Patai S., Rappoport Z. 1996 The chemistry of functional groups. The chemistry of amino, nitroso, nitro and related groups / 0205 248

5. The chemistry of ionized, protonated and cationated amines in the gas phase 215

C2H3 + NH4+

+ NH3

SCHEME 6

-DIs might be expected to eliminate an alkene with production of an ˛-DI, as was illustrated previously by the generation of žCH2NH3C from žCH2CH2CH2NH3C (equation 1). However, this view is complicated by the possibility of isomerization to the corresponding ionized amine by a 1,4-H shift. This conventional isomer may then fragment by ˛-cleavage. Thus, the CID spectrum of ions generated as žCH2CH2CH2NH3C is dominated

by CH3CH2ž loss via rearrangement to CH3CH2CH2NH2Cž17 . Parallel isomerizations to form isomeric DIs or ionized amines occur readily for υ- and other DIs in which the charge and radical sites are sufficiently far apart to permit facile hydrogen shifts.

An interesting contrast with the analogous -DIs corresponding to ionized alcohols

emerges at this point: a 1,4-H shift is not observed for žCH2CH2CH2OH2C7,17 , which fragments by loss of water in preference to isomerizing to ionized n-propanol. Thus, the 1,4-H shifts occur more readily in nitrogenous systems; this contrast is intelligible in terms of the lower critical energies for hydrogen abstraction by ionized amino groups, which in turn may reflect the less stringent geometrical restraints compared to the corresponding H-shifts in the analogous ionized alcohols7, as uncovered by MO calculations53,54. However, žCH2CH2CH2CH2OH2C and related υ-DIs containing oxygen do undergo facile 1,5-H shifts17.

As might have been anticipated, the principal isomerization pathway for many DIs is hydrogen transfer. This process usually involves at least a five-membered ring transition state. However, isolated exceptions are known. Thus, as noted previously, žCH2CH2NH3C undergoes an irreversible 1,3-H shift to form CH3CH2NH2Cž , which then expels CH3ž . The unidirectional nature of this hydrogen transfer is established by the loss of CH2Dž

with high specificity from žCH2CH2ND3C via rearrangement to CH2DCH2NH2Cž14 . Skeletal isomerizations are also important for ˇ-DIs, which undergo a facile rearrange-

ment corresponding to a 1,2-NH3 shift. Thus, žCH2CH2NH3C interconverts rapidly with H3NC CH2CH2ž (equation 7). The ease of this degenerate rearrangement was predicted by early MO calculations5, supported by later theoretical studies20,55 57 and confirmed by labelling experiments14. Thus, metastable žCD2CH2NH3C and žCH2CD2NH3C behave

žCH2CH2NH3C is large compared to the extremely small barrier (ca 10 kJ mol 1) for the

corresponding 1,2-OH2 shift in the oxygen analogue, žCH2CH2OH2C55 57 . Nevertheless, it remains sufficiently facile that 1,2-NH3 migration in ˇ-DIs occurs more rapidly than fragmentation. Thus, the CID spectra of related pairs of isomeric DIs such as

(CH3)2Cž CH2NH3C and žCH2(CH3)2Cž NH3C often are indistinguishable41,42, as would be expected if the 1,2-NH3 shift occurred readily (equation 8).

This 1,2-NH3 migration is the key step in the reorganization of the heavy atom skeleton which precedes pseudo-˛-cleavage of ionized long-chain alkylamines (Scheme 3). The transition state for this process may be considered to resemble a tight complex of an ionized alkene (ethylene in the case of the archetypal ˇ-DI, žCH2CH2NH3C ) and NH3 (equation 9). This idea is consistent with the behaviour of adduct ions [CnH2nNH3]Cž generated by direct combination of the appropriate ionized alkene and NH358,59.

At least some -DIs, including those derived from ionized branched primary amines, have appreciable bonding between the ˛- and -carbon atoms48 50,60 62. In the case of homologues of žCH2CH2CH2NH3C , formation of a full C C bond would lead to an ionized cyclopropane and ammonia (or an alkylamine, if the initial DI has more than one substituent on nitrogen). However, the ionic and neutral components in such systems may remain bound by virtue of ionic forces. Species of this kind are called ion-neutral complexes (INCs)63. The ionic and neutral partners may be attracted together so strongly by ion dipole and related forces that the INC is substantially stabilized (by 50 100 kJ mol 1, in favourable cases) relative to the sum of the enthalpies of the isolated components. These INCs provide a means of interpreting many previously baffling fragmentations in a unified and mechanistically satisfying manner. The essence of INC-mediated explanations is that the ionic and neutral components become sufficiently ‘free’ to display their inherent properties. Thus, an incipient cation may isomerize and hydrogen transfers between the partners may take place; more complex processes, in which the components recombine in new ways, are also possible. The defining characteristic of INCs is the ability of the partners to rotate around one another. It is this geometric freedom which permits hydrogen transfers between initially remote sites and novel recombinations of the components. True INCs are often considered to occupy discrete potential energy wells; however, it is possible that some INCs correspond to entropic bottlenecks rather than to stable intermediates.

The possibility of forming species resembling an ionized cyclopropane coordinated to ammonia or an alkylamine offers an attractive route for isomerizing the skeleton of the original -DI via a process which corresponds to a 1,3-NH3 shift48 50. Thus, CH3(žCH2)CHCH2NH3C may rearrange to CH3(NH3C )CHCH2CH2ž via this means (Scheme 7). The equivalent 1,3-rearrangement for -DIs formed from the analogous ionized ethers is extremely facile and of greater general importance61,64 67. Nevertheless, this 1,3-NH3 migration provides an explanation for several unexpected alkyl radical eliminations from ionized n-alkylamines which cannot be formulated either as ˛-cleavage of the initial structure or as pseudo-˛-cleavage occurring after a 1,2-NH3 shift in a ˇ-DI.

5. The chemistry of ionized, protonated and cationated amines in the gas phase 217

SCHEME 7

B. Reactions of Ionized Alkylamines

1. Overview and comparison with ionized alcohols and ethers

In general, the behaviour of ionized amines shows many similarities to those of the analogous ionized alcohols or ethers. Both classes of radical-cation tend to dissociate at high internal energies via ˛-cleavage without prior rearrangement and the ease of fragmentation increases dramatically with branching at the carbon atom carrying the heteroatom68. However, there are important differences which reflect the disparate influences of the two heteroatoms. The corresponding chapter on the chemistry of ionized alcohols and ethers69 should be consulted for a more detailed analysis of the structure and reactivity of CnH2nC2OCž radical-cations.

In fast reactions, ionized amines show an even greater propensity to undergo the ubiquitous ˛-cleavage than do ionized alcohols and ethers. This distinction may reflect the superior stability of the immonium ions compared to their oxonium ion counterparts18,70,71. Thus, the hydride anion affinities [D RC H , corresponding to the heterolytic bond dissociation energy of the conjugate compound] of immonium ions are ca 100 kJ mol 1 lower than those of the analogous oxonium ions [e.g. D RC H of CH2DNH2C and CH2DOHC are 912 and 1054 kJ mol 1, respectively]72.

Another difference is the reduced importance of fragmentations entailing C N fission compared to the analogous routes involving C O cleavage. Even ionized amines containing a tertiary alkyl substituent rarely decompose directly to give a simple carbonium ion, CnH2nC1C . The analogous tertiary alcohols and ethers do show appreciable signals corresponding to CnH2nC1C in their spectra. Thus, the relative intensities (RIs) of the peak at m/z 57 in the 70 eV spectra of t-butylamine, t-butanol and t-butyl methyl ether are 2 7, 9 18 and 25 27%, respectively73. Moreover, this trend persists in the low-energy, low-temperature (LELT) spectra, obtained by ionization with 12 eV electrons at a source temperature of 350 K. However, analysis of the LELT spectra of larger ethers shows that the CnH2nC1C ions may be secondary fragment ions, formed by dissociation of oxonium ions produced by ˛-cleavage, rather than primary fragments of ionized ethers74,75.

Similarly, ionized alcohols and ethers containing a chain of at least three contiguous carbon atoms attached at one end to the oxygen atom frequently expel water or the alcohol derived from the smaller alkyl group76 80. However, the corresponding ionized amines rarely eliminate ammonia or small alkylamines in great abundance. This contrast reflects energetic factors. Water and small alcohols are extremely stable molecules ( Hf D 240 and 190 kJ mol 1, respectively, for water and methanol), but ammonia and methylamine are not particularly stable ( Hf D 20 and 25 kJ mol 1, respectively)82,83. Moreover,

218 Richard D. Bowen

a nitrogen atom is even better than an oxygen atom at stabilizing a positive charge on an adjacent carbon atom81. Consequently, the combination of products corresponding to CnH2nCž and RZH is energetically much less favourable when Z D N than when Z D O, particularly when compared to the energy of the alternative products obtained by ˛-cleavage.

Several of these differences, including the enhanced tendency of species generated as CnH2nC1ORCž to lose ROH, remain in slow reactions, particularly those of metastable ions with moderately long alkyl chains (i.e. containing υ-hydrogen atoms). Nevertheless, some similarities also become apparent. Thus, many metastable Cm H2mC1(CH3)CHZHCž (Z D O, NH) and Cm H2mC1(CH3)CHOCH3Cž species eliminate an alkane, Cm H2mC2, derived from the principal alkyl substituent at the branch point and a hydrogen atom from the adjacent methyl group65,84,85. These reactions, which may be interpreted in generic terms as a 1,2-elimination with a low degree of concert perhaps involving INCs (equation 10), give rise to ionized enols, enol ethers and enamines, respectively.

H

Despite this superficial similarity, however, subtle differences between the behaviour of ionized amines and the analogous ionized alcohols and ethers remain. Thus, metastable ionized 2-butylamine loses 80% ethane; in contrast, ionized 2-butanol eliminates both ethane (35%) and methane (40%)85. The latter reaction corresponds to loss of the smaller methyl group and an ˛-hydrogen atom from the larger ethyl substituent at the branch point. Methane loss does not occur from ionized amines with a methyl substituent on the ˛-carbon, with the solitary exception of ionized isopropylamine which does expel methane (10%). However, ionized 3-hexylamine eliminates both ethane (35%) and propane (20%)85.

Other similarities and contrasts include the occasional importance of fragmentations corresponding to single and double hydrogen transfer which result in alkene (Cm H2m ) and alkenyl radical (Cm H2m 1ž ) loss, respectively. Thus, the major fragmentation of metastable ionized isobutyl alcohol is expulsion of an allyl (C3H5ž ) radical, but the analogous amine does not undergo this process to an appreciable extent86,87. However, this trend is reversed for the neopentyl homologues: metastable ionized neopentanol loses CH3OH but not C4H7ž , whereas metastable ionized neopentylamine does undergo double hydrogen transfer with elimination of a methallyl radical45,88. Many of these rearrangements involve DIs and pertinent examples are discussed in Section III.B.3.

2. Fragmentation of unrearranged ionized alkylamines

Definite trends are observed in the intensities of the signals due to the molecular ion and the primary fragment ions in the EI spectra of alkylamines. These trends are more clearly apparent in the LELT spectra, because the relative intensities of the molecular ions are enhanced relative to those in the conventional 70-eV 500-K spectra. A survey of the LELT spectra of about 30 small alkylamines containing up to six carbon atoms revealed three important trends in the EI spectra of amines75. The relative abundance of the molecular ion is markedly reduced by branching at the ˛-carbon atom and significantly diminished by increasing the length of the principal alkyl substituent, but it is usually enhanced by progressive methylation of the nitrogen atom.

As noted previously, ionized primary and secondary alkylamines isomerize to DIs provided they have sufficiently long alkyl chains and are allowed enough time. These

5. The chemistry of ionized, protonated and cationated amines in the gas phase 219

isomerizations are usually reversible. Consequently, provided that the DI reverts only to the original ionized amine, fragmentation of the regenerated radical-cation will appear to occur from the initial structure. Indeed, such a specific interconversion with DIs might be undetectable, even by isotopic labelling. However, this situation rarely obtains in practice. Further hydrogen transfers and/or skeletal rearrangements are possible, as illustrated previously. Thus, once an ionized long-chain primary alkylamine has isomerized to a DI by a 1,4- or 1,5- or 1,6-H shift from carbon to nitrogen, additional 1,4- or 1,5- or 1,6-H transfers between carbon atoms often become feasible. The end result is extensive exchange of the hydrogen atoms on the various sites within the original alkyl group, if it is long enough, or between alkyl chains if the nitrogen atom carries more than one substituent. Moreover, if the relay of hydrogen shifts may transfer the radical site to the ˇ- carbon atom, facile NH3 migration and skeletal rearrangement occurs to give an isomeric ˇ-DI, which may undergo subsequent hydrogen transfer(s) leading to pseudo-˛-cleavage (Section III.B.3.a).

a. ˛-Cleavage. In view of the complications arising from the possibility of intramolecular hydrogen transfers, detailed mechanistic studies on ˛-cleavage generally should be conducted on ionized tertiary alkylamines, which do not rearrange to DIs. Another approach is to study ionized amines which have alkyl chains that are too short to permit the hydrogen transfer process. The importance of these caveats has been appreciated only relatively recently and must be borne in mind in assessing early mechanistic work on ˛-cleavages.

˛-Cleavage has traditionally been regarded as an extremely simple process, in which a C C bond is broken essentially without reverse critical energy other than that which might arise if the products happen to have a total enthalpy of formation lower than that of the fragmenting ion. This view was undermined by the discovery that several ionized t-butylamines, (CH3)3CNHRCž [R D H, CH3 or (CH3)3C], expel a methyl radical with the production of a broad dished metastable peak, even though the resultant products lie 30 50 kJ mol 1 higher in energy than the reactant89. The observation of this kinetic energy (KE) release (11 21 kJ mol 1) indicates that there is a definite energy barrier towards the reverse reaction; moreover, a relatively specific part of this reverse critical energy is partitioned as translation. Methyl radical loss from ionized isopropylamines also is accompanied by a significant KE release (ca 5 kJ mol 1), but the corresponding metastable peaks have a Gaussian profile, rather than a flat or dished top. In contrast, the loss of larger alkyl groups is characterized by narrow Gaussian metastable peaks corresponding to small KE releases (<2 kJ mol 1).

The distinctive behaviour encountered for methyl loss by ˛-cleavage may indicate that there is something unusual about reactions involving this particular radical. A simple treatment of energy partitioning in terms of the direction of the transition state co-ordinate (dynamical theory) predicts that a significant portion of any reverse critical energy will be released as translation (i.e. kinetic energy) only if the expelled neutral species does not contain more than four or five atoms90 92. This criterion would include methyl, but not ethyl or higher alkyl radicals.

A related point concerns the relative ease of alkyl radical elimination from ionized amines. It has been known for many years that the relative rates for competing ˛-cleavages of ionized amines increase with the size of the expelled radical in the conventional 70eV El spectra of alkylamines and similar substrates3,68. In particular, Hž is expelled much more slowly than CH3ž , which in turn is lost much more slowly than C2H5ž and larger radicals, which are eliminated slightly more readily as their size increases. This trend, which does not always reflect the energetics of the competing fragmentations, is occasionally referred to as a ‘degrees of freedom’ effect, because it appears to follow probability factors. However, more recent work on alkyl radical loss from ionized tertiary

220 Richard D. Bowen

amines of various lifetimes has revealed that the kinetics of this fundamental process are not as simple as was hitherto thought93 95.

The order of ease of alkyl radical loss at low internal energy (i.e. in the dissociation of metastable ions) differs from that at high internal energies. The strong initial trend (Hž − CH3ž − C2H5ž ) still holds good, but C3H7ž , C4H9ž and larger groups are lost progressively less readily than C2H5ž , which is lost at a faster rate than any other simple alkyl group. An identical order in the relative rates was observed for alkyl radical elimination from R1R2CHCHDC(OH)2Cž radical-cations96 98; moreover, the corresponding R1R2CHCHDCHOCH3Cž species appear to behave similarly99. In the former case, an explanation98 for the maximization of the rate for expulsion of C2H5ž was offered in terms of frontier orbital100,101 effects. Although these conclusions cannot necessarily be extrapolated to ˛-cleavage of ionized amines, it is likely that the occurrence of a common trend reflects a generic influence of the various alkyl groups on the rate of bond fission at a branch point which applies both to formal ˛- and -cleavages.

˛-Cleavage is also subject to interesting isotope effects. Most isotope effects observed in the fragmentation of gaseous ions are normal: the unlabelled species is lost more rapidly than its labelled analogue at both high and low internal energies, with the magnitude of the isotope effect increasing as the internal energy of the dissociating ions decreases90,102 105. Normal isotope effects of this kind are observed in the ˛-cleavage of tertiary alkylamines labelled in the near vicinity of the bond which is broken. Thus, CH3N(C5H11)CH2CD2CH2CH2CH3Cž , in which the C D bonds are immediately adjacent to the C C bond which is broken in ˛-cleavage, showed a normal isotope effect of 1.034 (per deuterium atom) increasing to 1.30 for loss of a butyl radical in fast reactions at 70 eV in the ion source and in the slow dissociation of metastable ions in the second field-free region, respectively93. These isotope effects per deuterium atom are obtained by taking the square root of the overall isotope effect induced by substitution to give a CD2 group (or cube route, in the case of substitution to produce a CD3 group, etc).

In contrast, unusual trends in the isotope effects were found when the C D bonds were located three bonds away from the C C bond that is broken in ˛-cleavage of

CH3N(C5H11)CH2CH2CH2CD2CH3Cž . In fast reactions at 70 eV, a small inverse isotope effect of 0.986 was observed; but, at the longer lifetimes and lower average internal

energies appropriate to fragmentation of metastable ions in the second field-free region, a normal isotope effect of 1.08 was found93.

Subsequent work confirmed this apparently abnormal behaviour. Deuteriation at remote sites (the υ- or ε-position) induces small inverse secondary isotope effects in ˛-cleavages occurring in the ion source, but normal isotope effects in the decomposition of metastable ions in the field-free regions94,95. The time dependence of the isotope effect was also studied by field ionization kinetics, which permit the analysis of fragmentations occurring after lifetimes as short as 10 12 s 1. It was found that the inverse isotope effect favouring loss of the deuteriated radical operates at times shorter than 10 9 s95.

An explanation for the isotope effects was given in terms of differences in the zero-point energies of the transition states and the influence of slight reductions of isotope-dependent frequencies on the state sums.

The first factor is responsible for normal isotope effects, which arise because the bonds being affected by deuteriation are weakened in the transition state, but the absolute effect is greater on the bonds to deuterium rather than protium because the former have higher vibrational frequencies (typically by a factor of ca 1.37). This factor essentially reflects zero-point energy effects, so it becomes progressively more important at lower internal energies.

The second factor is the absolute magnitude of the molecular vibrational frequencies which change as the transition state is being formed. This factor reflects the influence

5. The chemistry of ionized, protonated and cationated amines in the gas phase 221

of the term allowing for the density of states in the Rice Ramsperger Kassel Marcus (RRKM)106 theory for the rates of the competing fragmentations. Lower frequency vibrations contribute more than higher frequency vibrations to the total number of states because the spacing between adjacent states is smaller and the number of states within a given energy interval is increased. Consequently, the term reflecting the density of states is more sensitive to changes in lower frequency vibrations than to variations in higher frequency vibrations. As a result, when the reduction in frequencies associated with the weakening of the relevant bonds is considered, the influence of reducing the C D frequencies is greater than that of reducing the C H frequencies, even though the latter are reduced by a greater amount than the former. This statistical weighting effect should become more important relative to the zero-point energy effect at higher internal energies, thus explaining the inverse isotope effect in ˛-cleavage of ionized tertiary alkylamines labelled in the υ- or ε-position.

The observation of relatively small secondary isotope effects on these ˛-cleavages indicates that the developing radical does not isomerize to a more stable structure. Thus, the loss of labelled and unlabelled butyl radicals in the ratio 1.10:1 from metastable ionized diisopentylmethylamine containing a C D methine group in one pentyl chain is inconsistent with the occurrence of a 1,2 shift in the developing isobutyl radical107. Such a rearrangement would lead to a t-butyl radical, which is ca 20 kJ mol 1 more stable than its isobutyl isomer108. However, any shift of this kind would be expected to be quite strongly suppressed by a much larger primary deuterium isotope, as is observed in alkyl radical loss from suitable ionized alkanes109. Parallel effects also operate in the analogous system in which a 2-phenethyl radical, C6H5CH2CH2ž , rather than the more stable methylbenzyl radical, C6H5CHž CH3, is lost107. These experiments show that simple radicals are stable with respect to 1,2-H shifts, even when these shifts produce more stable isomeric radicals. The barriers to 1,2-H shifts in radicals is in stark contrast to the behaviour of the corresponding cations, which readily isomerize in this manner110. The slow rate of such 1,2-H shifts to spin centres is also a major feature of the chemistry

of DIs26,97 99,111.

b. Alkane elimination. This process does not compete effectively with ˛-cleavage at high internal energies, but becomes more noticeable as the energy of the dissociating ions is reduced. Thus, the LELT spectrum of 2-butylamine shows a significant [M CH4]Cž at m/z 57, though the base peak at m/z 44 corresponds to loss of the larger alkyl group (C2H5ž ) by ˛-cleavage75. As noted previously, CH4 loss accounts for 10% of the metastable ion current for dissociation of ionized 2-butylamine84.

Alkane loss without prior rearrangement typically shows a distinct regioselectivity corresponding to a formal 1,2-elimination. Consequently, it is related to ˛-cleavage in that the departing alkyl group picks up a hydrogen atom from the other substituent at the branch point, e.g. equation 10. However, the 1,2-selectivity in alkane elimination may be undermined if the alkyl chains are sufficiently long to permit hydrogen transfers to precede fragmentation. Thus, metastable (CH3CH2)2CHND2Cž loses C2H6 with high selectivity (ca 95%), but propane and butane loss from (CH3CH2CH2)2CHND2Cž and (CH3CH2CH2CH2)2CHND2Cž , respectively, occur after extensive hydrogen exchange84.

3.Fragmentation of rearranged ionized alkylamines

a. Pseudo-˛-cleavage. This reaction is probably the most important general fragmentation which involves rearrangement. A sequence of hydrogen transfers leads to a ˇ-DI,

which undergoes a 1,2-NH2 shift, followed by further hydrogen transfer to form an isomeric ionized amine (Scheme 3). This isomerized ionized amine then fragments by