10 and 16 in Table 1) [69].Ortho-substitution in N,N-dimethylaniline causes a considerably large shift of its 15 N-signal [33].This has been attributed to the torsional distortion of the NMe 2 group [33], which results in a decreased electron delocalization in the molecule [67].The data in Table 1 show that the changes of δ( 15 N) may be both positive (cf. 10 vs. 18; 16 vs.22; 19 vs. 13) and negative (4 vs. 6; 8 vs. 20, 29 and 30; 16 vs.12, 14, 15, 17, 21, 23 and 28).Thus, δ( 15 N) cannot be used as a direct quantitative measure of electronic effects of the N atom in anilines, although δ( 15 N) of N-(p-R-phenyl)aziridines qualitatively show, that the lone-pair electrons of aziridine nitrogen interact less effectively with benzene ring than those in the corresponding N,N-dimethylanilines [68].

Conclusions
In summary, one can see that the NMR chemical shifts of the C-4 aromatic carbon atom in aromatic amines is a very helpful tool to evaluate the substituent effects of different amino groups.The available literature data concerning the molecular structure of aromatic amines as well as their spectral and reactivity data support the correctness of evaluated substituent constants.The determined substituent constants for different amino groups are not absolute by character.To show the correctness of the determined substituent constants, in our next papers we are going to present also the correlations between these parameters and other physical data of aromatic amines, e.g. the fluorine NMR chemical shifts for p-fluroanilines.

Experimental
Most anilines are commercially available and known procedures were used to prepare others [38].They were recrystallized or distilled in vacuum before use.Their physical constants are consistent with these found in literature.All NMR spectra were recorded for 0.1 − 0.2 M CDCl 3 solutions at 303 K (unless otherwise stated) with a Bruker Avance DRX 500 FT NMR spectrometer equipped with an inverse detection 5 mm diameter broad band probehead and z-gradient accessory working at 500.13 MHz ( 1 H-), 125.76 MHz ( 13 C-) and 50.59MHz ( 15 N-), respectively.In proton composite pulse decoupled (Waltz-16) 13 C-NMR experiments the spectral width was 30300 Hz (240 ppm), the number of data points 65 K, the flip angle 30 o , and the number of scans typically > 10000 in order to observe reliably also the weak signals of the minor contributors.The FIDs were multiplied by an exponential window function of the digital resolution (0.92 Hz) prior to Fourier Transform (FT).The 13 C-NMR chemical shifts are referenced to the signal of CDCl 3 (δ = 77.00ppm from TMS).
2D z-pulsed field gradient (PFG) selected 1 H, 13 C HMQC [70,71], and 1 H, 13 C HMBC [72] experiments were run to assign reliably the 13 C-NMR spectra.In HMQC the matrix size typically was 2500 Hz/512 points ( 1 H = f 2 -axis) x 10000 Hz/512 points ( 13 C = f 1 -axis), which was multiplied by a sine-bell window function along both axes prior to FT.The number of scans was 32 and a composite pulse decoupling (garp) was used to remove proton couplings.In HMBC measurements 64 scans were accumulated for each f 1 -increment, the matrix size and windowing were the same as in HMQC.A lowpass filter to remove correlations transmitted via direct couplings and a 50 msec delay for an evolution of n J(C,H) couplings was included in the HMBC pulse sequence.In order to determine 15 N NMR chemical shifts, z-PFG 1 H, 15 N HMBC experiments were run.In these experiments the size of data matrix was 2500 Hz/512 points ( 1 H) x 22500 Hz/1024 points ( 15 N-axis).The 15 N-NMR chemical shifts were referenced to an external nitromethane (δ = 0.0 ppm) sample in a 1 mm diameter capillary tube inserted coaxially inside the 5 mm NMR sample tube.A sine-bell multiplication was done along both axes prior to FT. 64 scans were accumulated for every 15 N = f 1 -increment.A 100 msec delay for an evolution of n J(N,H) couplings was included in this HMBC pulse sequence.

31 Numerous
Scheme 1Structures of selected amines