Patai S., Rappoport Z. 1996 The chemistry of functional groups. The chemistry of amino, nitroso, nitro and related groups / 0001 84

1. Molecular mechanics calculations

41

is no point to include in the data set classes of molecules for which the force field has not been parameterized or, in the interest of generality, such with unusual functionalities. With respect to the second issue, the experimental results should preferably reflect gasphase conformational enthalpies. In the absence of such data, free energies measured in solution may be used but, in this case, comparison with calculations is strictly valid only when there is a good reason to believe that solvent and entropy effects are negligible.

Table 22 provides a comparison of conformational energies for several simple amino compounds and a single nitro compound between some of the commonly used force fields and experiment. The force fields compared here are MM2-91 (MacMinim/MM2 implementation which is computationally identical to the original MM2-9161), MM3-92 (Macintosh implementation which is computationally identical to the original MM39262), AMBER as implemented in MacroModel 4.063, DREIDING 2.2 and UFF 1.01 as implemented in Cerius264 (the latter force field was used as originally developed,

TABLE 22. A comparison of rotational barriers and conformational energies (kcal mol 1) for several amino compounds and a single nitro compound between several commonly used force fields and experiment (all experimental and calculated data are taken from Reference 60 unless otherwise noted); the last entry provides the Average Absolute Error (kcal mol 1) between theory and experiment60. Reproduced by permission of John Wiley & Sons, Inc. from Ref. 60

									DREID		Experi
					MM2-91	MM3-92	AMBER	UFF 1.01	-ING 2.2	Tripos 5.2	-ment
Rotational barriers					1.9a	1.4b	2.1c		2.1e	2.8f	2.0g
methylamine								d
dimethylamine					3.0a	2.8b	2.3c	d	2.9e	4.9f	3.6g
Ethylamine											0.7h
gauche				anti	0.1	0.1	0.1	0.7	0.1	0.1
A values					0.8i	1.0b	1.8c		1.6e	0.6f	1.1j
NO2								d
NH2					1.4	1.2	0.3	0.8	0.5	0.0	k
											1.5k
(CH3)2NH					1.0	1.1	1.2	2.0	0.6	1.5	1.3
Piperidine derivatives
(axial		equatorial)									3.2k
N-methyl					2.5	2.4	1.3	3.7	1.8	0.5
2-methyl					2.1	2.4	1.2	3.1	1.6	1.1	2.5l
3-methyl					1.6	1.5	0.5	1.3	1.0	0.8	1.6k
4-methyl					1.7	1.8	1.1	1.8	1.3	1.4	1.9k
Ave. Abs. Error					0.34	0.39	0.99	0.61m	0.73	1.03

aReference 5.

bMM3-94 calculations for this work (including parameters for the NO2 group). cCalculated for this work with MacroModel 5.0 implementation of AMBER.

dNot available. eReference 57. fReference 52.

gMicrowave measurements in the gas phase54. For dimethylamine, MM2 was originally parameterized to reproduce a later value of 3.22 kcal mol 1 as obtained by MW measurements. See J. E. Wallrab and V. W. Laurie, J. Chem. Phys., 54, 532 (1971).

h E measurement in the gas phase.

iMM2-91 calculations for this work (including parameters for the NO2 group). j G measurement in solution at room temperature55.

k G measurement in solution, low temperature. l G measurement in the gas phase.

mOver 7 comparisons.

42	Pinchas Aped and Hanoch Senderowitz

namely without the charge model) and Tripos 5.252 as implemented in Alchemy III65 (see Reference 60 for more computational details).

Rotational barriers. All the force fields examined here reproduce the experimentally observed increase in the rotational barrier on going from methylamine to dimethylamine and, in particular, MM2 and DREIDING do a good job in matching the experimental data.

Ethylamine. All force fields (save Tripos 5.2) predict the wrong (gauche) global minimum for this molecule. However, both the experimental and calculated energy differences between the anti and gauche conformers are small.

A-value. Both MM2 and MM3 do a good job in reproducing the A-value of the amino and dimethylamino groups. MM3 also faithfully reproduces the experimental A-value for the nitro group while MM2 slightly underestimates this number. None of the other force fields is consistent in reproducing the experimental results along the nitro, amino and N,N-dimethylamino series.

Piperidine derivatives. Again, both MM2 and MM3 do a good job in reproducing the experimental axial equatorial energy differences of piperidine derivatives. All other force fields rather seriously overestimate the stability of axial conformations and consequently underestimate the energy difference. The only exception is UFF, which overestimates the aforementioned energy difference for N-methylpiperidine and 2-methylpiperidine.

The overall performance of the different force fields in reproducing the experimental data can be estimated from the average absolute error. The results of this analysis are provided at the bottom of Table 22 and are divided into three groups. MM2 and MM3 have the smallest average absolute errors, 0.34 and 0.39 kcal mol 1, respectively, followed by UFF (0.61 kcal mol 1) and DREIDING (0.73 kcal mol 1) and finally by AMBER (0.99 kcal mol 1) and Tripos 5.2 (1.03 kcal mol 1). The good performance of MM2 and MM3 are not surprising as both force fields have undergone extensive parameterization for the amino and nitro groups, as discussed above. Perhaps more surprising is the relatively good performance of UFF (although they are greatly reduced when incorporating the recommended charge model) especially since this force field has been shown to perform rather poorly on a more extensive set of organic compounds60. The results obtained with DREIDING are encouraging and suggest that the problem of the huge number of parameters needed in force field calculations may be ultimately overcome by the development of atomic-based parameters and the derivation of appropriate combination rules. Based on these results, both AMBER and Tripos 5.2 can be employed in energetic calculations of amino compounds only in a qualitative manner. Finally, we would like to re-emphasize that the overall picture and conclusions presented here are subject to changes upon replacement or inclusion of additional molecules in the data set.

III. APPLICATION OF THE COMPUTATIONAL MODEL

The use of molecular mechanics calculations has become common practice in chemical research since the early 80s, when general-purpose force fields, incorporated into user-oriented computer programs, started to appear (Figure 1). As noted above, the most popular and extensively used force fields are undoubtedly those developed by Allinger’s group, namely MMI (early 70s), MM2 (1977 ) and, more recently, MM3 (1988 ).

From	among the different	classes of compounds considered in this work, most
of the	computational work	was done on amines, while less examples are found

for nitro compounds and very few for nitroso ones. The different studies may be classified into several major areas: (1) conformational analysis and structural investigation;

(2) spectroscopic experiments and study of chemical effects; (3) investigation of chemical reactions mechanism; (4) heats of formation and density calculations, especially of high energetic materials. In the following sections we will concentrate on molecular mechanics based research studies, or on such where molecular mechanics calculations played a

1. Molecular mechanics calculations

43

30.0

20.0

10.0

1965	1970		1975		1980		1985		1990	1995

FIGURE 1. Number of publications (per year) relating to force fields and dealing with amines, nitro or nitroso compounds, during the years 1968 1994. Most of the works, prior to 1975, are connected with vibrational force fields

dominant role, and provide examples from all four areas presented above. Clearly, more examples of occasional use of the method may be found in the literature.

A. Conformational Analysis and Structural Investigation

1. Tertiary amines

Among molecular mechanics calculations of nitrogen-containing compounds, the conformational analysis of tertiary amines is the single most studied subject. Based on steric crowding in the vicinity of the nitrogen, aliphatic tertiary amines may be classified into three groups and characterized by the relative energies of barriers to nitrogen inversion and rotation around single C N bonds where, in general, bulkier substituents around the nitrogen lead to lower barriers for inversion but higher barriers to rotation66,67a.

(i) relatively unhindered amines, for which inversion barriers are significantly higher than rotational ones; (ii) moderately crowded amines, where inversion and rotational processes have comparable barriers; (iii) highly crowded amines, for which barriers associated with isolated rotation are expected to be much higher than inversion ones. (In a recent study67b it was claimed that in such compounds, all the possible conformers may interconvert via one, or several successive, steps of an inversion-rotation process. Thus, isolated rotation processes are not detectable by NMR based techniques. See also ref. 67c). In the two extreme cases, (i) and (iii), the two types of process may in principal be studied separately, both experimentally and by calculations. Such studies usually start with the construction of a conformational map, including all possible conformational interconversion pathways followed by molecular mechanics calculations of thermodynamically stable and transition state forms and by dynamic NMR experiment (DNMR), the latter analyzed in conjunction with the theoretical results.

Tertiary amines of class (i) were studied by Bushweller and coworkers, starting with simple examples such as diethylmethylamine (DEMA) and triethylamine (TEA)68. The

44	Pinchas Aped and Hanoch Senderowitz
TABLE 23. Letter designation for naming tertiary amine conformations
Letter	Compound	Orientation
First letter
G	DEMA	CCH3 group gauche to the lp and to the NCH3 group
	TEA	Methyl group gauche to the lp and to an A group
	EMAB	Methyl (CH2N) group gauche to the lp and to the NCH3 group
	IDMA	An isopropyl methyl group gauche to the lp
	EMAP	CCH3 group gauche to the lp and to the NCH3 group
G0	DEMA	CCH3 group gauche to the lp and to the other N-ethyl group
	TEA	Methyl group gauche to the lp and to an A group
	EMAB	Methyl (CH2N) group gauche to the lp and to the 2-butyl group
	EMAP	CCH3 group gauche to the lp and to the isopropyl group
A	DEMA	CCH3 group anti to the lp
	TEA	Methyl group anti to the lp
	EMAB	Methyl (CH2N) group anti to the lp
	IDMA	An isopropyl methyl group anti to the lp
	EMAP	CCH3 group anti to the lp
Second letter
G	DEMA	Same as first letter
	TEA	Same as first letter
	EMAB	C1 methyl of 2-butyl gauche to the lp and to the N-methyl
	IDMA	An isopropyl methyl group gauche to the lp
	EMAP	The isopropyl methine H gauche to the lp and to the N-methyl
G0	DEMA	Same as first letter
	TEA	Same as first letter
	EMAB	C1 methyl of 2-butyl gauche to the lp and to the N-ethyl
	EMAP	The isopropyl methine H gauche to the lp and to the N-ethyl
A	DEMA	Same as first letter
	TEA	Same as first letter
	EMAB	C1 methyl of 2-butyl anti to the lp
	IDMA	An isopropyl methyl group gauche to the lp
	EMAP	The isopropyl methine H anti to the lp
Third letter
G	TEA	Same as first letter
	EMAB	C4 methyl of 2-butyl gauche to methine H and to the C1 methyl
G0	TEA	Same as first letter
	EMAB	C4 methyl of 2-butyl gauche to methine H and to the nitrogen
A	TEA	Same as first letter
	EMAB	C4 methyl of 2-butyl anti to methine H

DNMR spectra of DEMA suggest that the GG conformer is the global minimum (see Table 23 for naming conventions), but that it rapidly (on the NMR time scale at 102 K) interconverts with rotamers of different symmetry, such as GG0 and G0G. The assignment of the spectra largely depends on the availability of accurate chemical shifts values ( υ) for the NCH2 protons in gauche and anti orientations to the nitrogen lone pair (lp). These were obtained from the NMR spectra of a similar system, t-butylmethylethylamine and its deuterated derivatives which, based on MM2 calculations (1980 version with preliminary parameters for amines), were assigned to a single conformer where the diastereotopic proton assumed both orientations (all other rotamers of the systems were calculated to be at least 3 kcal mol 1 above the global minimum and thus should not be detectable in

1. Molecular mechanics calculations

45

the NMR experiment). The MM2 force field employed in this work was further tested for its ability to reproduce rotational barriers around C N bonds. The calculated value for trimethylamine (4.7 kcal mol 1) is in very good agreement with the experimental one

(4.4 kcal mol 169 ). Having satisfied this requirement, MM2 calculations were next used to map the potential surface of DEMA using the ‘double driver’ option to get a 5000-point potential energy grid as a function of the two lp N C C dihedral angles. The results are presented as a contour map in Figure 2 where in addition to the energy minima (i.e. conformers) indicated by their symbols, the energy peaks and saddle points (i.e. rotational barriers) are also marked. The MM2 calculations point out the GG0 (or G0 G) as the most stable conformer, however only slightly (0.05 kcal mol 1) below the GG one. The AG0 and AG are two additional low-energy conformers (0.47 and 0.66 kcal mol 1, respectively), while other stable forms (G0 G0, AA) are at least 2.96 kcal mol 1 higher in energy, as could be expected noting their severe 1,5 pentane-like interactions. Thus MM2 predicts DEMA to exist as a mixture of four NMR detectable conformers. The apparent contradiction with the NMR spectra, which revealed only two sets of peaks, was readily solved by examining the potential energy surface: Rotational barriers for the GG0 $ GG $ G0G and AG $ AG0 interconversions, which involve alkyl. . .lp eclipsing only, were calculated to be 4.5 kcal mol 1 and thus could not be separated on the NMR time scale which, at the experimental temperature (100 K), requires a minimum conformational interconversion barrier of ca 5 kcal mol 1. In contrast, the GG0 $ AG interconversion which proceeds

FIGURE 2. An energy contour map for diethylmethylamine recomputed using the MM2-91 force field. The separation between contour lines is 1.0 kcal mol 1

46 Pinchas Aped and Hanoch Senderowitz

through an alkyl. . .alkyl eclipsing conformation was calculated to have a rotational barrier of 6.0 kcal mol 1 resulting in separation into two conformational families.

Triethylmine (TEA) can be regarded as an extension of DEMA to a rotameric space defined by three lp N C C dihedral angles. The conformers are grouped into three low-energy rotameric families: G0G0 G0 , GAG (AGG, GAG, GGA) and GAG0 (AGG0 , G0 AG, GG0 A etc.), all within a 0.2 kcal mol 1 range (MM2). Other groups, G0 G0G0 (C1), G0 AG0, AAG and AAA, are all at least 2.9 kcal mol 1 above the global minimum and could therefore be excluded from the discussion. A symmetrically related system, tribenzylamine (TBA)70 shows a different picture: The lowest-energy conformer according to MM2 is of C3 symmetry (37), the two next ones are a C1 (1.17 kcal mol 1) and Cs (1.98) forms. A comparison of the areas below the NMR peaks assigned to the two lowest-energy forms, C3 and C1, indicated a free-energy difference of 0.18 kcal mol 1 in favor of the former. While this trend is reproduced by MM2, the calculated energy difference (1.17 kcal mol 1 in favor of the C3 form) is too large and is only slightly reduced (0.95 kcal mol 1) upon the introduction of an entropy correction term due to the 12:4 statistical preference of C1 over C3. This discrepancy between theory and experiment may well be attributed to the absence of suitable parameters in the force field version used in this study to adequately describe the Ar C N moiety. The rotational barriers in this system involve Ar. . .lp eclipsing and, in contrast with both DEMA and TEA, are

high enough ( G‡ D 5.5 kcal mol 1) to allow for conformational separation by DNMR. No attempt was made to calculate these barriers with MM2.

Ph H

Ph

H N

Ph H

H H

H

(37)

An example of a class (ii) tertiary amine is provided by N-ethyl-N-methyl-2- aminobutane (EMAB71), a moderately crowded amine in which some of the rotational barriers are energetically comparable to the N-inversion ones. In this compound a chiral carbon adjacent to a chiral nitrogen gives rise to four families of stereoisomers (defined by the chirality at the carbon and nitrogen atoms, respectively): RR, SS, RS and SR, each having 27 possible conformers. The RR/SS and RS/SR relate as enantiomeric couples, while the RR/RS and SS/SR families are diastereomers, and may interconvert via N-inversion. This leads to a total of 54 forms which, in principle, can be distinguished by NMR in achiral solvents. A combined DNMR molecular mechanics study of EMAB and some of its selectively deuterated derivatives found 18 of the latter populated enough to be NMR detectable. Four subspectra could be identified and were assigned to the diastereomeric couple RR (or SS; two subspectra with relative populations of 49% and 12%) and RS (or SR; two subspectra with relative populations of 22% and 17%). The interconversions among the rotamers within a group (same subspectra) are fast on the NMR time scale even at 104 K, while those among the groups (different subspectra) are detectable and

their rate constant and G‡ values could be measured. These are rotational processes when the groups involved belong to the same diastereomer (k1, k2 in Scheme 1), and inversion (ki) between the diastereomeric couples. 50 of the possible 54 forms converged during MM2 calculations, of which the G0 AG0 of the RR family (see Table 23 for naming conventions), assigned to the most populated NMR subspectra, was indeed found to be the global minimum. All the 9 lowest-energy conformers (Erel 0.76 kcal mol 1 according

1. Molecular mechanics calculations

47

Group population

NMR (MM2)

			H	H
	G′AG′			GAG′
	(0.00)
				(0.17)
49%	(63)
		H		H
	G′AG			GAG
	(0.61)			(0.82)
			k2
		∆G	= 6.4 kcalmol
				H
12%	(2)			GG′G
				(0.67)
			ki
	∆G	= 7.3 kcalmol
22%	(30)			GAG
	GAG′
	(0.08)			(0.73)
		H		H
			k1
		∆G	= 5.6 kcalmol
	GGG			G′GG
	(0.76)			(0.50)
			H	H
17%	(5)

SCHEME 1. Conformational map of the RcRN and RcSN diastereomers of N-ethyl-N-methyl-2- aminobutane (EMAB). Interconversions among conformers within dashed boxes are fast on the NMR time scale at 104 K. Those between dashed boxes occur via rotations about the methine carbon nitrogen bond with barriers which are DNMR-visible. The interconversion between the solid boxes occurs via nitrogen inversion (disstereomeric interconversion). The values in parentheses are MM2-80 results. Reprinted with permission from Reference 71. Copyright (1988) American Chemical Society

48 Pinchas Aped and Hanoch Senderowitz

to MM2) could be assigned to the four subspectra, and the relative populations of these groups at 104 K (assuming equal entropy) were calculated as 63%, 2%, 30% and 5%, giving the same order as, and good agreement with, the experimental results. All conformers having a methine proton anti to the nitrogen lp (e.g. RR: GGA; RS: AG0A) were found to be at least 1.09 kcal mol 1 above the global minimum, resulting in an expected relative population of less than 0.5% at 104 K. Indeed, no such structures were identified in NMR spectra. The rotational barriers for the interconversions within the groups were calculated by the dihedral driver option as 4.4 (G0AG0 $ GAG0) and 4.0 kcal mol 1 (G0 AG0 $ G0 AG; GAG0 $ GAG), i.e. predicted to be too fast on the NMR time scale even at 104 K, which confirms the conclusions drawn from the DNMR. The complete picture of the stereodynamics of EMAB is presented in Scheme 1.

More recent studies of class (ii) tertiary amines, namely isopropylamines, were performed by Bushweller’s group and employed a combination of 1H- and 13C-DNMR experiments and molecular mechanics calculations using a latter version of the MM2 force filed (MM2-87) with specific parameters for amines. Isopropyldimethylamine (IDMA)72 was found to exist as an equilibrium mixture of three conformers: 2 enantiomers with C1 symmetry (AG, GA) and a Cs form (GG), interconverting via rotation around the nitrogen methine carbon bond. The two NMR subspectra of approximately 3:1 ratio were assigned to the AG/GA and GG rotamers, respectively. The rotational barriers obtained by DNMR, 4.4 4.5 kcal mol 1 for the AG/GA $ GG interconversion, and a lower limit of 5.2 kcal mol 1 for the direct (i.e. not via the Cs form) AG $ GA one, seem reasonable: The latter process involves simultaneous eclipsing of 2 couples of methyl groups, while in the former, one of the eclipsed couples is H. . .Me. The ‘driver’ option was again used to calculate the rotational potential around the N CH(CH3)2 bond (see Figure 3) and the three rotamers were separately minimized. The calculations confirm the NMR picture of three, almost energetically equal conformers (NMR: g(GG-AG/GA) D 0.07 š 0.02 kcal mol 1; MM2: H(AG/GA-GG) D 0.19 kcal mol 1). The calculated 5.37 kcal mol 1 barrier for the AG/GA $ GG transition, and 7.84 kcal mol 1 for the enantiomeric interconversion, though probably a little overestimated, suggest that the actual exchange between the two enantiomers occurs via the Cs conformer. To further confirm that no isolated diastereotopic methyl rotations are involved in the NMR visible dynamic processes, all the barriers for such rotations in the AG and GG conformers were calculated by MM2-87 (such rotations may also average hydrogen signals and lead to

− ∆Hf (kcal mol 1)

−10
−12
−14
−16		AG		GA		GG		AG
−18		−60	0	60	120	180	240	300

Dihedral angle H-C-N-lone pair (deg)

FIGURE 3. Rotational energy profile around the methine carbon nitrogen bond of isopropyldimethylamine (IDMA) as calculated by MM2-87. Reprinted with permission from Reference 72. Copyright (1992) American Chemical Society

1. Molecular mechanics calculations

49

temperature-dependent spectra). As a preliminary test, the appropriate barrier in trimethylamine was calculated to be 4.37 kcal mol 1 (an improvement over the MM2-80 value of 4.7 kcal mol 1; see above) and is now in excellent agreement with the experimental

value (4.4			kcal mol 1; see above). All such rotations in IDMA were found to be in the
2.96		4.24	kcal mol 1 range, i.e. below the detectable threshold by NMR at 95 K.

A closely related system to both IDMA and EMAB is the chiral tertiary amine N- ethyl-N-methyl-2-aminopropane (EMAP)73. As in the case of EMAB, its DNMR spectra could be accurately simulated assuming four subspectra. These were assigned to the G0 G0 $ GG0 (59%), GG (34%), GA (2%) and AA (5%) conformational families. The DNMR simulation of EMAP and its d7 deuterated derivative, in the range of 95 130 K, also provided the rotational barriers for the appropriate conformational interconversions. As in the case of DEMA, MM2-87 calculations were used to map the conformational space of EMAP as defined by the two dihedral angles lp N CH CH3 and lp N CH2 CH3, providing results in excellent agreement with the DNMR ones. The calculated potential surface reveals twelve stable conformers separated by energy barriers. The five rotamers assigned to the four NMR subspectra were all calculated to be in the range of 0.53 kcal mol 1 above the global minimum (G0 G0), while all other forms are at least

2.7 kcal mol 1	higher in energy, i.e. predicted to be NMR invisible. The MM2 calcu-
lated rotational	barriers (see Scheme 2), though they seem to be consistently a little

H

GG

a

(0.13)

6

=.

G

4

kcalmol

∆

+

+

mol

K3

(5

.

K6

kcal

5)

.4

6

++

=

b

G

∆

K4

∆G≠ = 5.2 kcal mol

(5.6)c

AA

=2.5

GA

(0.39)

∆kcalG

(0.53)

H

H

++

mol

6

=.

K5

4

.4)

G

kcal

∆

+

(5

+

K2

mol

K1

mol

.7

kcal

+

4

+=

G

∆

H

++

d

H

(4.4)

∆G

< 4.5 kcal mol

G´G´

GG´

(0.00)

(0.21)

SCHEME 2. Conformational map of N-ethyl-N-methyl-2-aminopropane (EMAP). Reproduced with permission from reference 73. aMMP2-87 relative energies in parenthesis. bMMP2-87 H‡ values in parenthesis. cThe rotational barrier for the direct GG $ GG0 exchange was calculated as 8.5 kcal mol 1. dlower limit for DNMR detection in this study

50	Pinchas Aped and Hanoch Senderowitz

overestimated, have a standard deviation of only 0.5 kcal mol 1 from the experimental values.

Even more sterically hindered tertiary amines were studied by Lunazzi and coworkers75,76. In a series of N,N-diisopropyl66, N-t-butyl-neopentyl and N-t- butyladamantyl amines74 some of the NMR detectable dynamic processes are of inversion rotation type. Scheme 3 summarizes the possible interconversions in the diisopropyl series: For the neopentyl derivative 38 for example, the DNMR (1H and 13C) shows two successive processes during the cooling procedure, with barriers of 8.9 and 7.7 kcal mol 1. MM2-82 calculations of 39 define 3 possible rotamers around the R C N lp dihedral angle (Figure 4). Since the GC and G (gaucheC and gauche ) are enantiomeric forms, and the A (anti) conformer, with isopropyl groups on both sides of the t-butyl one, is much higher in energy (about 7 kcal mol 1), only one rotamer, the GC (or G ), should be considered. A further analysis of this structure called for a check of the various combinations of the isopropyl methine proton with respect to the lp, i.e. the two lp N C(CH3)2 H dihedral angles: 11 distinct conformers could thus be minimized by MM2, half of which lie within 1.5 kcal mol 1 of the lowest form, and should be considered when determining significantly populated conformations.

				(39)
	R			R
		Pri*	Pri*
	N	inversion/rotation		N
		++	= 8.9 kcal mol
		∆G
H		H	H	H
	Pri			Pri
	rotation		rotation	= 7.7 kcal mol
				++
				∆G
	R			R
Pri				Pri
	N	inversion/rotation		N
H		H	H	H
	Pri*			Pri*

SCHEME 3. Reproduced with permission from Reference 74

For N-ethyl-N-tert-butylneopentylamine (ETNA, 40)74, three successive processes are sequentially revealed during the cooling procedure in the DNMR spectra, with barriers of 8.1, 7.3 and 6.0 kcal mol 1. As in the diisopropylamine series, the highest barrier is attributed to an inversion/rotation process (40a $ 40b), and the lower ones to rotations