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Basicity study of substituted N,N-dimethylanilines in

solution and in the gas phase

Ivari Kaljurand† ,*, Roman Lilleorg†, Algis Murumaa†,#,, Masaaki Mishima‡,*, Peeter Burk†, Ivar

Koppel†, Ilmar A. Koppel†,*, Ivo Leito†,*

Institute of Chemistry, University of Tartu, Ravila 14 Str, 50411 Tartu, Estonia

Kyushu University, Institute for Materials Chemistry and Engineering, Hakozaki, Higashi-ku, Fukuoka

812-8581, Japan

[email protected] või Ilmar? Ivari?

Footnotes† University of Tartu.‡ Kyushu University.* To whom correspondence should be addressed. #täienda seda Phone: +372 7 375 259. Fax: +372 7 375 264.

# Current address: otsida

ABSTRACT (Word Style “BD_Abstract”).

KEYWORDS (Word Style “BG_Keywords”).

1

Introduction

N,N-dimethylaniline (DMA) and its derivatives are used for production of polymers, dyes,

pharmaceuticals, agricultural chemicals etc. (1, 2-4, 6). In a more wider and rather simplified view the

N,N-dimethylaniline is a one of the first steps then going from simple nitrogen bases as ammonia or

alkylamines towards more complex nitrogen bases as various heterocyclic bases (pyridines, azoles,

amidines, guanidines etc), by introducing some -bond character, steric interaction etc not yet directly,

but to the vicinity of the protonisation center.

Acid-base properties of N,N-dimethylaniline (DMA) and its derivatives have been of interest already

several decades ago. Their basicities have been determined in water 7,18,19, in aqueous dimethylsulfoxide

22 and also in gas-phase8, 10 , Tafti juures tehtud tööd. Also the affinities of substituted DMA-s against

trimethylsilyl cation have been studied 11.

Recently self-consistent basicity scales of organic bases have been established in THF12 and

acetonitrile (AN) 14, 12d. Both of these scales contain over 100 compounds (alkylamines, pyridines,

anilines, phosphazenes, etc). These scales include also DMA, the parent compound of the family that is

one object in the current study. Amines have been considered as zero order member of homological row

of phosphazenes13. DMA-s can be viewed as zero order member of homological row of substituted

phenylphosphazenes that have been very useful compounds on building above-mentioned self-

consistent basiscity scales in THF and AN. It was shown in previous study14 that inclusion of first

phosphazene fragment into DMA molecule increases its basicity in AN nearly 10 orders of magnitude

whereas further fragments increase the basicity by ca 5 orders of magnitude. The similar trend is also

observed in THF and gas phase13. It is of interest to compare besides parent compound DMA also aryl-

substituted members of this family with analogous phosphazenes to see resulting basicity change.

Basicity of a base B in solvent S is defined using Equation and is expressed as dissociation constant

Ka of the conjugate acid HB+ of the base B or more commonly its negative logarithm pKa.

2

HB+ + S Ka B + HS+ ()

pKa = -logKa ()

To exclude the necessity to measure the solvated hydrogen ion (HS+) activity in AN the following

equilibrium between two bases B1 and B2 was studied:

B2 + HB1+ HB2

+ + B1 ()

The relative basicity of the two bases B1 and B2 (pKa) is defined as follows:

()

The simple acid dissociation equilibrium (Eq. ) used to describe the strength of an acid in polar

solvents (water, acetonitrile, etc.) does not describe the actual situation in media of relatively low

polarity (D ≤ 15 .. 20)16 such as THF, where an extensive ion-pairing takes place. The extent of ion-

pairing of protonated base cations with anions (A-) depends on the solvent, the size of the ions and the

charge distribution in ions. The general trend is that small ions tend to form solvent separated ion-pairs

(SSIP) (Eq. ) while large ions with delocalized charge tend to form contact ion-pairs (CIP) (Eq. ).

HB+ + A- HB+s · A-

s ()

HB+ + A- [HB+A-]s ()

In THF we consider the ions to be fully ion-paired and thus the proton distribution equilibrium

between two bases B1 and B2 (Eq. ) can be presented in the following form:

K

1-

2 BAHB ()

The constants Kd are the dissociation constants of the respective ion pairs. The directly measured

quantity is the relative ion-pair basicity – pKip – of bases B1 and B2. It is expressed as follows:

3

()

If the Kd values can be measured or estimated then the pK (an estimate of the pKa) can be found as

follows:

()

The Kd values were estimated using the Fuoss equation as described in refs 12 and 23. Ionic radii are

given in Table S2 in Supporting Information.

In aqueous media two well-known methods17 were used for determination of pKa values. In water the

studied equilibrium can be presented as follows:

Ka

HB+ + H2O B + H3O+ ()

()

The gas-phase basicity (GB) and proton affinity (PA) refer to the following equilibrium:

B + H+ Gb, Hb BH+ ()

GB and PA are defined as follows:

GB = –Gb PA = –Hb ()

The directly measured quantity is the relative basicity of two bases Gb:

B2 + B1H+ Gb B2H+ + B1 , ()

where:

()

4

()

The p values are the partial pressures of the respective species.

The experimental gas-phase basicity values of many substituted DMA-s were initially determined by

one of us (M.M.) by using FT-ICR method# and these data have been incorporated into NIST database

in modified form without reference to the source and experimental details. In this work the details of

these experiments and correct gas-phase basicity values, which have been never previously published

are presented. The experimental data are supplemented with calculated gas-phase basicities. The set of

basicity values from this work and literature in three solvents and gas phase enables to analyze the

structural and medium effects on this family of compounds.

Experimental

The experimental set-up, compounds and relative basicity measurement details in AN, THF and gas-

phase, also absolute basicity measurement in water are provided in Supporting Information (SI). The

pKa values in AN (Table S1 in SI) and pKip (Table S3 in SI) values in THF for the equilibria between

bases were calculated similarly as described previously12, 14 using the reference bases from these works.

For the pairs of bases in which one member had small difference in the spectra of neutral and

protonated form (dimethylamine, cyclohexylamine, N-methyl-cyclohexylamine, N,N-dimethyl-

cyclohexylamine) we also used the calculation method12 in which in addition to the spectra also exact

amount of moles of the compounds in titration vessel and added titrant are taken into consideration for

pKa calculations. The measurements in AN and THF are relative, i.e., the basicity difference

(expressed either as pKa in AN or pKip in THF) between the two bases is obtained. Absolute pKa and

pKip values, respectively were find as in previous works12, 14 and keeping literature pKa and pKip values

constant by minimizing the sum of squares of differences between directly measured pKa values in AN

or pKip values in THF and assigned pKa or pKip values, while keeping the pKa or pKip values of

reference bases (taken from ref-s 12 or 14) constant. The correction for ion-pairing in THF was

5

calculated by using the Fuoss equation as described in refs 12 and 23 resulting pKin THF. For two

compounds in Table S4 the pKa in water was found by two methods. The consistency of these results is

good. Gas-phase Gb measurement results are presented in table S5. The absolute GB values were

found similarly to pKa and pKip values by keeping the reference GB values from NIST database8

constant. Calculation results of GB-s at B3LYP DFT 6-311+G** or G3(MP2) level of bases are

presented in Table 1.

Results and Discussion

The basicity data for DMA-s and related bases from this work and literature in AN, THF, water and

gas phase are presented in the Table 1 and in Tables S1, S3 to S5 in Supporting Information.

Table 1. Basicity Values from This Work and Literaturea.

6

No Base pKa(H2O) pKa(AN) pKip (THF) pK(THF) GBexpb GBcalc(N) b,d,f GBcalc, otherb

,d

A N,N-Dimethylanilines (DMA)

1 H 5.13i, 5.10k, 5.15l, 5.07m, 5.21p

11.43o 6.5h 4.9h 217.4, 217.3c, 215.4g

216.0, 217.7e

211.6 (ring,para), 209.3 (ring,ortho)

2 2-Me 5.86p 221.2c

3 2-NMe2 227.1c 229.0

4 2-COOMe 3.78l

5 2-Cl 4.22l

6 2-Br 4.20l

7 2-NO2 2.92l 217.6

8 3-Me 5.34m 219.1, 219.4c, 217.0g

218.6

9 3-C(CH3)=CH2 218.8c

10 3-COOMe 3.86l 216.3, 216.0c

214.6

11 3-COMe 215.6, 215.5c

213.7

12 3-CHO 214.3 209.6

13 3-MeO 4.74i 11.21 6.5 5.0 213.7c 216.9

14 3-F 213.3, 211.6g

210.9

15 3-Cl 3.84 l 213.3 211.4

16 3-Br 3.81k 9.63 4.6 3.1

17 3-SCF3 209.6

18 3-CF3 3.27l 211.0, 210.8c

208.4

19 3-SF5 209.5 203.6#kahtlane

20 3-CN 2.97m 207.9, 207.5c

205.7

21 3-NO2 2.55k, 2.47l 8.26 3.3 1.8 207.9, 207.4c

204.4

22 3-Tf 206.9 203.0

23 4-NMe2 6.39i, 6.35l 226.5

24 4-NH2 6.45i 222.0, 221.9c

224.9 215.3 (NH2),

25 4-C(CH3)=CH2 224.2c

26 4-MeO 5.80i, 5.85l 12.74 7.9 6.4 220.7, 220.5c

220.5

27 4-Me 5.57i, 5.63l 12.23 7.0 5.5 219.5, 219.4c

218.6

7

28 4-COMe 217.4, 216.6c

210.2 220.4 (O)

29 4-F 215.1, 214.7c, 213.2g

212.3

30 4-CHO 1.61l 215.1, 214.7c

205.9 215.7 (O)

31 4-Cl 4.40l 214.5, 214.2c

212.3, 214.0e

32 4-Br 4.23k, 4.23l 10.12 5.1 3.6 212.3

33 4-COOMe 2.52l 214.1, 213.7c

211.1

34 4-SCF3 211.5 208.0

35 4-SCN 3.04k 8.77 3.9 2.3 206.9 198.3 (SCN)

36 4-CF3 2.67l 8.59 3.5 2.0 209.9, 209.6c

206.8

37 4-SO2Me 205.9

38 4-SF5 208.9 r

39 4-NO2 0.61l 6.45 207.8, 208.0c

200.8 209.0 (NO2)

40 4-CN 1.78m 206.5, 206.2c

203.7 206.8 (CN)

41 4-NO 4.15j, 4.17k, 4.54l

11.25 5.7 4.1 202.6 213.6 (NO)

42 4-Tf 202.7 199.7 192.5 (Tf)

43 3,5-Me2 218.1

44 3,5-(CF3)2 205.4, 205.2c

202.4

45 2,6-Me2 5.82l, 61.0l 221.0, 220.7c

219.9

46 4-MeO-2,6-Me2 223.0 222.5

47 4-Me-2,6-Me2 222.3 221.9

48 4-COOMe-2,6-Me2

218.3, 218.2c

217.0

49 4-F-2,6-Me2 217.8, 217.7c

216.4

50 4-Br-2,6-Me2 215.8c 216.2

51 4-CN-2,6-Me2 212.5, 212.0c

210.4 203.0 (CN)

52 4-NO2-2,6-Me2 212.0, 211.8c

208.8 206.4 (NO2)

53 2,4-t-Bu2 225.2c

B Anilines

54 H 4.63m, 4.58p

10.62o 7.0h 5.2h 203.3c #ilmar G3(MP2)

55 N-Me 4.85l 10.95 6.4 4.8 212.7c 209.8

56 N-Et 5.11p 213.4c 209.6

8

57 N-Pr 5.04l

58 2,6-Me2 3.87l 207.9c

59 N-Me,2,6-Me2 6.12l

60 1,3,5-(NMe2)3 229.5

61 N-Et, N-Me 6.02l 218.1c 218.7

62 N,N-Et2 6.56p 221.8c 219.8

63 N,N-(n-Pr)2 5.68l 222.5c 220.9

64 N,N-(i-Pr)2 8.14l

65 N(C2H4) ,

(1-Ph-aziridine)

214.1c

66 N(C3H6) ,

(N-Phenylazetidine)

215.7c

67 N(C4H8) ,

(N-Phenylpyrrolidine)

218.7c

68 N(C5H10) ,

(N-Phenylpiperidine)

221.4c

69 N(C6H12) ,

(1-H-Azepine, hexahydro-1-phenyl)

221.3c

C Other bases

70 NH3 9.25l 16.46l 195.7c

71 MeNH2 10.62l 18.37n 206.6c

72 EtNH2 10.65l 18.40l 210.0c

73 PrNH2 10.53l 18.22l 211.3c

74 Me2NH 10.73l 18.73n 214.3c

75 Et2NH 11.0l 18.75l 219.7c

76 Ph2NH 0.78l 5.97o 206.1

77 Me3N 9.81l 17.61n 219.4c

78 Et3N 10.7l 18.5n 227.0c

79 Cyclohexylamine 10.68l 18.35 215.0c

80 N-Me-cyclohexylamine

11.04l 18.89223.0e

81 N,N-Me2-cyclohexylamine

10.30l 18.66227.7c

82 Ph2NMe 0.86q 213.6

83 Ph3N -3.91q 209.5c 209.3

84 Benzoquinuclidine (3,4-Dihydro-2H-1,4-ethanoquinoline)

226.8c

85 1-NH2-napthalene 3.94l 9.77o 209.2c

9

86 1,8-(NH2)2-napthalene

218.0c

87 1,8-(NHMe)2-napthalene

222.5c

88 1-NMe2-8-NHMe-napthalene 227.5c

89 1,8-(NMe2)2-napthalene

12.1o 18.62o 11.7h 11.1h 238.0c 239.1

90 4-Me2N-pyridine 9.61l 17.95o 232.1c 205.6 233.7 (Py)

91 3-Me2N-pyridine 6.48l 225.4c 209.8 227.2 (Py)

92 2-Me2N-pyridine 6.98l 225.0c 213.7 226.2 (Py)aThis work if not noted otherwise, pKa(AN), pKip(THF), pK(THF) values are those of assigned

values for bases which were found from experimental data using equations , , respectively.

Experimental equilibrium measurement data are given in Tables S1, S3 in Supporting Information. b

GB values are in kcal mol-1. c values from 8. d DFT Calculations B3LYP 6-311+G** . e Calculations

G3(MP2). f protonation on amino nitrogen. g ref 10. h ref 12a. i Values from potentiometric titration.

Each value is the average of three determinations; standard deviation was always less than 0.01 pKa

units. j Value from potentiometric titration, average of two determinations. k Values from combined

method of potentiometry and spectrophotometry, standard deviation was always less than 0.03 of pKa

unit. l ref-s 18, 19. m ref 7. n ref 20. o ref 14. p ref 24. q ref 25. r HF eliminates from protonated form.

Experimental data for substituted DMA-s and related bases in the literature is insufficient for making

firm conclusions about the effects of structure and medium on the basicities of this compound family.

Relatively more information is available for water and the gas phase (see Table 1). The present results

supplement the basicity data in non-aqueous media to an important extent. Experimental values of this

work in aqueous media are in good agreement with the literature values.

Analysis of experimental and calculated gas-phase basicities in Table 1. Previously8 the

experimentally determined GB-s for 18 substituted DMA-s and for 5 2,6-Me2-DMA-s have been

published. Correlation of the experimental data (this work) with literature values gives following

equation. GB(this work) = 0.990GB (literature) + 2.49 , s(slope) = 0.013, s(intercept) = 2.77, r2 = 0.997,

S = 0.26. For the ring-substituted 2,6-Me2-DMA-s quite similar results are obtained: GB(this work) =

0.990GB (literature) + 2.45 , s(slope) = 0.023, s(intercept) = 4.88, r2 = 0.998, S = 0.18. This means that

data published in NIST derived partially from the present data are consistent with the absolute GB

10

values derived from the original data having in general 0.3 kcal mol-1 lower values. However, we

recommend using the experimental GB values determined in this work.@Ma arvan, et selline soovitus

on väga kohane, aga see tuleks anda päris diskussiooni lõpus

# siia jutt mõõdetud ja arvutatud GB-de korr analüüsist. Tuua altpoolt siia jutt mitte-N aluste kohta?

Sigma rho analysis

4-x-DMA

Table 2. Statistical Analysis of Basicity of Substitute DMA-s with field-inductive, polarizabilty and

resonance effect parameters.

series GB0 s(GB0) F s(F) R s(R) s() S r2 n

4-X substituted DMA GBcalc(N)

216.84 1.21 -22.21 2.37 -27.23 3.12 -6.85 2.58 2.03 0.945 19

4-X substituted DMA GBexp(this work)

217.00 1.09 -17.46 1.94 -16.51 3.00 -5.89 2.38 1.65 0.931 17

4-X substituted DMA GBexp(NIST)

218.65 1.47 -17.37 2.81 -15.34 4.23 -5.34 3.65 1.91 0.888 12


218.76 1.15 -20.71 2.70 -24.32 3.43 2.39 0.919 19

4-X substituted DMA GBexp(this work)

218.81 0.95 -16.64 2.23 -12.73 3.03 1.93 0.898 17


220.15 1.11 -17.27 2.98 -11.35 3.42 2.03 0.86 12


218.13 1.22 -20.295 2.93 2.13 0.813 13

3-X substituted DMA

217.01 0.66 -14.906 1.55 1.11 0.902 12

11

GBexp(this work)


218.70 0.64 -17.418 1.67 1.08 0.948 8

()

Effect of the stepwise amine structure change on basicity in various media. Stepwise methylation

of ammonia increases its basicity non-additively in the gas phase (Scheme 1). Due to the polarizability

and positive inductive effect of the first methyl group the basicity of ammonia increases by 10.9 kcal

mol-1, followed by slightly lower increase by 7.7 and by 5.1 kcal mol -1 upon addition of the second and

third methyl groups, respectively. The first cyclohexyl group has almost two times higher base

strengthening effect on ammonia than methyl group, mainly due to its more than two times higher

polarizability ((Me)=-0.35 vs (c-hexyl)=-0.76). Analogously to the methylation of ammonia series

the non-additivity is also observed on further methylation of cyclohexylamine. Here the basiscity

increases by 8.0 and by 4.7 kcal mol-1 units, respectively. Non-additivity is even more expressed on

stepwise N-methylation of aniline. Here, bringing the first methyl group into a molecule increases its

basicity by 9.4 kcal mol-1, only slightly lower change than by produced by methylation of ammonia.

The second methyl group changes basicity by 4.6 kcal mol-1, comparable to cyclohexylamine series and

slightly lower than in case of methylation of ammonia. Replacement of methyl group in simple primary,

secondary or tertiary amine with cyclohexyl group strengthens the corresponding methylated amine by

8.3 to 8.7 kcal mol-1. The change of cyclohexyl group of primary, secondary or tertiary amine by phenyl

group results in the weakening of the base by 11.7 to 10.3 kcal mol-1.

12

The basicity change on the consecutive phenylation of ammonia is non-additive; 7.6, 2.8 and 3.4 kcal

mol-1, respectively. The addition of the second phenyl group has the lowest effect. In this series the base

strengthening effect is mainly determined by higher polarizability of phenyl group ((Ph)=-0.81); this

effect stabilizes the protonated form, following smaller negative resonance (mesomeric) effect, (R-

(Ph)= 0.22) which stabilizes neutral form, and smaller inductive/field effect (F(Ph)= 0.10), which

stabilizes the neutral form. Stepwise substitution of methyl groups in trimethylamine for phenyl groups

has from previous series a different trend of the basicity change, -2.0, -3.8 and -4.1 kcal mol-1,

respectively. In this series is lost in part the gain from polarizability ((Me)=-0.35 vs (Ph)=-0.81)

and small field inductive effect. The net base weakening effect from negative resonance and steric strain

dominate. Both these suggest that addition of a second and third phenyl group introduces more steric

strain into molecule.

NH2 NH

N

NH2 NH

N

NH2 NH

NNH3

NH2

NH

N N

215.0 223.0 227.7

203.3 212.7 217.4

206.6 214.3 219.4

7.7

8.4 8.7 8.3

4.78.0

5.1

-10.3

9.4

-11.7

4.6

-10.3

10.9

195.7

209.2

206.1 209.5

5.9

2.8

3.4

7.6

-2.0

213.6

-4.1

-3.8

19.3

13

Scheme 1. Basicity change in the gas phase upon stepwise change of amine structure. Numbers below

structures show absolute GB values in kcal mol-1, numbers above or next to the arrow show their

basicity differences. @N-metüüldifenüülamiin peaks minu meelest lähtuma N-metüülaniliinist, mitte

dimetüülaniliinist. Ivari: lisan selle joone peagi

In water (Scheme 2) the effect of structural changes on basicity is significantly different from the gas

phase. Basicity change on stepwise introduction of substituents into ammonia is, in addition to the

inductive effect, strongly influenced by solvation, especially hydrogen bonding of water to the NH+

bonds of the protonated amine. The advantage of cyclohexyl group over methyl group in base-

strengthening of ammonia that was observed in the gas phase is lost in water due its bulkiness and

resulting steric hindrance of solvation. The net base strengthening effect of both substituents is ca 1.4

pKa units. Substitution of methyl group with cyclohexyl group strengthens the primary amine only

slightly, makes secondary amine stronger by 0.3 pKa units and tertiary amine by 0.5 pKa units. This

shows that solvent has strong stabilizing effect on the cation when forming the hydrogen bonds.

Substitution of the cyclohexyl ring by phenyl ring weakens the base strength in water considerably: by

approximately 5.2 to 6.2 pKa units. Upon stepwise methylation of the basicity center in

cyclohexylamine it is observed that the primary and tertiary amines are weaker than the secondary

amine. Methylation of nitrogen in aniline shows that basicity change of aniline behaves additively.

Stepwise phenylation of ammonia reduces basicity by -4.65, -3.82 and -4.69 pKa units, respectively.

This is the opposite direction when compared to the basicity change of same series in the gas phase. The

main reason for the basicity decease in this series is the loss of N-H+ bond solvation by reduction of the

number of N-H+ bonds, which can form N-H+···OH2 bonds when going from ammonium ion to

triphenylammonium ion. Similar trend, basicity decrease by -4.68, -4.27 and –4.77 pKa units, is

observed on stepwise replacement of methyl groups with phenyl groups of tertiary amine –

trimethylamine. The direction of basicity change is the same as in the gas phase. Here, all compounds

are tertiary amines, i.e. the number of possible hydrogen bonds is the same in all conjugate acids and

14

the reason for the basicity decrease is different from that in the previous series. The main contributor on

basicity change is similarly to gas phase the net base weakening effect from negative resonance and

steric strain.

The comparison of pKa values of ring substituted DMA-s from this work and literature reveals that

the 4-NO-dimethylaniline deviates from the otherwise very good linear correlation between the

common compounds: pKa(H2O literature) = 0.11 + 0.98pKa(H2O this work); s(intercept) = 0.07,

s(slope) = 0.01, n = 6, r2 = 0.999, S = 0.04. Either our pKa value (4.17) or the literature value (4.54) for

this compound is wrong. One probable explanation to this inconsistency is that some nitroso compounds

are light-sensitive and can decompose if exposed to light during storage as bulk or as solution.

Decomposition can be sometimes be observed as color change. However, we did not observe color

stability problems with bulk compound or prepared solutions. Also, two different pKa determination

methods on different days and with different batches of solutions gave the same results.

15

NH2 NH

N

NH2 NH

N

NH2 NH

NNH3

NH2

NH

N N

10.68 11.04 10.30

4.60 4.85 5.13

10.62 10.73 9.81

0.11

0.06 0.31 0.49

-0.740.36

-0.92

-5.17

0.25

-6.08

0.28

-6.19

9.25

1.37

3.94

-0.66

0.78 -3.91

-3.82

-4.69

0.86

-4.77

-4.27

-4.65

-4.68

1.43

Scheme 2. Basicity change in water upon stepwise change of amine structure. Numbers below

structure show absolute pKa values, numbers above or next to the arrows show the change of pKa. @N-

metüüldifenüülamiin peaks minu meelest lähtuma N-metüülaniliinist, mitte dimetüülaniliinist. Ivari:

lisan selle joone peagi

In acetonitrile the stepwise methylation changes the basicity of ammonia in a similar way as in water.

The introduction of the first methyl or cyclohexyl fragment into ammonia has also similar effect.

Basicity change on replacement of one methyl group in primary, secondary and tertiary methylamines

with cyclohexyl group is non-monotonous, -0.02, 0.16, 1.05 pKa units respectively. This all confirms

the importance of also AN solvent in stabilizing the protonated cations of alkylamines. Stepwise

16

methylation of the basicity center in cyclohexylamine is non-monotonous; addition of the second

methyl group weakens the base.

Replacement of the cyclohexyl ring for phenyl group weakens the base basicity in AN approximately

by -7.2 to -7.9 pKa units.

NH2 NH

N

NH2 NH

N

NH2 NH

NNH3

NH2

NH

18.35 18.89 18.66

10.62 10.95 11.43

18.37 18.73 17.61

0.36

-0.02 0.16 1.05

-0.230.54

-1.12

-7.23

0.33

-7.73

0.48

-7.94

1.91

16.46

-5.84

1.89

9.77

-0.85

5.97

-4.65

-6.18

Scheme 3. Basicity change in AN upon stepwise change of amine structure. Numbers below the

structures show absolute pKa values, numbers above or next to the arrows show the change of pKa.

Protonation site of DMA in gas phase. PA on para-C4 of DMA is reported to be 1.2 kcal mol-1 (5 kJ

mol-1) lower than PA on nitrogen (PA(N)=223.5 kcal mol-1 (936 kJ mol-1)26. Our B3LYP DFT 6-

311+G** calculation results in GB(N)=216.0 kcal mol-1, GB(C4)=211.6 kcal mol-1, GB(C2)=209.3 kcal

mol-1 confirm that observation. For several compounds also GB values are calculated on the assumption

that the ring-substituted DMA base is protonated on a basicity center different from NMe2 i.e. on the

17

substituent. Calculation results from Table 1 show that protonation on ring substituent is favored over

NMe2 protonation for the following compounds: 4-NO2–DMA (209.0 kcal mol-1 vs 200.8 kcal mol-1 on

NMe2), 4-NO–DMA (213.6 kcal mol-1 vs 202.6 kcal mol-1 on NMe2), 4-CN–DMA (206.8 kcal mol-1 vs

203.7 kcal mol-1 on NMe2) and 4-COMe–DMA (220.4 kcal mol-1 vs 210.2 kcal mol-1 on NMe2). 4-

COOMe-DMA can be also protonated on substituent, its experimental GB is 3.0 kcal mol-1 higher than

calculated GB(N), however, this difference is not large enough to be sure about the protonation site. GB

values which were obtained from FT-ICR experiments confirm that products protonated on substituent

do really exist. 2,6-Me2-DMA is ca 4 .. 5 kcal mol-1 stronger base than DMA, mainly due to the

polarizability of methyl groups ((Me)=-0.35) in phenyl ring. At the same time calculations show that

4-CN-2,6-Me2-DMA and 4-NO2-2,6-Me2-DMA will not protonate on substituent in phenyl ring,

because 2,6-Me2 substituents in ortho position to the NMe2 group destroy, due to the steric hindrance to

the resonance, the direct resonance between NMe2 and acceptor groups (NO2, NO etc) in 4-position.

Protonation on these substituents is even more unfavored as compared to protonation on same

substituents in DMA by –3.8 and -2.6 kcal mol-1, for CN and NO2 substituent, respectively. For 4-SF5-

DMA the calculations show that HF eliminates from the substituent SF5 and also one can assume that

inconsistency of experimental and calculated GB values for 3-SF5-DMA are of same origin.

Table 3. Statistical Analysis of Basicity Values in Water, AN, THF, and Gas Phase.

No Abscissa Ordinate a b s(a) s(b) S r2 n Comments

1 pKa(H2O) pKa(AN) 1.22 5.35 0.08 0.33 0.39 0.963 11 All

2 pKa(H2O) pKa(AN) 1.33 4.80 0.06 0.26 0.21 0.985 9all, excl NO2, NO

3 pKa(H2O) pK(THF) 1.34 -1.70 0.08 0.36 0.29 0.970 10All, excl 4-NO

4 pKa(AN) pK(THF) 0.99 -6.40 0.06 0.59 0.27 0.975 104-NO deviates

5 GB pKa(H2O) 0.22 -44.0 0.02 4.25 0.44 0.890 18All excl NO2, NO

6 GB pKa(AN) 0.314 -56.9 0.026 5.53 0.37 0.961 8 All excl

18

NO2, NO

7 GB pK(THF) 0.317 -63.9 0.029 6.29 0.42 0.951 8All excl 4-NO

8 GB(DMA) GB(PhP1(pyrr)) 0.693 101.05 0.082 17.93 1.100 0.959 5

9pKa(DMA) in AN

pKa(PhP1(pyrr)) in AN 0.740 13.761 0.019 0.189 0.092 0.998 5

10pK(DMA) in THF

pK(PhP1(pyrr)) in THF 0.498 12.838 0.009 0.055 0.030 0.999 4

11pKa(DMA) in H2O

pKa(PhP1(pyrr)) in H2O 0.378 9.635 0.027 0.134 0.078 0.985 5

All, excl 4-NO

5

8

11

14

0 2 4 6

pK a(H2O)

pKa(A

N)

4-MeO

4-Me

4-H3-MeO

4-Br

4-NO

3-Br

4-SCN

3-NO2

4-CF3

4-NO2 lit

lit

Figure 1. Correlation of the basicities of the studied DMA-s in water and acetonitrile.

Most deviating pKa-s are 4-NO- and 4-NO2- substituted DMA-s (Figure 1). This is caused by SSAR

(substituent solvent assisted resonance) effect#viide Taftile in water in which substituent solvation by water

molecule enhances substituent influence on a base strength and makes these two compounds weaker

bases as they should be. When leaving these two SSAR able compounds out from correlation is

19

observed that AN is 1.33 (sd 0.06) times better differentiating solvent than water. This is in very good

agreement with our previous findings in ref 14 where it was observed the value for this parameter 1.31

(sd 0.05) over a wide basicity range and wide selection of bases. It can also be that 4-NO 2 and 4-NO

substituted DMA-s are not in the solvents aminobases, but protonate on substituent. However we do not

have spectral evidence. In THF besides the 4-NO substituted DMA, also 3-MeO and 4-MeO substituted

DMA-s are weaker bases in water? as these could be.

Correlation of pKa values in AN and THF reveal that most deviating points are again 4-NO, 3-MeO

and 4-MeO substituted DMA-s. One probable explanation for deviation of 4-NO-DMA is that in THF it

will protonate not on amino N but on nitroso O similarly to gas phase. #Selle aine UV-Vis spektrid

(H2O, AN, THF) on aga kujult väga sarnased, muutuvad ainult maksimumide ja isosbestiliste punktide

asukohad. 3-NO2-DMA korral on näiteks lai ja nõrk pika lainepikkuse (400-410 nm) neutraalse vormi

neeldumine vees madalam kui AN ja selles omakorda madalam kui THF-s võrreldes neeldumisega mis

jääb 250-260 nm kanti.

1

3

5

7

2 3 4 5 6

pKa(H2O)

pK(T

HF)

4-MeO

4-Me

4-H

3-MeO

4-Br

4-NO

3-Br4-SCN

3-NO2

4-CF3

Figure 2. Correlation of the basicities of the studied DMA-s in water and THF. #SI-sse

20

1

3

5

7

8 9 10 11 12 13

pK a(AN)

pK(T

HF)

4-MeO

4-Me4-H3-MeO

4-NO

4-Br

3-Br

4-SCN

4-CF3

3-NO2

Figure 3. Correlation of the basicities of the studied DMA-s in acetonitrile and THF. #SI-sse

0

2

4

6

200 205 210 215 220 225

GB (kcal/mol)

pKa(H

2O)

4-MeO4-Me

4-H

3-MeO

4-NH2

4-CF33-NO2

3-CF3

3-CN 3-Cl

4-Br 4-NO4-Cl 3-Me

4-CN

4-NMe2

4-SCN

4-NO2

3-COOMe

4-COOMe

4-NO2

4-NO

calc

4-CN

exp

21

Figure 4. Correlation of the basicities of the studied DMA-s in gas phase and water. Protonation center

on substituent is underlined.

Outlying point of 4-NO-DMA (experimental pKa in water and calculated aminoprotonation GB value)

recommends that in water 4-NO-DMA is not aminobase?

6

8

10

12

14

200 204 208 212 216 220 224

GB (kcal/mol)

pKa(A

N)

4-MeO

4-Me

4-H

3-MeO

4-CF3

3-NO2

4-NO

4-Br4-SCN

4-NO2

4-NO

4-NO2

Figure 5. Correlation of the basicities of the studied DMA-s in the gas phase and acetonitrile.

Protonation center on substituent is underlined.

In AN solvent the SSAR effect is not expressed or is much more weaker than in water. The

correlation shows that calculated GB value of NMe2-protonated 4-NO2-DMA is located on overall

correlation line. This means that in AN it is aminobase and in gas phase it is O-base. GB value of

aminoprotonated 4-NO-DMA deviates from line.

22

1

3

5

7

202 206 210 214 218 222

GB (kcal/mol)

pK(T

HF)

4-MeO

4-Me

4-H

3-MeO

4-CF33-NO2

4-NO

4-Br

4-SCN

4-NO

Figure 6. Correlation of the basicities of the studied DMA-s in gas phase and THF. Protonation center

on substituent is underlined. #SI-sse

Similar to AN

23

244

248

252

256

260

208 212 216 220 224 228

GB (DMA)

GB

(PhP

1(pyr

r))

4-MeO

4-H4-Br

4-CF3

4-NMe2

Figure 7. Correlation of GB values of phenylsubstituted DMA-s and PhP1(pyrr) phosphazenes. #SI-

sse

9

10

11

12

13

-2 0 2 4 6

pK a(DMA) in H2O

pKa(P

hP1(p

yrr)

) in

H 2O

4-MeO

4-H

4-Br

4-CF3

4-NMe2

4-NO2

Figure 8. Correlation of pKa values in water of phenylsubstituted DMA-s and PhP1(pyrr) phosphazenes.

#SI-sse

24

Correlation of basicities of phenylsubstituted DMA-s and PhP1(pyrr) phosphazenes in water confirms

that in water base weakening effect of 4-NO2 substituent in DMA is reduced by SSAR.

18

20

22

24

6 8 10 12

pK a(DMA) in AN

pKa(P

hP1(p

yrr))

in A

N

4-MeO

4-H

4-Br

4-CF3

4-NO2

Figure 9. Correlation of pKa values in AN of phenylsubstituted DMA-s and PhP1(pyrr) phosphazenes.

Excellent correlation of phenylsubstituted DMA-s and corresponding PhP1(pyrr) phosphazenes will

prove that in AN SSAR is not expressed on 4-NO2-DMA.

25

14

15

16

17

1.5 3.5 5.5

pK(DMA) in THF

pK(P

hP1(p

yrr))

in T

HF

4-MeO

4-H

4-Br

4-CF3

Figure 10. Correlation of pK values in THF of phenylsubstituted DMA-s and PhP1(pyrr) phosphazenes.

The slopes of correlations of basicities of phenylsubstituted DMA-s and PhP1(pyrr) phosphazenes in

gas phase, water, AN and THF are as follows: 0.69, 0.38, 0.74 and 0.50 respectively. This means that

basicity of PhP1(pyrr) is in all of these media less sensitive toward substitution in the aromatic ring than

basicity of DMA-s. In reference media, gas phase, this sensitivity difference is caused by the

contribution of the ylenic structure in the substituted PhP1(pyrr) series and delocalization of the positive

charge of the protonated form into the large phosphorane moiety14. Lower slope values in water and

THF are caused by the added solvation effects. Both of these solvents can solvate cations. DMA-s are

less sterically hindered than PhP1(pyrr)-s and the solvent molecules can stabilize corresponding DMA

cations better. AN does not solvate cations, in this solvent the slope is not lower but even higher than in

gas phase.

26

208

212

216

220

224

200 205 210 215 220GB(DMA)

GB

(2,6

-Me 2

-DM

A)

4-COOMe

4-MeO4-Me

4-H

4-F

4-Br4-CN

4-NO2

Figure 11. Correlation of GB values of phenylsubstituted DMA-s and 2,6-Me2-DMA-s.

27

6

11

16

21

26

31

0.5 1.5 2.5 3.5

pKa i

n AN

4-MeO

H4-Br

4-CF3

DMA PhP1(pyrr) PhP2(pyrr)

Figure 12. Dependence of the pKa values in acetonitrile of substituted phenylphosphazenes on the

number of phosphazene groups, N,N-dimethylanilines are the compounds with zero number of

phosphorus atoms.

In Figure 13 the substituted DMA-s are considered as zero order alkylphosphazene. It was observed,

that inclusion of first phosphazene subunit increases the basicity much more than addition of the

following units. Similar trend is seen when going from DMA to higher phenylphosphazenes, see

Figures 12 and 13. Para-substituted phenyl homologues form similar trend with non-substituted series.

It is seen that phenylphosphazenes are less sensitive toward substitution in aromatic ring than N,N-

dimethylanilines. The difference of basicities of 4-MeO- and 4-CF3- substituted N,N-dimethylanilines is

4.2 pKa units, in case of PhP1(pyrr) and PhP2(pyrr) with the same substituents the differences are

respectively 3.0 and 2.9 pKa units, i.e. the influence of the substituent decreases ca 1.4 times upon

addition of phosphazene subunits.

28

3

8

13

18

23

0.5 1 1.5 2 2.5 3 3.5 4 4.5

pKip

in T

HF4-MeO

H4-Br

4-CF3

DMA PhP1(pyrr) PhP2(pyrr) PhP3(pyrr)

Figure 13. Dependence of the pK values in THF of substituted phenylphosphazenes on the number of

phosphazene groups, N,N-dimethylanilines are the compounds with zero number of phosphorus atoms.

With this scheme it is difficult to do the same analysis as with previous because some points are

missing. The difference of basicities of 4-MeO- and 4-CF3- substituted N,N-dimethylanilines in THF is

4.4 pK units, in case of PhP1(pyrr) and PhP3(pyrr) with the same substituents the differences are

respectively 2.2 and 2.6 pK units.

Kas annab vorrelda ka Me3Si-ga vms

ACKNOWLEDGMENT This work was supported by grants Nos. 6699 and 8162 from the Estonian

Science Foundation and by the targeted financing project of Ministry of Education and Science of

Estonia SF0180089s08.

SUPPORTING INFORMATION PARAGRAPH (Word Style “TE_Supporting_Information”). The

contents of Supporting Information may include the following: (1) large tables, (2) extensive figures,

29

(3) lengthy experimental procedures, (4) mathematical derivations, (5) analytical and spectral

characterization data, (6) molecular modeling coordinates, (7) modeling programs, (8) crystallographic

information files (CIF), (9) instrument and circuit diagrams, (10) and expanded discussions of

peripheral findings.

REFERENCES

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3. Sittig, M. Handbook of Toxic and Hazardous Chemicals and Carcinogens. 2nd ed. Noyes

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1987. #jäta ära

6. Amoore, J.E.; Hautala, E. Journal of Applied Toxicology, 3(6):272-290. 1983.

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8. Hunter, E. P. L.; Lias, S. G. J. Phys. Chem. Ref. Data. 1998, 27, 3, 413-656.

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9. Taft, R. W., Topsom, R. D. Progr. Phys. Org. Chem., 1987, 16, 1-83.

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Rodima T., Barten J., Lork E., Roschenthaler G.-V., Kaljurand I., Kütt A., Koppel I.,

Mäemets V., Leito I. J. Am. Chem. Soc. 2005, 127, 50 17656-17666. (d) Rõõm, E.-I.; Kütt,

A.; Kaljurand, I.; Koppel, I.; Leito, I.; Koppel, I.A.; Mishima, M.; Goto, K.; Miyahara, Y.

Chem. Eur. J., 2007, 13, 27, 7631 - 7643.

13. Koppel, I. A.; Schwesinger, R; Breuer, T.; Burk, P.; Herodes, K.; Koppel, I.; Leito, I.;

Mishima, M. J. Phys. Chem. A 2001, 105, 9575-9586

14. (a) Kaljurand, I.; Kütt, A.; Sooväli, L.; Rodima, T.; Mäemets, V.; Leito, I.; Koppel, I. A. J.

Org. Chem. 2005, 70, 1019-1028. (b) Toom L., Kütt, A., Kaljurand I., Leito I., Ottosson H.,

Grennberg H., Gogoll A. J. Org. Chem. 2006; 71, 19, 7155-7164.

15. Sooväli L., Rodima T., Kaljurand I., Kütt A., Koppel I. A., Leito I. Org. Biomol. Chem. 2006,

4, 11, 2100-2105.

16. Reichardt, C. Solvents and Solvent Effects in Organic Chemistry, 3rd Ed, VCH, Weinheim,

2003.

17. Albert, A.; Serjeant, E. P. The Determination of Ionization Constants, Chapman and Hall,

New York, NY, 1984.

18. Tables of Rate and Equilibrium Constants of Heterolytic Organic Reactions; Palm, V. Ed.;

VINITI: Moscow-Tartu, 1975-1985.

31

19. Perrin, D.D. Dissociation Constants of Organic Bases in Aqueous Solution: Published as a

Supplement to Pure and Applied Chemistry, Butterworth, London, 1965

20. Izutsu, K. Acid-Base Dissociation Constants in Dipolar Aprotic Solvents; IUPAC Chemical

Data Series No. 35; Blackwell Scientific: Oxford, 1990.

21. Kaznelson, M. Prigotovlenije sinteticheskih himiko-farmatsevticheskih preparatov; 2. Ed.;

Gosudarstvennoje tehnicheskoje izdatelstvo, Moscow, 1923, 95-97.

22. Yates, K.; Welch, G. Canadian Journal of Chemistry. 1972, 50, 474-478.

23. Abdur-Rashid, K.; Fong, T. P.; Greaves, B.; Gusev, D. G.; Hinman, J. G.; Landau, S. E.;

Lough, A. J.; Morris, R. H. J. Am. Chem. Soc. 2000, 122, 9155-9171

24. Pankratov, A. N.; Uchaeva, I. M.; Doronin, S. Yu.; Chernova, R. K. Journal of Structural

Chemistry, 2001, 42, 5, 739-746.

25. Hoefnagel, A. J.; Hoefnagel, M. A.; Wepster, B. M. J. Org. Chem., 1981, 46, 21, 4209-4211.

26. Nguyen, M. T General and theoretic aspects of anilines.,. in Patai Series: The Chemistry of

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2007, 75-165.

Voimalikud Mustanir; Mishima, Masaaki. Binding interaction of the trimethylgermyl cation with acetophenones in the gas phase. Journal of the Chemical Society, Perkin Transactions 2 (2001), (5), 798-803.Harrison, Alex. G.; Tu, Ya-Ping. Site of protonation of N-alkylanilines. International Journal of Mass Spectrometry (2000) pKa(GB) = 2.30 GB(kcal/mol)/RT = GB(kcal/mol)/1.364.

32

Supporting information

Basicity study of substituted N,N-dimethylanilines in

solution and in gas phase

Ivari Kaljurand†, Roman Lilleorg†, Algis Murumaa†,#,, Masaaki Mishima‡, Peeter Burk†, Ivar Koppel†,

Ilmar A. Koppel†, Ivo Leito†,*

Institute of Chemistry, University of Tartu, Ravila 14 Str, 50411 Tartu, Estonia

Kyushu University, Institute for Materials Chemistry and Engineering, Hakozaki, Higashi-ku, Fukuoka

812-8581, Japan

Experimental details

Compounds for experiments in AN, THF and water. 4-methoxy-N,N-dimethylaniline, 4-

trifluoromethyl-N,N-dimethylaniline, 4-methyl-N,N-dimethylaniline were used previously11.

Compounds 4-tiocyano-N,N-dimethylaniline and 4-nitroso-N,N-dimethylaniline were purified using

crystallization from mixture of hexane isomers, 3-nitro-N,N-dimethylaniline, 4-methoxy-N,N-

dimethylaniline, 4-nitro-N,N-dimethylaniline, 4-bromo-N,N-dimethylaniline, 4-trifluoromethyl-N,N-

dimethylaniline, 4-amino-N,N-dimethylaniline, 1,4-N,N,N’,N’-tetramethyldiaminobenzene were

purified using crystallization from ethanol. Compounds 4-methyl-N,N-dimethylaniline, 3-methoxy-

N,N-dimethylaniline, 3-bromo-N,N-dimethylaniline were purified by distillation in vacuum,

compounds N-methylaniline (puriss., ≥99.5% (GC)), cyclohexylamine (puriss., ≥99.5% (GC)), N-

33

methylcyclohexylamine (99%) and N,N-dimethylcyclohexylamine (purum, ≥99.0% (GC)) were used

without purification. Dimethylamine was prepared from dimethylamine hydrochloride (99%) as

described in ref. 21: into the test tube was placed the mix of dimethylamine hydrochloride (1.12 g) and

calcium oxide (0.43 g) in 2:1 molar ratios and on top of mixture was put layer of calcium oxide. Test

tube was closed by white rubber septa through which Teflon capillary for carrying the gaseous

dimethylamine was passed. Test tube was heated on the hot plate, and evolved dry dimethylamine was

condensed in vial, that was cooled on the mix of ice and sodium chloride. Vial with condensed pure

dimethylamine was closed air-tightly and was stored in refrigerator.

Scheme 4. Compounds used in this work. #To be supplemented with GB compounds.

Solvents THF (Romil, >99.9%, Super Purity Solvent, water content stated by producer <0.005%) and

AN (Romil, >99.9%, Super Purity Solvent (far UV), water content stated by producer <0.005%) were

used without additional purification. For some experiments with AN, the solvent was kept over

molecular sieves (3 Å).@tuleks välja tuua, millised, ja kasutada seda infot selleks, et argumenteerida, et

kasutatud solvent oli (või ei olnud) piisavalt kuiv. For preparation of solutions for the potentiometric

titration was used deionized water (water resistivity > 15 M cm) and for preparation of solutions for

the combined method of spectrophotometry and potentiometry was used distilled water. For UV-Vis

34

spectrophotometric titration in AN and in THF solution of trifluoromethanesulfonic acid (Aldrich, 99+

%) was used as acidic titrant and solution of triethylamine (Aldrich, 99%) and tBuP1(pyrr) (≥98%) was

used as basic titrant. For potentiometric titration method in water 0.1 M solution of HCl was prepared

from a concentrate in a sealed ampoule (lach:ner, 0.1M f=1.000±0.002, where f is the factor of a

volumetric solution that shows the accurate molarity divided by the nominal molarity).

UV-Vis spectrophotometry in THF and AN. The spectrophotometric titrations in THF and in AN

were carried out in MBraun inertgas gloveboxes under the atmosphere of argon which was constantly

circulated through a purification system that removed oxygen, water vapor and volatile organics.

Concentrations of water and oxygen in the atmosphere of the gloveboxes during all experiments in THF

and most of experiments in AN were below 0.1 ppm, during some older measurements in the AN the

concentrations were below 1 ppm. For all titration experiments in THF and for most of experiments in

AN media was used Ocean Optics HR2000+ high resolution fiber optical CCD spectrophotometer

equipped with Ocean Optics DH2000-DUV type light source and Quantum Northwest TLC 50F™

thermostatable cuvette holder with an internal stirrer. The light source, cuvette holder and

spectrophotometer were located in the glove box. For some experiments in AN and in THF Perkin-

Elmer Lambda 40 spectrophotometer equipped with quartz fiber optic system, an external sample

compartment positioned into the glovebox was used. All solutions both in AN and in THF media were

prepared in glovebox and were made fresh daily (for measurements in AN media some solutions were

used for two days). The concentrations of studied DMA-s stock solutions were in 1.5-20 mM range.

The concentrations of studied DMA-s solutions in cuvette were in 1.5×10-5 – 5×10-5 M range. Studied

bases were titrated in quartz cuvettes using Hamilton Gastight microliter syringes. After each addition

of titrant and before taking spectra the solutions were stirred on magnetic stirrer. Was obtained basic

(neutral) and acidic (cationic) spectra of each titrated pure bases and 12 to 20 spectra of mixture of two

measured bases during the titration. For both AN and THF media the pKa and pKip (pK),

respectively, calculation procedures are described earlier.14,12 In AN was carried out 31 titration

35

experiments and 15 pKa values were determined. In THF was carried out 21 titration experiments and

pKip and pK for 10 compounds were determined.

Table S4. Results of UV-Vis Spectrophotometric Titration Experiments in AN media for DMA-s and

related bases.

No Base B1 Reference Base B2 pKa pKa (HB2+)b pKa (HB1

+)c

1 Dimethylamine 2,6-Cl2-C6H3P1(pyrr) 0.45 18.56 19.02

2 2-Cl-C6H4P1(dma) -0.05 19.07

3 N-Me-cyclohexylamine 2,6-Cl2-C6H3P1(pyrr) 0.34 18.56 18.89

4 2-Cl-C6H4P1(dma) -0.19 19.07

5 N,N-Me2-cyclohexylamine 2,6-Cl2-C6H3P1(pyrr) 0.04 18.56 18.66

6 2-Cl-C6H4P1(dma) -0.36 19.07

7 Cyclohexylamine 2,6-Cl2-C6H3P1(pyrr) -0.21 18.56 18.35

8 2-Cl-C6H4P1(dma) -0.73 19.07

9 4-MeO-DMA Pyridine 0.18 12.53 12.74

10 2-Me-Pyridine -0.55 13.32

11 4-Me-DMA 2-Me-Pyridine -1.07 13.32 12.23

12 8-NH2-Quinaldine 0.71 11.54

13 4-NO-DMA 5-NO2-Benzimidazole 0.88 10.39 11.25

14 DMA -0.21 11.43

15 3-MeO-DMA 4-Br-DMA 1.10 10.13 11.21

16 4-NO-DMA -0.04 11.24

17 2-MeO-Pyridine 1.28 9.93

18 N-Me-Aniline 5-NO2-Benzimidazole 0.57 10.39 10.95

19 8-NH2-Quinaldine -0.59 11.54

20 4-Br-DMA 2-Me-Aniline -0.37 10.5 10.12


22 3-Br-DMA 1-NH2-Naphtalene -0.14 9.77 9.63

23 2-MeO-Pyridine -0.30 9.93

24 4-SCN-DMA 1-NH2-Naphtalene -0.99 9.77 8.77

36

25 4-CF3-Aniline 0.74 8.03

26 4-CF3-DMA 2,4-F2-Aniline 0.20 8.39 8.59

27 1-NH2-Naphtalene -1.18 9.77

28 3-NO2-DMA 4-CF3-Aniline 0.25 8.03 8.26

29 2,4-F2-Aniline -0.15 8.39

30 4-NO2-DMA 2,5-Cl2-Aniline 0.24 6.21 6.45

31 2,6-(MeO)2-Pyridine -1.20 7.64

aExperimental value of this work (pKa(HB1+)- pKa(HB2

+)), equation for pKa is given in eq . bValues

from this work or from 12. cAssigned pKa value for bases.

Table S5. Ionic Radii Used for Correction for Ion Pairing.

ion ion-pair radius, Å ion ion-pair radius, Å

X-pyridineH+

X-anilineH+

X-N-Me-anilineH+

222.1

X-N,N-Me2-anilineH+

X2-C6H3P1(pyrr)H+

CF3SO3-

2.242.5

X = H or substituent

Table S6. Results of UV-Vis Spectrophotometric Titration Experiments in THF for substituted

dimethylanilines and related bases.

No Base B1 Reference base B2 pKipa pKip (HB2+)b pKip (HB1

+)c pK( HB1+)d

1 4-MeO-DMA 2-NO2-4-CF3-C6H3P1(pyrr) -1.62 9.53 7.9 6.4

2 2,6-(NO2)2-C6H3P1(pyrr) 0.42 7.48

3 4-Me-DMA 0.89 7.02

4 4-Me-DMA 4-NO-DMA 1.37 5.65 7.0 5.5

5 2,6-(NO2)2-C6H3P1(pyrr) -0.46 7.48

6 3-MeO-DMA 4-Br-Aniline 0.7 5.79 6.5 5.0

7 2,6-(NO2)2-C6H3P1(pyrr) -1.00 7.48

8 N-Me-Aniline Pyridine -0.92 7.33 6.4 4.8

9 2,6-(NO2)2-C6H3P1(pyrr) -1.07 7.48

10 4-NO-DMA 2-MeO-Pyridine 1.27 4.38 5.7 4.1

37

11 4-Br-Aniline -0.13 5.79

12 4-Br-DMA 4-NO-DMA -0.56 5.65 5.1 3.6


14 3-Br-DMA 4-NO-DMA -1.06 5.65 4.6 3.1


16 4-SCN-DMA 2-MeO-Pyridine -0.50 4.38 3.9 2.3

17 4-Br-Aniline -1.92 5.79

18 4-CF3-DMA 4-SCN-DMA -0.35 3.88 3.5 2.0

19 2-MeO-Pyridine -0.85 4.38

20 3-NO2-DMA 4-SCN-DMA -0.59 3.88 3.3 1.8

21 2-MeO-Pyridine -1.08 4.38

22 DMAe 6.5e 4.9e

aExperimental value of this work (pKip(HB1+)- pKip(HB2

+)), equation for pKip is given in eq . bValues

from this work or from 12. cAssigned pKip values for bases. dAfter rearrangement at eq . e From 12a.

Potentiometric titration method in water.

Measurements were carried out using automatic titrator Mettler Toledo T90 equipped with DG115-

SC combined glass electrode for titrations in aqueous solutions (combined electrode with ground-glass

sleeve frit, Ag/AgCl reference element and 3 M KCl electrolyte saturated with AgCl), temperature

sensor DT1000 (PT1000, type B) and 5 ml burette. Combined electrode was calibrated daily at 25.0 ±

0.1 oC using four standard calibration solutions with the following pH values: 1.68, 3.56, 6.86, 9.18. All

standard calibration solutions were stored under argon. The slope of calibration graph varied from –

59.155 mV to –59.310 mV (100.0 % to 100.3 % from theoretical value), zero-point varied from 6.910

to 6.925 pH units. The concentration of acid titrant hydrochloric acid was also controlled daily by

titration of ca 0.1 M KOH primary-standard solution, which was prepared by dissolving HgO

(Reakhim, pure) and KI (Reakhim, pure for analysis) in deionized water. This solution was kept under

argon. Solutions of studied DMA-s were prepared one day earlier using deionized water. The

38

concentrations of solutions were in 1.5-4.5 mM range. 50 ml of measured solution was taken into

measuring cell that was thermostated at 25.0 ± 0.1 oC and titration data was collected on a PC.

Increment of titrant was fixed at 0.05 ml and solution was stirred before taking pH reading and next

addition of titrant until the change of potential drift on the electrodes was less than 0.025 mV/s, but not

less than 30 seconds.

In method of potentiometric titration known amount of base is neutralized by titration with an acid

solution with known concentration. The pH and added volume of titrant are recorded at any titration

point. At any titration point – i - is assumed that a(B)i ≡ [B]i, where [B]i is concentration of neutral

base, and a(HB+)i ≡ [HB+]i∙fi, where [HB+]i is concentration of protonated base and fi is activity

coefficient for the single charged species. Then eq can be rearranged as follows:

()

At any titration point the analytical (total) concentration of base Cbase, i can be presented as a sum of

concentration of both neutral and protonated form: Cbase, i = [B]i + [HB+]i. After rearrangement

[B]i = Cbase, i + [HB+]i ()

From the electroneutrality comes:

[HB+] i + [H3O+] i = [A-] i + [OH-] i ()

Deprotonated acid anion concentration [A-] i is equal to acid titrant concentration Ctitr,i

[A-]i = Ctitr,i. ()

The ion-product constant of water Kw is presented as follows: Kw = a(H3O+) ∙ a(OH-)=1.008∙10-14 at 25

ºC. If a(H3O+) = 10-pH and a(OH-) = [OH-]∙f , then [OH-]i can be presented as follows:

()

By definition

()

39

By introducing eq-s , , into eq and after rearrangement is obtained

()

By introduction of eq and into eq and after rearrangement is obtained

()

Here, on the right side of the equation all values except fi are known or obtained directly from

experiments. Activity coefficient fi is calculated for the species with a radius of 5.0 Å according to the

Debye-Hückel equation as follows:

()

Ionic strength Ii is calculated as follows

()

As [A-]i and [OH-]i are calculated according eq-s , and the solution is electroneutral the eq

rearranges to

()

Here fi is unknown value. The assigned value of fi is obtained by iterative method. For the first

iteration activity coefficient is taken as unity fi, 0=1 and using the eq-s and logfi,1 is calculated. The

process was repeated again. Three iterations were found to be enough.

Combined method of spectrophotometry and potentiometry in water.

Potentiometric measurements were carried out using same automatic titrator and electrode as in

previous method. Calibration standard buffers and conditions were also same. UV-Vis spectra were

40

recorded at Perkin-Elmer Lambda 2S spectrophotometer equipped with thermostated (25.0 ± 1oC)

cuvette holders. As in this method exact concentrations of measured bases were unnecessary, so the

concentrations of diluted and buffered solutions were approximately in 0.1-0.01 mM range to achieve

optimal optical absorbance in UV-Vis spectral range. As working buffers in this method were used 0.1

M HCl solution, the same that was used as titrant in potentiometric titration, 0.1 M glycine (Reakhim,

pure for analysis) solution, 0.1 M Tris (Reakhim, pure) solution and 0.005 M acetate buffer prepared

from glacial acetic acid (USP/FCC) and sodium hydroxide (Reakhim, pure for analysis) pH~4.7. All

buffers except HCl solution contained also 0.1 M KCl (Reakhim, chemically pure) to achieve exact

ionic strength. Into measuring cell was taken 5 ml of studied base solution, 25 ml of water and 5 ml of

buffer. As buffer was taken pure solution of one working buffer or two of these, that were mixed in

different ratios to achieve needed pH. As a result different ratios of cationic and neutral forms of

studied base are present in the mixture. The pH value was measured at 25.0 ± 0.1oC and then this

solution was taken into measuring quartz cuvette. Into reference cuvette was taken solution that was

obtained by mixing 30 ml of water and the same buffer or buffer mixture. From 8 to 10 spectra of

studied base solutions at different pH were registered.

This approach for pKa determination in water is a combined method of spectrophotometrical and

potentiometric measurement of buffer solutions containing the analyte base. If the Cbase is maintained

constant during experiment series then eq can be rearranged for m-th buffer mixture at certain

wavelength

()

Here Am is measured optical absorption, Ac is optical absorption of buffer solution containing fully

protonated base and An is optical absorption of buffer solution containing fully neutral base.

In case, when it was impossible to achieve optical absorption of fully protonated base (pKa was too

low), the Ka was calculated using regression analysis of following equation:

()

41

log fm was always kept the same by using indifferent electrolytes (the ionic strength was equal in all

measurements). Buffer components were chosen so that they did not absorb at analytical wavelength.

UV-Vis spectra, pH and volumetric data from experiments were collected in digital format into and

processed in spreadsheet program MS Excel.

In water was determined pKa values for 11 bases.

Table S7. Experimental pKa Values of substituted DMA-s in Water from This Work. ##Viia SI-sse

Base pKa

1 4-NH2-DMA 6.45a

2 4-NMe2-DMA 6.39a

3 4-MeO-DMA 5.80a

4 4-Me-DMA 5.57a

5 DMA 5.13a, 5.10 c

6 3-MeO-DMA 4.74a

7 4-Br-DMA 4.23 c

8 4-NO-DMA 4.17b, 4.17 c

9 3-Br-DMA 3.81 c

10 4-SCN-DMA 3.04 c

11 3-NO2-DMA 2.55 c

a Values from potentiometric titration. Each value is average of three determinations; standard

deviation was always less than 0.01 of pKa unit. b Value from potentiometric titration, average of two

determinations. c Values from combined method of potentiometry and spectrophotometry, standard

deviation was always less than 0.03 of pKa unit.

Compounds and experimental setup in gas-phase. Most of compounds were available from

previous studies. Some were prepared and purified according to standard procedures. FT-ICR

42

experimental setup is described in ## In gas phase were carried out #88 equilibrium measurements and

GB values for 35 DMA-s were determined.

Table S8. Results of Experimental GB measurements.a

No Base B1 Reference Base B2 GB(reference)c G

1 4-SO2CF3-DMA t-Bu2C=O 198.7 -3.5

2 4-MeC6H4COMe 201.6 -1.5

3 n-Bu2S. does not fit on the picture 198.7 1.0

4 Me2NCO2Me 202.5 0.0

5 2-F-pyridine 203.8 0.8

6 3,5-(CF3)2-DMA c-Pr2C=O 203.3 -1.9

7 3-CF3-Py 205.7 0.1

8 4-CF3-Py 206.0 0.4

9 t-Bu2S 206.5 1.2

10 3-SO2CF3-DMA d 1.4

11 3-SO2CF3-DMA 2-F-Py 203.8 -3.0

12 4-CF3-Py 206.0 -1.1

13 4-CN-DMA 4-CF3-Py 206.0 -0.4

14 3-CF3-Py 205.7 -0.6

15 2-Cl-Py 208.0 1.3

16 3-NO2-DMA 2-Cl-Py 208.0 0.1

17 4-SF5-DMA d 1.0

18 4-SF5-DMA 4-CF3-Py 206.0 -2.2

19 3-CN-DMA 2-Cl-Py 208.0 0.0

20 3-Cl-Py 208.3 0.5

21 4-SF5-DMA d 1.0

22 4-CF3-DMA d 1.9

23 4-NO2-DMA 4-CF3-Py 206.0 -1.5

24 2-Cl-Py 208.0 -0.2

25 4-SF5-DMA 4-CF3-DMA d 0.8

43

26 3-CF3-DMA d 1.6

27 3-SF5-DMA 4-CF3-DMA d 0.4

28 3-CF3-DMA d 1.5

29 4-CF3-DMA CH2=CHCH2NH2 209.2 -0.5

30 3-SF5-DMA d -0.4

31 EtNH2 210.0 -0.2

32 4-SCF3-DMA d 1.5

33 4-SCF3-DMA 3-CF3-DMA d -0.6

34 3-CF3-DMA 4-SF5-DMA d -1.6

35 3-SF5-DMA d -1.5

36 EtNH2 210.0 -1.2

37 n-PrNH2 211.3 0.3

38 4-Cl-Py 211.3 0.5

39 3-SCF3-DMA d 1.3

40 EtCONMe2 211.2b 1.5

41 3-F-DMA d 2.1

42 4-SCF3-DMA 4-NO2-2,6-Me2-DMA d 0.4

43 4-NO2-2,6-Me2-DMA 3-SCF3-DMA d 0.5

44 4-CN-2,6-Me2-DMA d 0.4

45 3-SCF3-DMA 3-F-DMA d 0.8

46 3-Cl-DMA d 0.8

47 4-CO2Me-DMA d 1.6

48 4-CN-2,6-Me2-DMA n-PrNH2 211.3 -1.0

49 t-BuCH2NH2 213.7 1.0

50 3-F-DMA 3-CF3-DMA d -2.1

51 3-Cl-DMA d 0.1


53 4-Cl-DMA d 1.1

54 Py 214.7 1.2

55 4-CO2Me-DMA 4-F-DMA d 0.8

44

56 4-Cl-DMA 3-F-DMA d -1.1

57 4-F-DMA d 0.4

58 4-CHO-DMA 2-MeO-Py 215.8 0.6

59 DMA d 2.1

60 3-CHO-DMA 4-F-DMA d 0.8

61 4-F-DMA 4-CHO-DMA d -0.1

62 3-COMe-DMA d 0.6


64 3-COMe-DMA Py 214.7 -0.7

65 DMA d 1.7

66 3-CO2Me-DMA 2-MeO-Py 215.8 -0.6

67 DMA d 1.0

68 4-COMe-DMA DMA d 0.0

69 3-Me-DMA d 1.6

70 4-F-2,6-Me2-DMA DMA d -0.3

71 3-Me-DMA d 1.2

72 4-Me-DMA d 1.7

73 4-CO2Me-2,6-Me2-DMA DMA d -0.8

74 3-Me-DMA d 0.7

75 4-Me-DMA d 1.1

76 3-Me-DMA DMA d -1.7

77 c-C6H12NH 220.7 1.5

78 4-Me-DMA DMA d -2.1

79 c-C6H12NH 220.7 1.0

80 4-OMe-DMA DMA d -3.4

81 c-C6H12NH 220.7 0.0

82 2,6-Me2-DMA c-C6H12NH 220.7 0.0

83 Me2NEt 222.1 0.7

84 4-NH2-DMA c-C6H12NH 220.7 -1.1

85 Me2NEt 222.1 -0.2

45

86 4-Me-2,6-Me2-DMA c-C6H12NH 220.7 -1.3

87 Me2NEt 222.1 -0.5

88 4-MeO-2,6-Me2-DMA c-C6H12NH 220.7 -2.1

89 Me2NEt 222.1 -1.2a Previously unpublished G equilibrium measurements determined by one of us (M.M.) using FT-ICR-MS. All values are in kcal/mol. b EtCONMe2 is 15.5 kcal/mol stronger than NH3 (195.7 in ref 8). c

GB values in kcal/mol are taken from ref 8. d this work, see table 1.

Calculations of GB values.

#Ilmar

GB-s for ## substituted DMA-s and related bases were at DFT Calculations B3LYP DFT 6-311+G**

or G3(MP2) level.

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